l-^ ^,.'> . * i }r.»^/> "- . ..*• ? *-?^-:, r^ ' > : Ti* . -^v < * /•♦ •* y . .y r^^?^-/ 1U_ ,„'jv.' *^^ " 7..* .- -"•lib-'' - ■f- yjj '}' ■ : . 1:^ / CORNELL UNIVERSITY. THE THE GIFT OF ROSWELL P- FLOWER FOR THE USE OF THE N. Y. STATE VETERINARY COLLEGE 1897 Digitized by IVIicrosoft® ?.^ GhM C)/t Cornell University Library QP 1.R88C pt.l - Contributions to our icnowiedge of the co 3 1924 000 311 179 Digitized by IVIicrosoft® This book was digitized by Microsoft Corporation in cooperation witli Cornell University Libraries, 2007. You may use and print this copy in limited quantity for your personal purposes, but may not distribute or provide access to it (or modified or partial versions of it) for revenue-generating or other commercial purposes. Digitized by Microsoft® |N|o. 2,0 o6r VIII. Contributions to our knowledge of the connexion between Chemical Constitution, Physiological Action, and Antagonism.^ By T. Lauder Brunton, M.D., F.R.S., and J. Theodore Cash, M.D. Received June 13, — Read June 21, 1883. [Plates 8-1 O.J The great object of Pharmacology is to obtain sucb a knowledge of tbe relation between the chemical constitution and physiological action of bodies as to be able to predict with certainty what the action of any substance will be. One of the most important steps towards this object was made by Crum-Brown and Fraser, who showed that the introduction of methyl into the molecule of strychnia or thebaia changed the tetanising action of those poisons on the spinal cord into a paralyzing one on the ends of the motor nerves. As the organic alkaloids are compound ammonias, it seemed probable that a similar change ia the chemical constitution of ammonia itself might produce a corresponding change in physiological action. This was tested by Crum-Brown and Fraser, who found that trimethyl-ammonium iodide possessed a paralyzing action similar to that of methyl strychnia or methyl thebaia, while ammonia itself has been shown by Funke and Deahna to have a tetanising action very much like that of strychnia. A number of other ammonium compounds have been shown to have a similar paralyzing action ; but there is no complete investigation of the whole series, nor has the relation of the acid with which the base is combined been determined. In the present research we have attempted — 1st. To ascertain how the general action of ammonia is modified by its combination with an acid radical. Under this heading we have investigated : (a) the alteration in its general effects upon the organism ; and (b) the alterations in muscle and nerve by which the general effects are to a great extent determined. 2nd. To investigate the general action of the compound ammonias containing the more common radicals of the alcohol series in the same way as the ammonium salts in the first part of the paper. * The present research forms part of an inyestigation into the action of certain drugs on muscle and nerve, for which a grant was given to one of us (Beunton) in 1877, but the prosecution of which was much delayed by various circumstances, amongst others, the rebuilding of the laboratory in which the experiments were made. Digitized by IVIicrosoft® 198 DRS. T. L. BRUNTON Ai^D J. T. CASH ON CHEMICAL CONSTITUTION, 3rd. To compare the action of ammonia on muscle and nerve with that of other substances nearly allied to it in chemical properties, and belonging to the group of alkalies. 4th. To examine the action of acid and alkali upon muscle independently of the chemical composition of the acids or alkalies employed. 5th. To extend the research on muscle and nerve to the elements belonging to the group of alkaline earths. General action of Ammonium Salts. From experiments with ammonium chloride, sulphate, phosphate, tartrate, benzoate, and hippurate, Feltz and Ritter concluded that ammoniacal salts all had a similar action, producing convulsions and coma, slowing of the pulse and lowering of the temperature. They considered the action to be the same in kind, but differing in intensity. The convulsions produced by ammoniacal salts were shown by Funke and Deahna to be similar to the tetanus produced by strychnia, differing from it only in the fact that a single convulsion instead of a series of convulsions was produced by the poison. The cause of this result they believed to be the rapid production of paralysis of the motor nerves by the ammoniacal salt, which prevented the occurrence of more than one tetanic convulsion. As the action of chloride of ammonium has already been pretty thoroughly investi- gated, it seemed to us unnecessary to make any more experiments upon its general action. We have therefore restricted our researches to the action of the bromide, iodide, sulphate and phosphate, and have experimented only on Frogs with the bromide. The result of these experiments seems to be that ammonium chloride, bromide and iodide form a series. At one end of it is ammonium chloride having a stimulant action on the spinal cord, and, at the other, the iodide having a paralyzmg action upon motor nerves. Ammonia and ammonium chloride produce tetanus ; the bromide, hypersesthesia, with some clonic spasm, passing into tetanus, which, however, comes on very late in the course of the poisoning. The iodide produces rapid failure of higher reflexes, such as that from the conjunctiva, and caused in our experiments progressive paralysis, but no tetanus. At an early stage of poisoning by it the Frog responded with a creak when stroked on the back, and as this has been shown by Goltz to occur after removal of the cerebral hemispheres, its occurrence in poisonuig by ammonium iodide may be looked upon as a proof that the higher centres are poisoned first. After injection of ammonium phosphate also, there is throughout an absence of true spasm. The usual movements become sprawl- ing, and when taken up and gently set down again, the animal remains plastic, with the limbs extended. Before the cessation of reflex in the hind limbs, slight twitchings are observed to accompany induced movement. After the injection of sulphate of ammonium a slight degree of hypersesthesia is developed. In a variable length of time Digitized by IVIicrosoft® PHYSIOLOGICAL ACTION, AND ANTAGONISM. 199 twitchings occur. They appear first in the anterior extremities, and then spread all over the body to the hind limbs. This spasm increases in intensity, and often manifests itself by a number of clonic convulsions occurring at tolerably regular intervals. These seldom pass into a rigid tetanus. They are, however, provoked by touching the animal, by the application of cold to the surface of its body, or by a blow upon the table upon which it is resting. When the sciatic nerve was divided on one side before the injection of the poison, twitchings did not occur upon that side. The action of the salts of ammonia upon the circulation was also found to be various. Thus, in poisoning by the bromide, it was unusual to find the heart materially influenced in its activity, even when the most marked motor symptoms had been developed. With the iodide, however, an early arrest of the heart in diastole, with the auricles and ventricle distended by dark blood, was very usual. A larger dose of the phosphate, and not unfrequently an equal dose of the sulphate, had a somewhat similar effect. An examination of the blood showed that after poisoning by bromide of ammonium, a marked change had taken place in the red blood-corpuscles. These exhibited numerous coagulations in their stroma ; a.n increase of free nuclei was like- wise observed in the blood ; where the blood from the corresponding limb to which the poison had not had access was examined, no such changes were observed. A similar result is occasionally noticed after poisoning by the sulphate ; it is much more unusual where the iodide and phosphate have been employed. Examination of the reaction of the muscle to direct and indirect stimulation was made as rapidly as possible, when it was desired to examine their reaction at any stage which the poisoning had reached. The ligatured limb was used for a contrast ; and as it has been shown by Kuhne* that in cold-blooded animals the irritability of the muscle declines when containing blood in a condition of stasis, allowance must be made for this decrease in irritability when contrasting its reaction with that of the poisoned muscle. The irritability was tested by means of approximating the secondary coil of a DU Bois Reymond's inductorium to the primary, the greatest distance at which a minimal contraction was produced being registered both for direct and indirect stimulation. This figure was controlled by removing the secondary coil from the primary, in which case contraction often persisted at a more distant position than it was observed at when the coil was approximated.t The muscle poisoned by bromide showed an in- crease of irritability in the early stages, and before the action of the poison was com- plete. There was a slight but less marked increase occasionally in the case of iodide, but usually the irritability in cases of slight poisoning is diminished. There is usually no marked increase of irritabiHty in muscles poisoned by the phosphate and sulphate, though in exceptional cases it has been observed as a temporary condition in both The muscle responds to direct and indirect stimulation (opening shock) by a long, at first equally high, but then rapidly falling curve, in comparison with the normal. The * ArcHv. f. Anat. u. Ptiysiol., 1859. t The excitability of the muscle appearing to be increased by its contraction. Digitized by IVIicrosoft® 200 DRS. T. L. BRUKTON AND J. T. CASH ON CHEMICAL CONSTITUTION, response to indirect stimulation is, however, much feebler than to direct. The tetanus of both is impaired, but especially that of indirect stimulation. The total failure of reaction upon stimulation of the nerve frequently occurs whilst the muscle yields a moderate tetanus. If the heart has not been arrested by the injection of too large a dose of ammonium iodide before the circulation has distributed the poison sufficiently, it is often found that stimulation of the nerve does not produce any contraction, or it may be only a few faint tvntches of the muscle. In poisoning by the phosphate of ammonium direct stimulation produces, as a rule, a tolerably good, though pro- longed contraction, but the failure of reaction to direct and indirect stimulation is more parallel than in poisoning by the iodide, and if the irritability of the nerve is entirely lost, it is usually found that the muscle when stimulated directly contracts but very feebly even to the strongest tetanising current. Ammonium sulphate paralyses both muscle and nerve. The reactions given by the former are, however, longer, and outlast those of the latter. The tetanus curve of both is feeble, even in cases of rapid poisoning. Action of Compound Ammonias. Our experiments with these bodies were made upon frogs, rats, and rabbits. The substances employed, twenty-six in number, were : — Ethylamine, trimethylamine, triethylamine ; the chlorides of methyl-ammonium, ethyl-ammonium, amyl-ammonium, dimethyl-ammonium, diethyl-ammonium, trimethyl-ammonium, and triethyl-ammo- nium ; the iodides of methyl-ammonium, ethyl-ammonium, amyl-ammonium, dimethyl- ammonium, diethyl-ammonium, trimethyl-ammonium, triethyl-ammonium, tetramethyl- ammonium, and tetraethyl-ammonium ; the sulphates of methyl-ammonium, ethyl- ammonium, amyl-ammonium, dimethyl -ammonium, diethyl-ammonium, trimethyl- ammonium, and triethyl-ammonium. The action of aU these bodies was tested in Frogs, but the whole of the series was not investigated in Rats and Rabbits. All the salts of the compound ammonias which we used were obtained from Messrs. Hopkins and "Williams, who prepared them expressly for us, and guaranteed their purity. The poison was in aU cases administered by subcutaneous injection. We have compared first the action of the compound ammonias, uncombined with an acid radical, with the action of ammonia itself We have then compared the actions of the chlorides, iodides, and sulphates, of the compound ammonias with each other, and with the corresponding salts of ammonium. It will be noticed that there is a considerable difference between the action of the compound ammonias and of am- monia. The tendency to produce tetanus resembliag that of ammonia was noticed in ethylamine, which was the only one of the compound ammonias containing only one atom of hydrogen, replaced by a radical, that we investigated in a free state, uncom- bined with acid. When used as a chloride, the convulsive action was less marked. The substitution of even a single atom of hydrogen by an alcohol radical appears to Digitized by IVIicrosoft® PHYSIOLOGICAL ACTION, AND ANTAGONISM. 201 lessen the tetanising action of ammonia, and this diminution is increased by the substitution of two or three atoms, then a change takes place, and when the ammonia is combined with four atoms of an alcohol radical, a convulsant action again becomes more marked, though it is not so great as in the case of ammonia itself With these exceptions, the symptoms were those of gradual motor paralysis. This motor paralysis appeared to us to be due, in a great measure, to a paralyzing action of the substance on the spinal cord, as motion ceased in the animal at a time when the muscles and motor nerves were still capable of vigorous action. The tetiamethyl- and tetraethyl-ammonias appear to have a particular tendency to paralyse the higher reflexes before the lower, so that reflex from the cornea disappears sooner than from the foot. They appear also to aflPect the heart more than the other compound ammonias, so that in poisoning by them the heart was generally found motionless, in complete diastole, and distended with dark blood. We did not observe the same marked difierence between the action of the different salts of the compound ammonias that we did in the case of ammonia itself Tlie iodides, however, appear to affect the heai't more powerfully than other salts, and to cause its arrest in diastole. The chlorides and sulphates also appear to have a greater tendency to produce muscular tremor than other salts. We have drawn up, in a tabular form, an epitome of the symptoms of poisoning produced by salts of the compound ammonias in Frogs, Rabbits, and Rats. The tables may appear bulky, but the number of salts experimented upon was great, and as they were difficult to prepare, and expensive to procure, we have thought it advisable to give an example of the general action of each drug, as well as a summary of the results which we have obtained. We have, however, put them as shortly as possible, and restricted ourselves to one experiment with each substance on each kind of animal. MDCCCLXXXIV. 2 D Digitized by IVIicrosoft® 202 DRS. T. L. BRUNTON AND J. T. 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Trimethyl-ammon. sulphate. 10 c.c. Ethyl-ammon. iodide. 10 c.c. Triethyl-ammon. iodide. 10 c.c. Diethyl-ammon. chloride. 10 c.c. Triethyl-ammon. chloride. 10 c.c. Amyl-ammon. iodide. 10 o.c. Diethyl-ammon. iodide. 16 c.c. Triethyl-ammon. iodide. 20 c.c. Amyl-ammon. sulphate. 20 c.c. Ethyl-ammon. sulphate. 20 c.c. Diethyl-ammon. sulphate. 20 c.c. Dimethyl-ammon. sulphate. 19 c.c. Methyl-ammon. sulphate. 20 c.c. Methyl-ammon. iodide. 20 c.c. Dimethyl-ammon. iodide. 17 c.c. Trimethyl-ammon. iodide. 17 c.c. Diethyl-ammon. chloride. The order of fatality considering — L The salt. 1. Iodides. 2. Chlorides. 3. Sulphates. II. The ammonia compound. 1. The tetraethyls and tetramethyls. 2. The triethyls and trimethyls. 3. The diethyls and dimethyls. 4. The amyls, ethyls, and methyls. appears to be : — The former (I.) is of very secondary importance to the latter, and the difference between the iodides, and chlorides, and sulphates is magnified by the fact that in the case of the iodides alone were the tetra compounds employed. In regard to rapidity of action, we find (l)tetramethyl-ammonium-iodide (5 c.c.=:'5 gr.) fatal in 5™ ; (2) triethyl-ammonium sulphate (20 c.c.) in 17™, and tetraethyl-ammonium- iodide (5 c.c.) in 30". No symptom of pain occurred in any case after the injection, nor of physical change in animal. There appeared occasionally a slight loss of co- ordination, but this may have been, in some cases, due to paralysis. The pupil was markedly affected in the case of trimethyl- ammonium chloride and tetramethyl- ammonium-iodide. * Each CO. is equal to "1 grm. of the substance named. 2 E 2 Digitized by Microsoft® 212 DRS. T. L. BRUNTON AND J. T. CASH ON CHEMICAL CONSTITUTION, From these experiments it appears that amongst the drugs contained in the table; the most marked disturbance occurs in the Rat in the case of the ethyl-ammomum sulphate, amyl-ammonium sulphate, amyl-ammonium iodide, diethyl-ammomum- sulphate, diethyl-ammonium chloride, triethyl-ammonium chloride, and tetra-methy la- mine ammonium iodide. In aU of these tremors were noticed, and in some — the diethyl-, triethyl-, and amyl-ammonium salts — a peculiar rapping of the head upon the table was noticed, which appeared to be of a convulsive character. The two most powerful convulsants were the amyl-ammonium-sulphate, and the tetramethyl-ammonium-iodide. We found that the iodides not enumerated amongst those causing marked nervous disturbance have httle tendency to produce spasmodic movements. In them loss of reflex, first in the hind legs, and then in the anterior part of the body, is most marked. It appears to us that as a group the salts of the compound ammonias have a complex action : they affect the spinal cord, motor nerves, and muscles. The extent to which these structures are affected by the different compounds varies with each compound. The spinal cord appears to be first stimulated, and then paralyzed. The symptoms which lead us to suppose that it is first stimulated are the twitchings which occur in the early stage in Rabbits and Rats, when poisoned with the substances mentioned in the tables, and the convulsions which occur in Frogs poisoned by ethylamine and tetraethylamine-iodide. That the spinal cord is paralyzed at a later stage, both as a conductor of motor stimuli and as a reflex centre, we infer from the failure of reflex action both in Frogs and Mammals, and from the fact that a stimulus applied to the hind foot frequently induces motion, not of the corresponding hind leg, but of one of the fore legs. The convulsions which occur shortly before death in mammals are, perhaps, to be regarded as due, not to the irritant action of the poison on the nerve centres, but rather possibly to its paralyzing action on the motor nerves : this motor paralysis causes enfeebled breathing, and a consequent venous condition of the blood with asphyxial convulsions. That the compound ammonias and their salts paralyze the motor nerves is shown by our direct experiments on the nerve muscle preparation, in which the nerves were almost always paralyzed before the muscle. The muscles, however, are by no means unaffected — at first their power may seem to be increased, so that they respond by a more powerful contraction to irritation ; afterwards, however, they become weakened, and tend to become completely paralyzed by the continued action of the poisons. This increase of irritabiUty is not observed in the case of some of the compounds, even as a temporary condition. Digitized by IVIicrosoft® PHYSIOLOGICAL ACTION, AND ANTAGONISM. 2] 3 Comparison between tpie Action of Ammonia and the Compound Ammonias. Ammonia itself has a convulsant action, the convulsions apparently being due to its effect upon the spinal cord, like those of strychnia. It differs, however, from strychnia in this respect, that the convulsions do not continue long, apparently because the motor nerves soon become exhausted, so that the excited spinal cord can no longer induce muscular contractions. The only one of the compound ammonias, in which one atom of hydrogen only is replaced by an alcohol radical, that we have experi- mented with is ethylamine ; and this we find has also a convulsive action, probably the same in nature as that of ammonia. It has but a feeble paralyzing action on motor nerves. But this is only true of a single stimulus or of a few stimuli. "When the nerve is subjected to rapidly repeated stimulation, it becomes very quickly exhausted. Ethylamine, therefore, while not directly paralyzing the excitability of the nerve, greatly lessens its endurance and power of work. It will thus have a similar effect to ammonia in shortening the convulsions, and thus rendering them like those of ammonia, and unlike those of strychnia. Its action on muscle itself appears to be very similar to that of ammonia. First it increases the excitability of the muscle, but afterwards diminishes it, and renders the curve both lower and longer. Trimethylamine was found by Husemann to have a tetanising action even on Frogs, like that of ammonia. In our experiments, however, we found gradual failure of the circulation and of reflex without any spasm. This difference between his results and ours may be possibly due either to our having employed different kinds of Frogs or to our having experimented at different seasons and under different temperatures. Another possibility is, that the Frogs he employed were stronger, and that their circulation was more vigorous than ours : for we have already noted that ammonium bromide produced tetanus in Frogs, but this came on at a late period in the poison- ing, and unless the Frog was strong, and the circulation vigorous, the animal died before the tetanus made its appearance, With triethylamine we noticed a great failure of reflex, unaccompanied by spasm ; with both triethylamine and trimethylamine the action appeared to be slower than that of ethylamine. In one case of poisoning by the latter, tonic spasm occurred in 70™ after injection, whilst in two hours after the injection of a larger quantity of triethylamine and trimethylamine, a faint reflex action was still present, and the circulation was maintained. The action of trimethylamine and triethylamine on motor nerves and muscle is very much the same as that of ethylamine or ammonia. From a comparison of ammonia with these compound ammonias it appears that the replacement of hydrogen by alcohol radicals tends to diminish the convulsant action of ammonia itself, and that the diminution is greater in proportion to the number of hydrogen atoms substituted. We have not obtained any distinct evidence that the substitution of alcohol Digitized by IVIicrosoft® 214 BUS. T. L. BRUNTON AND J. T. CASH ON CHEMICAL CONSTITUTION, radicals for hydrogen increases the paralyzing action of ammonia on motor nerves, or indeed alters its effect upon the muscle. We shall presently have to notice, however, the marked change which occurs in physiological action, when we pass from an ammonia in which nitrogen is combined with three atoms of an alcohol radical to those in which we have it combined with four atoms as tetramethyl- and tetraethyl-ammonium iodides. Chloeides. Ammonium chloride has been shown by Boehm and Lange to produce convulsions resembling ammonia itself. Amylamine hydrochlorate has been shown by Dujaedik-Beaumetz to have a convulsant action upon Rabbits. Our experiments on Frogs have led to the following results : — We found that methylamine chloride caused gradual failure of reflex action generally unaccompanied by spasm, while the diminished reflex produced by ethylamine chloride was of a spasmodic nature, though there was no true tetanus. With amylamine chloride we observed no spasm. In one case there was a tendency to spasm chiefly in the hyoglossus muscle. The dimethyl- and diethyl -ammonium chloride cause weakness, lethargy, and failure of reflex action, but no distinct spasm. A tremor is observed on movement, but this seems to be rather due to failure of motor nerves than to increased excitability of nerve centres. Their action upon motor nerves and muscles appears to have been much the same as that of ethylamine : the nerve not being directly paralyzed, but its power of transmitting stimuli continuously being greatly diminished. The muscle has at first its contractility increased but afterwards diminished (Plate 8, fig. 1, a, h, c, d). In these experiments on Frogs the chlorine does not appear to have altered the action of the compound ammonias with which it is combined. From experiments on Rats we find that both diethyl- and triethyl- ammonium chlorides have a similar action. The most marked symptoms are motor weakness and tremor. The tremor is most perceptible when the animal moves, and there is a very curious spasmodic movement of the head causing the chin to rap upon the floor. Before death, convulsions occur, but these are probably asphyxial. In Rabbits the effect is somewhat similar. The movements become tremulous are exaggerated and scrambling in character, suggestive of impaired co-ordination; No anaesthesia was observed. Reflex was lost gradually and disappeared, first in the hind limbs. The most marked effect of the chlorine in altering the action of the compound ammonias appears in these experiments to be a tendency to produce tremor. It is perhaps not quite easy to say positively what the cause of this tremor is, but we are Digitized by Microsoft® PHYSIOLOGICAL ACTION, AND ANTAGONISM. 215 inclined to regard it rather as an indication of failing power in motor nerves than to increased irritability in nerve centres. Iodides. As we have already shown in an earlier part of this paper, ammonium iodide has a powerful paralyzing action, both on nerve centres and motor nerves, producing sluggish movements and motor paralysis. From experiments on Frogs we find that methyl- (Plate 8, fig. 2, a, h), ethyl-, and amyl- (Plate 8, fig. 3, a, b, c) ammonium iodides all produce torpor. In the ethyl- ammonium iodide, Goltz's "croak" experiment succeeded as it did in the case of simple ammonia iodide. With the amyl-ammonium iodide, jerking or staccato movement of the limbs was observed, apparently due to failure of motor power. The methyl-, ethyl-, and amyl-ammonium iodides in small doses increase the excitability both of nerve and muscle. In large doses they are powerful poisons to motor nerves ; they have a tendency to alter the formation of the muscle curve, and produce in it a curious hump, but they do not appear to afiect muscle as much as nerve. The occurrence of the croak in the ethyl-ammonium iodide would appear to indicate rapid paralysis of the higher nerve centres ; and the staccato movement in the amyl-ammonium iodide, more rapid failure of motor nerves. The dimethyl- and diethyl-ammonium iodides produced increasing lethargy, with no spasm ; with the diethyl-ammonium iodide the " croak " experiment succeeded, as it did with the ethyl-ammonium iodide. Their action upon muscle and nerve seems to be similar to that of the methyl- and ethyl-ammonium iodides. Trimethyl- and triethyl-ammonium iodides have an action like that of the dimethyl- and diethyl-ammoDium iodides, but they appear to have a greater paralyzing action on muscle and nerve (Plate 8, fig. 4, a, h, c), the primary increase in excitability not being marked, and paralysis of both occurring more readUy. The tetramethyl- and tetraethyl- (Plate 8, fig. 5, a, h, c) ammonium iodides present a marked contrast to the other iodides, as Frogs poisoned by them exhibit spasmodic tvdtchings of the trunk and extremities. The higher reflexes cease very rapidly. The nerve is generally completely paralyzed. The muscle is only slightly afiected when the poisoning is rapid, but if it be slow it is completely paralyzed also. AU the iodides render the beats of the heart slow, and tend to produce stiU-stand in diastole. In the case of triethyl-ammonium iodide a vermicular movement of the heart was observed. The tetraethyl- and tetramethyl-ammonium iodides appear to have a more powerful action than the others in producing diastolic still-stand of the heart. Digitized by IVIicrosoft® 216 DBS. T. L. BEUNTON AND J. T. CASH ON" CHEMICAL CONSTITUTION, Experiments on Rats. Methyl-, ethyl-, and amyl-ammonium iodides all" produce increasing weakness with a sprawling or waddling gait. The power of the cord to conduct motor impulses appears to be diminished so that the hind legs become more paralyzed than the fore legs. Its conducting power for sensory impressions is not paralyzed at this time, as stimulation of the hind legs will produce movement in the anterior part of the body. In the case of poisoning by amyl-ammonium iodide, twitching of the limbs and head were more marked than that of the methyl or ethyl compounds. The dimethyl- and diethyl-ammonium compounds also cause progressive paralysis. In the case of the diethyl-ammonium iodide, an occasional instantaneous twitching in back and forelimbs was observed, resembling an effort at hiccough. The tetramethyl-ammonium iodide has an action very different from the others, producing powerful convulsions. It kills also much more rapidly, and is fatal in very much smaller dose. Experiments on Rabbits. In Eabbits the methyl-, ethyl-, and amyl-ammonium iodides all cause increasing weakness. The conducting power of the cord appears here also to be affected, the hind legs becoming sooner paralyzed than the fore legs. In the case of the methyl-ammonium iodide there is a distinct trembling of the body not noticed in the other two. General Action of the Iodides. A distinct alteration appears to be effected in the action of the compound ammonias by the combination with iodine. All the iodides, both of ammonia itself and the compound ammonias, have a powerful paralyzing action on the motor nerves. Muscular irritabihty is as a rule decreased ; occasionally it is increased at first, as in the case of the methyl-, ethyl-, and amyl-ammonium iodides. The muscle curve in all cases shows a tendency to become humped. This tendency is more marked in the methyl, ethyl, and amyl compounds than in the di- or trimethyl, ethyl, and amyl compounds. It is more marked when the muscle is stimulated directly than when it is stimulated through the nerve. They all render the muscle more easUy exhausted, so that the tetanic curve becomes lower and is sustained for a shorter time. Digitized by Microsoft® PHYSIOLOGICAL ACTION, AND ANTAGONISM. 217 Sulphates. Experiments on Frogs. Ammonium sulphate soon causes the movements to be accompanied with twitchings and clonic spasm. It sometimes, though rarely, produces complete tetanus ; the peripheral ends of motor nerves are paralyzed by it, and the muscular substance is also paralyzed, though later than the nerve. The heart is considerably affected by the poison, and is frequently found arrested in diastole, and filled vs^ith dark blood. In this point it appears to agree with the iodide. Methyl, ethyl, and amyl sulphates all cause gradually increasing lethargy and failure of reflex movement. Methyl-ammonium sulphate paralyzes muscle and nerve very completely, the nerve being paralyzed before the muscle. The ethyl- and amyl-ammoniam sulphates have much less paralyzing action upon muscle and nerve, but render them liable to rapid exhaustion. In poisoning by them the heart was considerably affected, and beat very slowly ; pro- bably the slighter effect on the muscle of ethyl and amyl sulphates in our experiments was due to their greater effect upon the heart, so that they were carried in lesser quantity to the muscle. This is exactly what one finds with such a poison as vera- trine, which has an extraordinary effect on the muscle of a Frog in small doses, but has little effect on the muscle when the dose is large, the heart being so quickly arrested that but little effect is produced upon the mviscle. Dimethyl- and diethyl-ammonium sulphate both cause weakness, with tremulous movement ; but in the case of diethyl-ammonium sulphate, strong irritation causes a powerful movement in the limbs, occurring after a considerable latent period. The nerve appears to be powerfully paralyzed by the dimethyl-ammonium sulphate, while the paralyzing action is but sb'ghtly marked in the case of the diethyl-ammonium sulphate ; the paralysis of the muscular tissue is also more marked in the case of the dimethyl-ammonium sulphate (Plate 8, fig. 6, a, 6). Both lessen the activity of the circulation, and render the cardiac pulsations slow. The trimethyl- and triethyl-ammonium sulphates both cause the movements to become weaker and tremulous, and sometimes staccato. The tiimefchyl-ammonium sulphate (Plate 8, fig. 7, a, h, c, d) appears at first to increase the excitabUity of the animal, and even when the muscular power has failed, so that irritation of the foot no longer will cause it to be withdrawn, tremor occurs over the whole body from the stimulus. The nerve is either much weakened or paralyzed, so that it either soon gives way when tetanised, or does not respond to stimulus at all. The muscle is also paralyzed ; the minimal irritability is much impaired in poisoning by trimethyl-amrnonium sulphate, although the contractile power remains considerable. One of the most marked points in the action of the sulphates of ammonia and MDCCCLXXXIV. 2 F Digitized by Microsoft® 21 H DBS. T. L. BEUNTON AND J. T. CASH ON CHEMICAL CONSTITUTIOlSr, compound ammonias on the Frog appears to be their tendency to affect the circulation, and to render the beat of the heart slow, or arrest it entirely in diastole. Muscle and nerve are both paralyzed, the paralysis of the muscle being later than that of the nerve. We have noted above a number of more or less exceptional instances, but in many of those there can be little doubt, we think, that the exceptional action was due to alteration in the circulation caused by the poison. Tn their action upon the circulation the sulphates resemble the iodides. The spinal cord appears to be stimulated, so that convulsions or tetanus are produced by the ammonium sulphate. The combination with ethyl and methyl appears to lessen this stimulating action, although we notice in the case of the triethyl-ammonium sulphate a tendency to diffusion of stimuli in the cord, irritation of the foot being responded to by tremor over the body. In the case of the Rat we find the amyl-ammonium sulphate to be one of the most poisonous of the whole series used in the case of these animals. There is violent tremor, increased on movement ; a gait ]ike that of paralysis agitans ; sudden general clonic spasm, succeeded by springing from side to side. In the case of ethyl-ammonium sulphate and diethyl-ammonium sulphate the movements are likewise tremulous ; rapping of the head upon the floor is observed, and there is frequently a spasm of many of the trunk muscles, giving the impression of a hiccough movement. Respiration, at first accelerated, becomes very feeble, and a gradual loss of reflex precedes death. The circulation was slowed by the action of these poisons, the heart tending to diastolic arrest, the right side especially being much engorged. It was found that stimulation, both direct and indirect, elicited a powerful con- traction of the poisoned muscle. The changes in circulation no doubt account for the shght effect of the poison upon the muscle. In the case of the amyl-ammonium sulphate, congestion of the membranes of the brain and of the cord itself were observed. General action on Rabbits. In the case of Rabbits, in which the whole series of these poisons was investigated, there was observed a gradual loss of power, the animal tending to lie on the belly, with the legs extended : the hind legs appeared to be chiefly affected. In the case of the triethyl-ammonium sulphate, and the trimethyl-ammonium sulphate, there was a certain amount of tremulousness and starting when touched. The paralysis in the hind legs became complete before it did in the fore legs. In the case of trimethyl-ammonium sulphate, profuse salivation was an early symptom, and corneal reflex persisted to the last. The sulphates were less fatal to Rabbits than the corresponding chlorides or iodides, with the exception of trimethyl and triethyl sulphates, in which there was trembling and slight spasmodic movements, probably indicative of irritation of the spinal cord. Digitized by IVIicrosoft® PHYSIOLOGICAL ACTIOl^, AND ANTAGONISJI. 219 The symptoms were those of paralysis of the spinal cord and motor nerves. The conducting power of the cord for motor impressions appears to be paralyzed, as the hind legs fail before the fore legs. Death occurs in Rabbits and Rats by failure of respiration. Difference between the Action of the Salts of the Compoctnd Ammonias. Our experiments appear to us to show that the salts of the compound ammonias vary in their action : (a) according to the acid radical with which they are combined ; and (6) according to the number of the atoms of hydrogen which have been replaced in the ammonia by an alcohol i-adical. The influence of the acid, however, appears to us to be less marked than in the case of ammonia itself. The iodides appear to have the strongest paralyzing action, both on the central nervous system and on the peripheral nerves. Next to them come the chlorides, and the sulphates have the least action. The paralysis of the higher reflex, e.g., of the cornea, was more marked in Frogs than in Mammals. In the latter, indeed, corneal reflex was observed almost at the last. We have only examined the action of the iodides of tetramethyl- and tetraethyl- ammonium, so that we cannot compare their actions with those of the corresponding chlorides and sulphates. We have already drawn attention to the fact that their action appears to differ very greatly from the compound ammonias in which only three atoms of hydrogen have been replaced by an alcohol radical. In the tetra compounds convulsant action is very strongly marked, while in the triad compound ammonias it is much less so, or may be altogether absent. In the case of warm-blooded animals salivation was noticed before death in poisoning by trimethyl-ammonium siilphate, tetramethyl-ammonium iodide, and tetra ethyl- ammonium iodide ; it also occurred, to some extent, in amyl-ammonium iodide. In one or two others a similar action was observed to a less extent. We have not investigated fully the action on the spinal cord and higher nerve centres of these different compounds, because the number of substances on which we have experimented was so great that we thought it better to leave this subject for a subsequent research, and to confine ourselves more especially to their action on muscle and nerve. The results of our experiments on these tissues are shown in a condensed form in the following paragraphs : — Differences between the Action of Salts of the Compound Ammonias ON the Frog's Muscle and Nerve. For convenience sake we will group the bodies, first, according to the acid radical ; and secondly, according to the base they contain. 2 P 2 Digitized by Microsoft® 220 DRS. T. L. BRUNTON AND J. T. CASH ON CHEMICAL CONSTITUTION, Variations in Action accobding to the Acid Eadical. CMorides. (a.) Irritability is, as a rule, slightly increased. (b.) Tetamis from the muscle is often more extensive, whilst that from indirect stimulation is less extensive than on the normal side. (c.) The ctirve is often exaggerated in direct stimulation. It is frequently higher, and may be slightly shorter or longer than normal. On repeated stimulation, whether direct or indirect, the curve elongates to a greater or less extent. There is, as a rule, less elongation, less succeeding contraction, and less tendency to develop a distinct second hump than is to be seen in the iodides. {d.) The nerve gives way somewhat before the muscle, but these substances {i.e., chlorides) are not so fatal to nervous irritability as are the iodides. Amyl- aramonium chloride has a relatively stronger action on nerve than on muscle. Iodides. (a.) Irritability is, as a rule, decreased, the exception being occasionally found in ethyl-ammonium iodide, and di- and triethyl-ammonium iodides. (&.) Tetanus is diminished in extent in almost every case. (c.) The curve shows a strong inclination in all, but most in those lowest in the series, to become two-humped, the second horn or hump passing into a contracture, with very gradual decline. (d.) In all cases the nerve becomes paralyzed much before the muscle. Sulphates. (a.) Minimal irritability is increased, or normal in the case of ethyl-ammonium sulphate, diethyl-ammonium sulphate, and triethyl-ammonium sulphate. It is decreased by amyl-ammonium sulphate, and by all the methyl-sulphates. (b.) Tetanus produces more extensive contraction on direct stimulation in the case of the ethyls, and in very slight poisoning in some instances in the methyls, but in the latter it is usually diminished. (c.) The curve is chiefly affected by the methyl compounds, on which it is usually lower and longer, and shows increased viscosity. It seldom displays the strong tendency to the double hump form which is so common amongst the iodides. In the ethyl compounds the curve is usually somewhat exaggerated in relationship to the normal. (d.) The failure of the nerve occurs somewhat sooner than that of the muscle. This is much more marked in the methyl than in the ethyl compounds. On summing up those results, it appears that the iodides paralyze motor nerves more quickly than either chlorides or sulphates. We did not observe any marked Digitized by IVIicrosoft® PHYSIOLOGICAL ACTION, AND ANTAGONISM. 221 difference between the paralyzing action of the corresponding chlorides and sulphates. In the case of the' muscle we notice that the irritability is increased, as a rule, in poisoning by the chlorides ; is sometimes increased and sometimes diminished by the sulphates ; and, as a rule, though with some exceptions, it is decreased by the iodides. The contractile power of the muscle, as shown by the extent and duration of tetanic contraction on direct stimulation, appears to be least affected by the chlorides ; some- what more so by the sulphates ; and most of all by the iodides. The alterations in the form of the curve have already been described in detail. Variations amongst the Ethyls and Methyls. The least operative compounds examined were the diethyls and triethyls. Thus, in these alone, in the case of the iodides and sulphates, was minimal irritability equal to or greater than the normal. (a.) In the case of the chlorides, however (in which the ethyls, methyls, di- and trimethyls only were examined), . there was not a material difference between the corresponding compounds. {&.) Amongst the iodides there is a strong tendency to loss of irritability of the nerve with all the compounds, but this is pre-eminently the case with the tetraethyl- and tetramethyl-ammonium iodides, which have an extremely powerful paralyzing action. The methyl compounds appear, however, to be operative in a slightly smaller dose. (c.) The smaller group of the chlorides does not present such striking variations, but the corresponding methyls are slightly more active than the ethyls, {d.) Am.ongst the sulphates we find the ethyls more often to produce an exaggerated single curve and an increased tetanus than do the methyls. There may, however, as shown in the chart of trim ethyl-ammonium sulphate, be an increase in tetanic con- traction as a result of stimulation in an early stage of poisoning. (e.) The methyl compounds of the sulphate group are decidedly more fatal to the irritability of the nerve than are those of the ethyls. (/.) Ethylamine showed development of tetanic spasms 70°* after injection. There was a gradual failure of reflex and circulation. There was increased irritability to both direct and indirect stimulation ; the curve was higher, longer, and showed increased viscosity. Triethylamine — gradual failure of reflex and of circulation. Increased viscosity of the muscle was observed, without a marked lengthening of the curve. Trimethylamine — gradual failure of reflex and of circulation. Increased irritability and increase of viscosity. The curve is equal to or shorter than the normal. The methyls are onore active than the corresponding ethyls. The methyls, amyls, and ethyls are more effective than the corresponding di- and tri- compounds. The tetra compounds are, hoivever, most so of cdl. Digitized by Microsoft® 222 DBS. T. L. BRUNTON AND J. T. CASH ON CHEMICAL CONSTITUTION, Action op Salts op the Alkaline Group on Muscle and Nerve, and a Comparison of their Actions with that of Ammonia. The bodies usually included in the group of alkalies are, in addition to ammonia, lithium, sodium, potassium, rubidium, and caesium : these are all monads. Mendelejepf includes in the monad group copper, silver, and gold, in addition to the substances just mentioned; but there is such a well marked diflFerence between the general properties of the metals last mentioned and those of the alkalies that we have not included them in our research. On comparing the general action of ammonia with these substances, the first thmg that strikes us is that ammonia is the only one which has any tetanising action. Sometimes reflex action seems to be a little excited at first in poisoning by potassium and rubidium, but this excitement is slight, soon passes ofl", and is succeeded by torpor. In the case of sodium, lithium, and caesium, the symptoms in Frogs are those of gradually increasing torpor. Sodium has no action at all in small quantities, but in concentrated solutions appears to paralyze nerve centres, nerves, and muscles, all at the same time. Lithium, rubidium, and caesium have a tendency to affect either the upper part of the spinal cord or the higher motor centres connected with the fore limbs, as in poisoning by lithium and caesium the reflex disappears sooner from the arms than from the legs, and stiffness was noticed in the arms in poisoning by lithium and caesium, though no distinct spasm was observed. The motor nerves are not paralyzed by sodium or rubidium, but with these exceptions they are paralyzed to a greater or less extent by the other substances belonging to this group. Lithium and potassium are most powerful. In considering the effect of the alkalies, and still more, perhaps, in the case of the alkaline earths, we have carefully to distinguish between the action of the poisons on the active contraction of muscle and on the residual shortening, which continues for a greater or less time after the contraction has passed. To this shortening we have sometimes given the name of viscosity, at others, and more generally, we have employed the term used by German and French writers, contracture. In regard to active muscular contraction also, we must- note both the height of the curve, indicating the amount of contraction and its length, indicating the length or duration of contraction. The exact difference between the action of the various substances will be seen more in detail by a glance at the accompanying tables and curves. But we may here state generally that the contractile power of the muscle, as shown by the height of the curve it describes, is increased by ammonium, potassium, and sometimes by rubidium and caesium. Digitized by Microsoft® PHYSIOLOGICAL ACTION, AND ANTAGONISM. 223 It is occasionally increased by sodium, but is otherwise unaffected, excepting in large doses, and it is diminished almost invariably by lithium. The duration of the contraction, as shown by the length of the curve, is increased by large doses of rubidium (Plate 8, fig. 8, a, h, c), ammonium (Plate 8, fig. 9, a, h), sodium (Plate 8, fig. 10, a, b, c), and caesium (Plate 8, fig. 11, a, b). It is shortened by ammonium (Plate 8, fig. 12, a, b), lithium (Plate 8, fig. 13, a, b), rubidium, and potassium (Plate 8, fig. 14, a, b, c). It will be seen from this enumeration that rubidium, ammonium, and sodium have a double action, sometimes increasing and sometimes diminishing the length of the contraction. In the case of rubidium and sodium the difference of action depends \ipon a difference of dose, small quantities tending to shorten the contraction, while large doses lengthen it. Prolonged contraction is accompanied, as we have already mentioned, by an increase of contractility in the case of rubidium, but by a diminution in the case of sodium, as shown by the height of the curve. The double action of ammonia does not seem to us to depend entirely on difference of dose, but rather to the ammonium having two different kinds of action. The residual shortening, viscosity, or contractttre, which sometimes succeeds an active contraction, is increased by large doses of rubidium, ammonium, lithium, and sodium. It is diminished by rubidium in small doses, ammonium, csesium, and potassium. Here, again, the different action of ammonia does not appear to us to depend entirely on difference of dose. Its double action appears to form, to a certain extent, a connecting link between the action of some members of the alkali group, such as potassium, and that of members of the group of alkaline earths. The relations between the various members of the present group have to be considered more fully in a subsequent section, because we find that some members of it, while having a somewhat similar action on normal muscle, wiU yet antagonise each other's action, and although either of them given alone will lengthen the muscular curve, the lengthening will be abolished, and the curve reduced to the normal, by the administration of the two together. Action of Substances belonging to the Gboxjp oe Alkaline Earths AND Eabths. The metals which we have examined belonging to the group of alkaline earths are calcium, strontium, and barium ; and to that of the earths beryllium, yttrium, didy- mium, erbium, and lanthanum. The first three are dyads. Beryllium is also a dyad. The atomicity of the last four is not determined. Possibly they are all triads, though lanthanum has been grouped by Mendelejeff amongst the tetrads. The first point of difference that we notice about this large group is that it may be subdivided into Digitized by IVIicrosoft® 224 DRS. T. L. BEUNTON AND J. T. CASH ON CHEMICAL CONSTITUTION, two sub-groups : — (a) containing beryllium, calcium, strontium, and barium ; and (b) containing yttrium, didymium, erbium, and lanthanum. In group (a) we notice a tendency to increased reflex action. In this particular it agrees with ammonium, but differs from members of the alkaline group. We have already noted that, in some members of the alkaline group, a slightly increased reflex action might be observed at the commencement of the poisoning, but this is consider- ably less than in the case of most of the members of group (a), with the exception of barium. Excitement of the spinal cord is most marked in poisoning by beryllium ; next come strontium and calcium ; and lastly barium, in which excitement, if present at all, is very shght. In group (b) reflex action in the cord is not increased, nor does it appear to be very much diminished till the last. In this group, however, the higher centres appear to be paralyzed. We infer this from the fact that yttrium greatly diminishes co-ordinating power in the Frog, rendering the movements ataxic, and causing the animal to lie with the legs fully stretched out, although neither muscle or nerve is paralyzed. Didy- mium, erbium, and lanthanum all have a similar action. In regard to their action on motor nerves, we notice the same well marked division into two groups as in their general action : beryllium, calcium, strontium, and barium all paralyzing the motor nerves to some extent. Lanthanum has also a paralyzing action, but yttrium, didymium, and erbium have none. In this respect these three bodies agree with sodium and rubidium, and differ from all the others belonging to these two groups which we have examined. In regard to their action upon muscle, we do not find that these bodies can be so readily subdivided into two well marked sub-groups. The contractility of muscle, as shown by the height of the curve, is greatly increased by barium (Plate 8, fig. 15, a-d), and occasionally, to a small extent, by erbium (Plate 8, fig. 16, a, b) and lanthanum (Plate 8, fig. 17, a, b). It is sometimes increased and sometimes diminished by yttrium (Plate 8, fig. 18, a, b) and calcium (Plate 8, fig. 19, a, b, c). It is diminished by didymium (Plate 9, fig. 20, a, b), strontium (Plate 9, fig. 21, a, b, c), and beryllium (Plate 9, fig. 22, a, b ; fig. 23, a, b). We have found that the small variations occurring in the extent of contraction are best observed when the poison is applied locally in the form of solution. Where the muscles have been examined of an animal completely poisoned with the substance, the ultimate, rather than the primary result, is obtained. The duration of the contraction, as shown by the length of the curve, is increased by barium, calcium, strontium, yttrium, and erbium. It is unaffected, or slightly diminished, by beryllium, didymium, and lanthanum (see figs. IV, 20, 22). It is obvious that the action of the rarer metals beryllium, erbium, didymium, lanthanum, and yttrium is but feeble in any direction when compared with the effect of calcium, &c. The contracture is increased by barium, calcium, strontium, yttrium, and beryllium. Digitized by IVIicrosoft® PHYSIOLOGICAL ACTION, AND ANTAGONISM. 225 Contracture produced by barium is enormous (Plate 9, fig. 24, a-g). When the drug is locally applied its curve resembles greatly that produced by veratria (Plate 9, fig. 24, b). It appears to us to be an interesting fact that an inorganic element and an organic alkaloid should have such a similar action. Their action coincides also in the modifica- tions which it undergoes by heat and by potash. The barium contracture, like that caused by veratria, is abolished by cooling the muscle down, or by heating it con- siderably above the normal. The contracture may be permanently removed by cooling down, so that it does not return when the muscle is again raised to the normal temperature. Like the veratria contracture, however, it is abolished much more certainly by heat (Plate 9, fig. 24). There is a more marked tendency fi^r the barium contractui'e to relax suddenly than that caused by veratria. It is also more easily abolished by repeated stimulation. In regard to the effect of these drugs on contracture, the same differences are to be observed between their action when injected into the circulation and when locally applied that we have already mentioned in regard to the active curve. In the accompanying diagram we have arranged some of the more important substances Contracture. Increased. Diminished. Altitude of Curve. Lowered. Heightened. Active Curve. Lengthened. Shortened. Bb. (in small doses) L. Na. (in moderate doses) Sr. Ca. Bb. (large doses) Ba. . NH3 (HCl) belonging to the alkalies and alkaline earths so as to show their action upon muscle graphically. It will be seen that they tend to form a series, the two ends of which present some points of approximation, ammonium appearing to form a connecting link between barium and potassium. It will be noticed that the substances here do not arrange themselves according to their atomic weight, nor yet according to their atomicities. We hope, however, to be able to consider this point more fully at a future time. We subjoin a table showing the relative position of the elements in regard to their action on motor nerves and muscles. MDOCCLXXXIV. 2 G Digitized by IVIicrosoft® 226 DES. T. L. BRUNTON AND J. T. CASH ON CHEMICAL CONSTITUTION, Table showing the relations of the Alkahes and Alkahne Earths as Poisons to Nerve and Muscle. The most powerful paralyzers of motor nerves are put at the head of the column, and the others follow in the order of decreasing activity. Those bodies which increase most the height and duration of muscular contraction and of muscular contracture are placed at the head of the corresponding columns, and at the foot are those which reduce them most. Muscle. Motor nerves. Height of Duration of contraction. contraction. Vyomrdcture NH, Ba Ba Ba L Rb Rb Rb K NH, NH, NH^ Be Er Na Na Ca K Ca Ca Sr Gs Sr Sr Ba La Yt L Cs Yt Cs Yt La — Er Be — Ca — Di Er Na Be Er Di — Di Rb Yt Di La NH^ Rb Sr — Cs Na Be NH, La L L Rb Na K K Digitized by IVIicrosoft® PHYSIOLOGICAL ACTION, AND ANTAGONISM. 227 o o o -p th ■A o m 'o Ph CQ c3 sc i I — I < O EO o i-H ■ K n a c P II to- > 13 rti 5 tj y '^ o d °°ll I "^ o .2 r >- 3 a o? 5 * p O oJ O Q " »Sg°o3 "•3 " a Eh g|5 ia.g« §5 o-a« II wi m W |-^ "rt-H (1. « II if ..Ah o £» = " C o>— >. pj: o 2 • ?►- s n.g o * a5 * 2 « S ■S .c i B» 00 r7 y 3 ® 03 OJ 3 3 « fl I p£ aj ■ -C -S o 3 •= -a M a o «S a s ■ -^ E-.< « .-3 Q) I -^S aj o U * ii g fi = 2 « S . 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Chajm-her ( lontjvtwdinoil ) For expUxnaii.on.- of Flga.-nts see text ized by Microsoft® B WestHewmsui.* C? liHi. Digitized by IVIicrosoft® [ 547 ] VIII. Contributions to the Study of the Connection between Chemical Constitution and Physiological Action. — Part II. By T. Lauder Brunton, M.D., F.R.S., and J. Theodore Cash, M.D., F.R.S. Received Marcli 2,— Read March 6, 1891. It is now more than four years since this research was begun, and it has necessitated such a lai'ge number of experiments that, if given in detail, they would fill several hundred pages, and, therefore, only a brief account of the results, with details of a few typical experiments, can be given here. During the time we have been engaged in this research a great deal of work upon the physiological action of aromatic compounds has been done by other observers ; but upon trying to collate their results, with a view to arriving at some general conclusions, it appeared that the conditions under which the various experiments have been carried out have differed to such an extent as to render comparison very difl&cult. In this research we have endeavoured to perlorm our experiments as nearly as possible under the same conditions, so that the results should be comparable. We have employed bodies of comparatively simple constitution, so that differences in their physiological action might be readily connected with differences in their chemical structure. Plan of the Research. The plan of' the present research to a certain extent resembles that of our former investigations into the action of the compound ammonias. We have studied : 1st. The alterations in action which occur when an atom of hydrogen in benzene is replaced by haloid radicles. 2nd. The action of the compounds formed when one, two, or more atoms of hydrogen are replaced by alcohol radicles. 3rd. The alterations produced by the introduction of one, two, or three atoms of hydroxyl. 4th. The alterations produced by the replacement of one hydrogen atom by the radicle NOg. 5th. By the replacement of one hydrogen atom by the amidogen radicle (NH^). MDCCCXCI. — B. 4 A 2 30.12.91 Digitized by Microsoft® 548 DBS. T. L. BRUNTON AND J. T. CASH ON THE CONNECTION We have also examined the modifications in the action of various members of the series by changes in temperature. Genekal Kesults. The most marked actions of those members of the benzene group which we have examined were exerted on the spinal cord and brain. The action on the spinal cord vras indicated by a tendency to tremor and the action on the brain by lethargy. We observed certain differences in the symptoms, both motor and sensory, caused by various members of the group. We were struck by the fact that the symptoms they cause in Frogs bear a certain resemblance to those produced by certain diseases of the spinal cord in Man. Thus, benzene causes a tremor which seldom occurs but when movement is attempted, and in this resembles the tremor of disseminated sclerosis, whilst monochlorobenzene, monoiodobenzene, and also amidobenzene cause the movements to assume a violent slapping character, which reminds one of the movements occurring in locomotor ataxy, a disorder in which the posterior columns of the cord are affected. Methods. The methods employed were : — 1st. To examine fully the action of the various substances upon the system generally of certain animals (Rats and Frogs being chiefly employed) ; and 2nd. To study their effect in detail upon the brain, spinal cord, nerves, and muscles in Frogs, and on the circulation in Cats. (1st.) Genebal Action. In the former class of experiments a known quantity of benzene or its compounds was injected in a state of emulsion into the dorsal lymph sac of a Frog or under the skin of the side of a Rat, and the progress of the poisoning observed. Of Examining the (2nd, a) Action on the Spinal Cord. If it was desired to test the irritability of muscle, spinal cord, and nerve, after the toxic symptoms had developed, the animal was decapitated and the various organs just mentioned were tested in the following manner: — The upper portion of the spinal cord was exposed and stimulated by means of a faradic current of electricity, the electrodes employed having platinum tips terminated by short threads of silk moistened in blood serum and resting upon the cord. The action of the drug upon the excitability of the cord was judged of by the effect which stimulation of the cord had upon the muscles. Digitized by IVIicrosoft® BETWEEN CHEISIICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 549 (2nd, b AND c.) Action on Nkrvb and Muscle. The action on the cord having been ascertained, a preparation of the gastrocnemius and the sciatic nerve supplying it was made and placed in a moist chamber for examiiiation. The nerve and muscle were then stimulated successively. Con- tractions resulting from single induction shocks were recorded upon a rapidly moving cylinder, and tetanic spasm of the muscle from stimulation by a faradic current was recorded on a slowly revolving cylinder. (2nd, d.) Blood-Pressure. The apparatus employed in the blood-pressure experiments was somewhat com- plicated, as we endeavoured to arrange it so that we could take a tracing of the mean arterial pressure representing a long time in a small space, and yet obtain at any moment on a more rapidly moving surface such a tracing as would give an actual Fig. 1. Diagi-am to illustrate the apparatus used in registering the blood-pressui-e, pulse, and respiration. A is the cannula for insertion into an artery. J? is a Y-tube by which the artery can be put in communication either mth a mercurial manometer D, or a Pick's kymograph F, or with both of them at the same time G and C are two clips by which the communication of either or of both manometers with the artery can be shut off at will. E is a slowly revolving cylinder on which the merctu-ial manometer registers the blood-pressure. G is a rapidly revolving cylinder on which the Fick's kymograph registers the pulse beats from time to time, and on which the respiration is also registered. indication of both the number and the form of the pulse beats and respirations in a given time. This was accomphshed by employing a mercurial manometer, which wrote on a blackened cylinder having a very slow speed of rotation (once m the hour), and in addition to this a Fick's spring manometer, which wrote upon a rapidly rotating cylinder. These manometers were capable of being clamped off from each Digitized by IVIicrosoft® 550 DRS. T. L. BRUNTON AND J. T. CASH ON THE CONNECTION other, and the system of tubes leading to the Fick's manometer contained a very short length of thick walled india-rubber tubing, in order that the form of the pulse wave might be communicated as accurately as possible to the apparatus. This may be more readily understood by means of the accompanying diagram. At any time whilst the experiment was in progress, we were able, by clamping oft the mercurial manometer and opening the clamp controlling the connection with the spring manometer, to obtain a tracing of the pulse unmasked by oscillation of the mercury in the former, which we could associate with the slow record by correspond- ing marks or figures. On the rapid drum we also registered the movements of respiration by means of a Marey's tambour, which was coimected with a double tambour applied to the walls of the thorax. SECTION I.— ACTION OP BENZENE AND SOME OF ITS COMPOUNDS ON FROGS.— GENERAL SYMPTOMS PRODUCED.— ACTION ON SPINAL CORD, MUSCLE, AND NERVE. Action of Benzene CgHe upon Rana Temporaria. The general action of benzene on Frogs is to produce : — • (a.) Lethargy and disinclination to voluntary movement; (b.) Tremor and jerking, which always occur on movement, and sometimes to a slight extent when at rest ; (c.) Alteration in the response to stimuli ; and (d.) Subsequent paralysis. The alteration in the response to stimuli observed in Frogs poisoned l:)y benzene consists in : — (a.) Increased sensibility ; (h.) Diminished local movement ; (c.) General diffusion of movement. For example, when the toes of a normal Frog are pressed very lightly, it generally happens that no movement occurs at all, or only a slight local movement of the foot away from the stimulus. In a Frog poisoned by benzene, such a stimulus produces tremor, not only in the foot touched but over the body generally, while if the foot is withdrawn at all the movement is feeble and tremulous. Effect of a Small Dose of Benzene. If one minim of benzene be injected into the dorsal lymph sac of a Frog, no marked symptoms are observed for from 1 r, to 30 minutes. At the end of this time, however, it is noticed that the leg, if gently extended, is drawn up with a tremulous or interrupted movement. This tremor develops further into jerking, which occurs Digitized by IVIicrosoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 551 spontaneously and also whenever active movement, such as jumping or rising from the dorsal position, is attempted. This jerking may be accompanied by general movements of the trunk of a " ducking " or " huddling" character. There appears to be in most cases a temporary but distinct hypersesthesia. This condition may appear exaggerated by attempted movement provoking tremor of the whole body. There are periods of complete rest between the attacks of jerking. This is the usual extent of the symptoms exhibited by Frogs of 30 grms. weight receiving one drop of benzene. Effect of Larger Doses. If a larger dose be injected, the inability to perform coordinate movement increases and at lengtli the animal lies Avith the legs extended, a mere twitch of the toes and fingers only occurring on stimulation of the foot. Later on, the reflex becomes localised to the foot stimulated, and is ultimately lost altogether. The reflex from the eye is long maintained. Absorption of benzene is slow and irregular, and it has been observed to cause a local rigor of muscle which may hinder absorption. The heart usually continues to beat after reflex movement has ceased, or if it has stopped it is found to be still irritable. Action on Individual Organs. Destruction of the brain diminishes the jerking because it stops all attempts at voluntary movement ; but if the Frog be left for a time till reflex movements are again active, the movements are to a large degree jerking. If the sciatic artery on one side be ligatured the jerking and tremor still occur on that side. This shows that the jerking is not due to a peripheral action of the drug on the motor nerves or muscles, but is due chiefly, if not entirely, to its action on the spinal cord. The jerking may sometimes be less on the ligatured side, but this is, we think, due to the effect of stasis in diminishing . the irritability of the nerves and muscles on that side, although we cannot with certainty altogether exclude the possibility of the drug having acted as a peripheral stimulus. In a brainless Frog, which has been slightly poisoned by benzene, if the upper end of the dorsal cord be exposed and stimulated, the consequent contraction of the leg may be found less on the side of the unligatured artery than on the side of ligature, indicating that benzene has had a certain paralyzing effect on the nerves or muscles of the unligatured leg. At a later period, stimulation of the cord is unattended by any contraction of the leg muscles on either side. This shows that the excitability of the cord is destroyed. Stimulation of the nerve itself on the unligatured side yields a feebler contraction than on the ligatured, but even in cases of deep poisoning, reaction to some extent is Digitized by Microsoft® 552 DRS. T. L. BRUNTON AND J. T. CASH ON THE CONNECTION present. This shows that either the motor nerve or muscle is enfeebled by this poison. Figs. A and A'. The curve obtained by directly stimulating the muscle is strong, but often — as in the case of indirect stimulation — slightly longer than on the ligatured side. This shows that the muscle itself is somewhat enfeebled. Figs. B and B'. Action of Benzene on Muscle and Nerve. Decerebrated Frog weighing 22 grms. Iliac vessels ligatured on the right side. 2 minims of benzene injected into the dorsal lymph sac. Examination of the muscles made 4 hours after the injection. Fig. 2. (A.) Ligatured (tmpoisoned) leg. Curves obtained by repeated stimulation of nerve. Fig. 3. (A'.} Unligatured (poisoned) leg. Curves obtained by repeated stimulation of nerve. Fig. 4. (B.) Ligatured (unpoisoned) leg. Curves obtained by repeated stimulation of muscle directly. Fig. 6. (£'.) Unligatured {poisoned) leg. Curves obtained by repeated stimulation of WMscZe directly. Time, 44 millims. = 0■l^ The function of the heart is bnt little affected by benzene subcutaneously admini- stered (Section II.). The chief action of the poison is, therefore, on the spinal cord, though it has some effect upon the muscle substance, and also upon the terminations of motor nerves. Alterations in the Action of Benzene by Heat and Cold. The effect of heat is to increase the symptoms at first and then greatly to accelerate the occurrence of paralysis. Thus, if a Frog be taken about an hour after the appear- Digitized by Microsoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 553 ance of tremor, but while all reflexes are still active, and placed in a hot bath slightly below 30'' C, in a short time all reflexes may have completely disappeared, while a control animal subjected to the same experiment still remains active. At a tempe- rature of 30° C. the reflex function of the cord of the Frog is suspended.* Cold has no marked eftect on the action of benzene, either in the way of accelerating or of retarding its action. E.vj)erimcnt. Frog Weighing 28 grms. Eoom Temperature, 63° Fahr. 0'' 0'"- One minim of benzene injected into tlio dorsal lymph sac. 25™. "Weaker. Slight tremor on jumping. 105>". Much tremor on touching. All reflexes. " Ducking " movements. No rigidity. 170™. Cannot crawl. Draws the legs up with jerking movement. Circulation active. Pigment cells much contracted. Placed in a hot watei' bath at 29° C. In 10™ after immersion reflex had entirely ceased. In 15™ „ ,, the legs were in a condition of rigid extension. After removal from hot water, reflex ti'emor of the anterior extremities, trunk, and legs occurred on irritating the foot. On touching the eye, no closure of the eye but tremor of fore arms and abdominal muscles occurred. (In benzene poisoning rigidity has been frequently noticed.) Mesult of TSxamination of Individual Orgnns. Cord still irritable to slight extent. Muscles of thighs and upper part of gastrocnemius in rigor. (1.) Replacement of Hydrogen in Benzene by Haloid Radicles. Haloid radicles do not modify the action of benzene to the same extent as they do that of ammonia,t but nevertheless they do produce certain modifications, and in somewhat the same directions as we found in our experiments on ammonia. This modification is most marked in the case of iodine, whose compounds with benzene (like its compounds with ammonia) have a tendency to produce paralysis of muscle, of motor nerves, and of cerebral reflexes, without the production of spasm. It appears to possess a depressant action on the heart. Monochlorobenzene appears to afiect the spinal cord greatly, causing spasm, and reflex action is more rapidly affected than after benzene. It diminishes the activity of the circulation, but it does not appear to affect motor nerves and muscles more than benzene. The bromo- and iodo-compounds appear to differ from benzene and from chloro- benzene in the more powerful paralysing action which they exert on the cerebrum. Weight for weight the chloro-compound is the most lethal, then the bromo-, and lastly the iodo-compounds. * M. Hall, ' Roy. Soc. Proc.,' 1831, p. 37. t Beunton and Cash, ' Phil. Trans.,' 1884. MDCCCXCI. — B. 4 B Digitized by IVIicrosoft® 554 DRS. T. L. BRUNTON AND J. T. CASH ON THE CONNECTION We shall now record three experiments selected as typical from others made with monochlorobenzene — the first at room temperature, the second under the action ot cold, the third with heat. Monoclilorobenzene. (C3H5CI.) This substance causes in Frogs weakness, tremor, especially on movement, and inco- ordination of a character which reminds one of locomotor ataxy in Man. The circu- lation is little affected. The pigment cells are contracted. Experiment. Rana Temporaria' oi 24 grms. weight. Nov. 3rd. One minim of monochlorobenzene was injected into tlie dorsal lymph sac. Laboratory tempera- ture 60° F. 4.')™. After injection. Slight tremnlonsness, both when attempting movement and when taken up. 87"^ On stimulation of foot both legs thrown out in a " slapping " fashion, and there is much tremor and twitching of the head, limbs, and trunk. Frog crawls slowly and tremulously. Cannot hop. Kicking with legs is kept up for a long time (once for 20^) after stimulation of foot. 100™. It cannot crawl; can only draw the legs up with great labour and jerking. Circulation active. Pigment cells contracted to balls. 1.30™. The brain was now destroyed by pegging. 1.35™. Reflex is recovering, and there is slow withdrawal of the foot with great tremor. Tremor and some jerking still occur when no stimulation is applied. 24''. Next day it lies with its legs out. Any touch of the foot is followed by tremulous movements of the feet and hands, but no withdrawal of the leg. On decapitating the animal and opening the lymph sac, it was found to contain some unabsorbed monochlorobenzene. The spinal cord was now destroyed from above downwards till reflex was almost gone. Much of spontaneous tremor now lost, but on pinching toe there was jerking of both legs. Action of Cold. Cold lessens the action of the substance, reducing the tremor and making the movement slower. Experiment. Frog of 25 grms. 0'' 0™. One minim of monochlorobenzene was injected into the dorsal lymph sac after exposure to cold (7° C.) for 25 minutes. 21™. No tremor, but great lethargy. If taken out, it crawls forward very slowly, drawing the legs up with remarkable slowness. 56™. Tremor is now distinct, though modified by the torpor of cold. 96™. Distinct tremor to some extent ; the frog feels markedly cold. 1.30™. It makes springing movements, but does not change its position. Is much more normal than the Frog (similarly poisoned) at the room temperatui'e, 60° F. Digitized by IVIicrosoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 555 146'". As before. General lurcliiDg of tlie body is frequent. 2#. All reflexes are present, but slow and tremulous. Jorkings of limbs and lurchings of body whilst sitting still. On stimulating the foot the leg is withdrawn slowly and with a jerking movement. Circulation in the web is slow and unsteady. Vessels are dilated. Pigment cells contracted. Action of Heat. Heat increases the action of the substance, rendering the jerking greater at first, and then rapidly lessening the reflexes, which are restored again by cold. Expei-ime')it. Frog of 27 grms. 0'' 0". One minim of monochlorobenzene was injected into the dorsal lymph sac. 65™. Tremor on movement is now well marked. Frog was put into a hot bath at 29° C. Jerking at first was much increased, but soon became reduced. lO'" after immersion reflex is almost entirely gone, but there is still twitching on stimulation of foot. (Control animal remains active.) Seems to recover somewhat when taken out of the bath. It was again placed in hot water at 29° C. 20"". A slight tremor of the adductors was the only sign of reflex left. It was now placed in an ice chamber. Temperature, 7° C. In 5™ the reflex was much increased; some active spontaneous movements likewise occurred. 30™ after being placed in the ice chamber, i-eflex, though slow from cold, was active in all paits. Again placed in warm bath. In 15™ all reflex was completely gone. It was now taken out and covered with ice. In 5™ it was endeavouring to shake ice off. In 20™ all reflexes were present ; it drew its legs up strongly. Sits up well. All reflexes active and without tremor. Crawls well ; does not attempt to hop. Next morning. After being 15™ in bath at 29° C. hops and springs well, and has, to a large extent, regained power of movement. Monohromohenzene. (CgHgBr.) This compound appears to cause more lethargy and less tremor than chlorobenzene. Exj^erimeMt. Frog of 32 grms. O'' O". Injected I minim of monobromobenzene into the dorsal lymph sac. 40". The springs are only a few inches in extent. It hops along the bench if left to itself, but is somewhat lethargic. 55™. On touching the eye there is a start of the whole body. 86^. It crawls. It can only spring from 2 to 3 inches at a time unless much roused. There is tremor in the limbs and trunk after a spring. Tremor is also provoked by tapping over the 4 B 2 Digitized by IVIicrosoft® 556 DRS. T. L. BRUNTON AND J. T. CASH ON THE CONNECTION occiput or along tlie spine. A squealing sound occurs at intervals whioli appears to be due to strong contraction of the abdominal muscles, causing expulsion of air from lungs. US'". Circulation in the web is slow but general. Eye is prominent. Much, tremor in all the limbs and trunk on attempting movement, which is now impossible. 180". Leg is drawn up weakly on irritating it. Frog seems, however, to be still hyperffisthetic. Some twitching of the muscles is noticed when movement is attempted. 275". Twitching and fibrillation of muscles on attempting movement, and also, but only to a slight extent, when lying still. There is no rigid spaam. 2i^. Cannot hop, but crawls. Very tremulous. Slow withdrawal of extended leg. 72''. Tremulous on movement, but can take a series of short hops (2-3 inches) ; no tremor whilst movement not attempted. Action of Larger Dose (in brief). Experiment. Qii 0™. The brain of a Frog weighing 35 grms. was desti'oyed by pegging. The left sciatic artery was ligatured. The right sciatic plexus was divided. 3 minims of monobromobenzene were injected into the dorsal lymph sac. 45'"- Very faint reflex on stimulating the left foot by pinching, no other reflex present. 80'"- As at 45'". Heart still beating. On stimulating the cord there was hardly any movement of left leg, and, of course, none of the right. The curve of contraction on indirect .stimulation is somewhat lower and longer from the muscle poisoned by broniobenzene, than from that protected by the ligature. Modifying Effect of Cold (in brief). Experiment. Frog of 32 grms. Eoom Temperature 15° C. 7''. The Frog was placed in a cold chamber. 3 drops of monobromobenzene were injected into the dorsal lymph sac. 40"". The Frog can crawl and hop short distances. This Frog is much less affected than a control Frog poisoned by the same dose and kept at the room temperature. Modifying Effect of Heat. Heat may temporarily increase movement, but it lessens tremor and hastens disappearance of reflex action. Digitized by IVIicrosoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 557 Expevli)ieHt. Frog of 33 grms. was kept for 20 minutes at a Temperature of 29° C. 1 minim of Mouobromobenzene Injected into Dorsal Sac. 10". Tempei'iiture maintained. Frog is cra-\\ding round the vessel. There is an occasional powerful extension of both legs. Head is " ducked " or depressed for an instant. 15™. Eye-re0ex gone, but the legs are still drawn up if extended. 30"'. Temperature maintained. No withdrawal of the foot, and only slight tremor of the leg on pinching the toe. Circulation is good, pigment cells are distended. (Control Frog exposed to same temperature springs actively.) SS-". Taken out of bath. 70"l. Reflex is retui-ning. Leg drawn up. There are movements of respiration. Put again into the hot chamber at 29° C. 76™. Reflex has totally disappeared. Condition of circulation, spinal cord, nerve, and muscles. The Frog was now decapitated and examined. Heart was beating. Stimulation of the upper part of the dorsal cord causes moderate contraction of the gastrocnemias. This shows that the conducting power of the spinal cord is not destroyed. The curves obtained from direct and indirect stimulation of this muscle are good, though the altitude is somewhat reduced and the duration slightly increased. Monoiodobenzene. (CgHgl.) Monoiodobenzene causes lethargy with some increase of reflex. Tremor occurs on movement, and spontaneous movements become much less sustained. Experiment. O'^O™. Room temperature 65° F. Half a drop of monoiodobenzene was injected into the dorsal lymph sac of a Frog weighing 36 grras. 35™. after injection. Lethargic, but springs well. 80™. Springs strongly if roused, is torpid. 120™. Legs are thrown out in a wild slapping fashion, extension is strong, but rather spasmodic. 155™. On stimulation it gives a few active springing movements, which are tremulous and unsustained, and only move the animal a few inches. 195™. Is now very tremulous on attempting movement, but not so when resting. 240™. Still springs 1-2 inches. Very tremulous. Twitching of muscles occasionally noticed. Eyes protruded in breathing. 24^^. Lies on belly. Withdraws legs slowly, but can hardly move ; great tremor. 72''. But little tremor now noticed, can hop repeatedly each movement very short, i.e., 2-3 inches. Digitized by Microsoft® 558 DRS. T. L. BRUNTON AND J. T. CASH ON THE CONNECTION Monoiodohenzene. Experiment. C' 0"'. 2 minims of monoiodobenzene were injected into the dorsal lympli sac of a Frog -weighing 20 grms. 5". Restless. Breathing accelerated. 8". Quieter. 29™. Quiet and lethargic. If roused it is slightly tremulous. 43"'. Reflex is increased. Still lethargic. Spring is short and tremulous. 68™. Reflex still increased. All movements very tremulous. Legs lie flat on the bench, the position of animal is low. It still draws its legs up if they are extended. When placed on its back, it can move round to the ventral position, but only with great effort. 223™. Still draws leg partially up, but very tremulously. When placed on its back it tries to get round, but the only result is a twitching of the muscles of the limbs and trunk. Bye reflex still present. 278"'. Condition the same. Heart accelerated. 24''- No respiration. No reflex of any kind, but when the Frog is placed on its back there is a faint tremor of fore limbs. In another experiment the brain was destroyed in the first instance, the iliac vessels were ligatured on one side and 2 minims of monoiodobenzene were injected. The cord was destroyed just when the reflex movement of the ligatured leg was disappearing, the unligatured leg had ceased to respond some time before. During the destruction of the cord there was a twitch of the leg, the vessels of which had been ligatured. All the muscles were dark red and injected, excepting those of the ligatured limb. Tetanus of the gastrocnemius on the poisoned side on stimulation of the nerve was weak and broken. The muscle reacted more strongly to direct stimu- lation, but the contraction still was less active than that of the companion muscle on the ligatured side. (2.) Modification of the Action of Benzene (CgHg) by Eeplacement op one ATOM OF Hydrogen by an Alcohol Radicle. The introduction of alcohol radicles into benzene in place of hydrogen appears to modify its action in much the same way as one would expect from a general considera- tion of the properties of the alcohol group, which, as a rule, have a sedative action on the nervous system. The compounds of benzene with alcohol radicles produce less tremor, less hyper- aesthesia, and greater lethargy than the halogen compounds. The circulation is but little affected by them. These compounds, like the halogen compounds already discussed, exercise little action on muscle and nerve, but where an effect is observed it is greater on the nerve than on the muscle. Digitized by Microsoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 559 The action of tlie alkyl compounds of benzene appears to be much more fleeting than that of the haloid compounds, the effect of the former generally passing off in 24 hours, while that of the latter often lasts two days or more. In the case of methylbenzene, CoHgCHa, a secondary increase of reflex action is sometimes observed after the reflexes have become greatly diminished and after spontaneous movement has quite disappeared. We have not yet been able to deter- mine whether this is due to a paralysis of inhibitory centres in the brain, or to decomposition of the methylbenzene molecule with liberation in the organism of some product of its decomposition, having an exciting action, or whether it may be due to some other cause than these. This secondary increase in the reflex action of the cord is of some interest, inasmuch as a similar phenomenon, though much greater in extent, has been noticed by Fraser in the case of atropine. A further analogy between methylbenzene and atropine was observed in one case in which, after reflex action had become greatly diminished, convulsions of the fore legs with a certain degree of gaping and opisthotonos occurred in a Frog poisoned by methylbenzene. We shall illustrate the action of this drug by the notes of two selected cases of poisoning, in one of which the convulsive symptoms followed the course we have just described. Methylbenzene. CgHgCHg. {Toluene.) Produces gradual failure of voluntary movement and reflex, accompanied by little or no tremor, occasionally convulsive movements of limbs and trunk occur. Experiment. Frog of 38 grms. Temperature 78° F. O'' 0™. 1 minim methylbenzene was injected into the dorsal lymph sac. 27™. Rather restless. Head rather dorsiflexed for a few seconds. 35™. If undisturbed will remain for a considerable time in one position. All reflexes are impaired, especially the eye reflex. Respirations 108 per minute. 50™. Can spring if roused, but is generally perfectly still; will sometimes lie a considerable time with legs extended. 53™. Moving about spontaneously. 65™. Has had several attacks of convulsive extension of fore legs with throwing back of head and gaping, which have resulted in the body being propelled backwards. The left leg is slightly extended, the right quiescent. 80™. Lies with the legs in any position. Spasm not provoked by touching bell jar covering it, or by striking the bench, but occurs on pinching the foot. 125™. Circulation in the left web is very active. There is still some spasm in the fore arm. All reflexes are present to some degree, though the eye reflex is much impaired. 24''. No tremor nor abnormality, except that the spring is short. Digitized by Microsoft® 560 DRS. T. L. BRUNTON AND J. T. CASH ON THE CONNECTION Methylbenzene. Experiment. Decerebrated Frog of 32 grms. Right Iliac Artery ligatured. Rooro Temperature, 69° F. Qii Om 2 minims of methylbenzene were injected into the dorsal lympt sac. 10™. All leg reflexes are present. There is no tremor, Frog draws the leg up well. .81™. No tremor, it lies with its legs half extended. Both legs are drawn up on touching, but more strongly on the ligatured side. 71™. All reflexes are gone. Circulation in the left web is decidedly good ; the pigment cells are contracted. There is a very faint cardiac impulse still, just causing circulation in right web. Condition of Spinal Gord, Nerves, and Muscles. Distance of secondary from primary coil, 12 centims. No contraction on stimulation of cord. At 10 centims. there is a twitch of both feet. 8 centims. tetanus of both legs (all tissues divided but the nerves). No contraction to speak of from nerve on the ligatured side, which seems exhausted by the few contractions caused by stimulation of the cord. On direct stimulation of the muscle tetanus occurred at 16 centims. Vnligatured Leg. There is no tetanus from the nerve ; muscle tetanus with coil at 13 centims. This case, therefore, shows relatively little or no affection of muscle. The nervous t issue is evidently the seat of the poisoning. Action of Dimethylbenzene. CgH42(CH3). Its action closely resembles that of the compound last described. There is, perhaps, a little more tendency to tremor occasionally manifested. The heart is but little affected. The result of stimulation of nerve and muscle is the same as in methyl- benzene. The only result observable on the day after injection is slight lethargy and a less vigorous spring than was executed before the administration of the drug. Experiment. Frog of 32 grms. 0^0™. 1'5 minims of dimethylbenzene were injected into tlie dorsal lymph sac. 5™. Breathing rapid. Restlessness. 32". Spring short and weak, no tremor, (^an get oif its back. 52™. Eye protruded, no longer closed on touching. All reflexes are present. Legs drawn up rather jerkily ; cannot get off back. 72™. Still faint twitch on pinching foot. This is often, however, a mere fibrillation, with no true movement of the limb. 102™. All reflex quite gone. Circulation active. Pigment cells contracted. Digitized by Microsoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 561 Condition of Gord, Nerves, and Muscles. On stinmlatiug- the upper end of cord there is a very faint twitch of the ]cf,'s. Stimulation oi the sciatic nerve gives a stronger contraction. Direct stimuliition oI tlio muscle causes more vigorous contraction. Heart beating strongly. After a dose such as 1 '5 miniius, or even twice as much, has been administered to a medium- sized Frog, recovery usually takes place. In 24 hours, excej^t for a little weakness and lethargy, the animal is scarcely to be separated from a normal Frog. There is no tremor. When equal doses of this and the preceding compound are severally administered to two Frogs of equal size, the action produced by the dunethylbenzene appears to be the stronger. Trimethylbenzene. CgH33(CH3). [Mesitylene.) This substance appears to be the most active of the methyl compounds which we have investigated. The eye reflex is lost comparatively early, and, after a dose of 1"5 minims, all body reflex frequently disappears within an hour. After the eye reflex is lost, touching the conjunctiva not unfrequently causes movement of the limbs. Experiment. Fkog of 32 grms. 0''0"'. Injected 2 minims of trimethylbenzol under skin of belly. 15™. If laid on its belly, will lie still with the legs in any position. If put on its back, it may still make efforts to change its position, but they are not persisted in. No closure of eye on touching, but if touched there is extension of both legs. All cii'culation has ceased in web. No reflex on pinching, but occasionally 4-5 spontaneous extensions. 60™. AU reflex is quite gone. Condition of the Cord, Nerves, and Muscles. On stimulating the cord there is feeble tetanus of both legs, which seems rather std'onger in the ligatured. On the unligatured side nerve tetanus is moderately good with undulations. Muscle tetanus is less good, probably owing to exhaustion from previous stimulation through the nerve. On the anligatured side both nerve and muscle tetanus are as extensive when commencing as on the ligatured side, but are not so sustained. (Circulation ceased early.) The comparatively early cessation of reflex was noticed in almost all cases of poisoning by this drug. Thus, one Frog of 48 grms. received 1'5 drops and another of 32 grms. 2 drops of trimethylbenzene. Reflex was gone in the former in 80 minutes, in the latter in 60 minutes. (Detailed results of reflex experiments are given in the next section.) MDCCCXCI. — B. 4 C Digitized by Microsoft® 562 DRS. T. L. BRUNTON AJSTD J. T. CASH ON THE CONNECTION Ethylhenzene. CgHgCgHg. This substance is more active in causing paralysis than the methyl or dimethyl compounds ; a slight degree of jerking may develop on attempting movement, If one minim of ethylhenzene be injected into the dorsal lymph sac of a Frog of 30 to 35 grms. weight, In 30™. The frog appears to be weaker, but, if roused, may give a series of short slapping extensions of legs, which move the animal but a very short distance. „ 50™. The ability to spring declines ; attempts at crawling still occasionally occur. There is increasing apathy. No twitching whilst at rest, but muscular movements are rather jerking owing to failure of centres (nervous). Frog lies with legs out, but still starts if touched. Eye reflex persists as long as limb reflexes. 5, 100". All reflex usually ceases, that in arms generally outlasting that in legs. Very occasionally a slight spontaneous start of legs occurs after all reflex has ceased. Sometimes touching the eye may cause twitch of toes when all stimulation of foot is inoperative to cause reflex. If the iliac artery be ligatured in a brainless Frog, the reflexes may appear rather more strongly on this side, but not invariably so, as often no difierence is discernible. The heart is usually found beating slowly ; the ventricle is pale, and contracts imperfectly. The circulation in the web may, however, cease at the same time as the reflex (as in one case 1 03 minutes after poisoning). Stimulation of the cord (brachial) usually gives only a feeble contraction of both legs, not amounting to a tetanus. In one case, 103 minutes after one minim of ethylhenzene, the cord was completely paralysed. In two other cases, when the poisoning took longer (150 minutes and 154 minutes), and a faint twitch still persisted as reflex, a distinct tetanus was obtained. If the iliac artery be ligatured on one side and poisoning carried to the abolition of reflex, the tetanus from the sciatic of the unligatured side is usually feeble or very feeble ; that of the muscle is much stronger, but still somewhat impaired in contrast with the ligatured side. In one case, after all reflex had gone, the cord still yielded tetanus without marked alteration in reaction from nerve and muscle on the unligatured side. Digitized by Microsoft® BETWEEN CHEMICAL CONSTITUTION AND PIIYSIOLOGICAL ACTION. 563 Action of Ethylbeuzene on Muscle and Nerve. Decerebrated Prog. Left iliac vessels ligatured. 1 minim of ethylbonzeno injected into the dorsal lymph sac. Unpoismed Nerve or Muscle. Fig. 6. (a) Ligatured (unpoisoned) leg. Twenty maximal stimulations of the sciatic nerve gave the above curves. Direct stimulation of the muscle gave similar curves. Poisoned Muscle Poisoned. Nerve. Eig. 7. (6) Unligatured (poisoned) leg. Twenty maximal stimulations of the nerve gave the lower of these two series. Twenty maximal stimulations of the poisoned muscle directly gave the upper series. Time 44 millims. equal to O'l^. Experiment. Frog of 35 grms, 0'' 0™. One minim of ethylbeuzene injected into the dorsal lymph sac. 43™. If touched sharply will spring six or eight times very rapidly. Spring is very short, but often repeated, and gives an appearance of great haste with but little progress. 81™. Cannot spring, but extension of legs is sharp and slapping ; lies with legs out ; no tremor or jerking ; starts when touched ; hypereesthetic. 10.3™. Reflex rapidly failing. 140™. All reflex quite gone, except slight tremor of foot on touching eye. Gonditimi of Cord,, Nerve, and Muscles. Stimulation of the cord gives a very feeble twitch of legs, but no true tetanus. On stimulation of the sciatic nerve the contraction is stronger, but still weak. Contraction from direct stimulation is very much stronger. 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The action of the compounds containing hydroxyl differs with the number of atoms of hydroxyl present and their position in the benzene molecule. In the case of monoxybenzene (phenol) the substance is identical whichever the carbon atom may be to which the OH group is attached in the benzene nucleus. Experiments on this substance are so numerous that we have not recorded any here. Dioxy- and Trioxybenzene. In the case of dioxybenzene there are three substances, ortho-, meta-, and para- dioxybenzene, having the hydroxyl groups in the positions 1:2, 1:3, and 1 : 4 respectively. The ortho-compound is usually known as pyrocatechin, the meta- as resorcin, and the para- as hydroquinone. We may anticipate our description of the action of the one of these bodies — resorcin — by saying that its action, though differing in degree, is very similar in kind to pyrocatechin and hydroquinone, as was also clearly shown by Bbieger'"'. When •002 to "003 grm. of the salt dissolved in a drop of distilled water is injected under the skin of the back of a Frog, in two minutes there is a certain amount of jerking observed in all the movements of the animal. This jerking rapidly extends to all the limbs and to the muscles of the trunk, so that in four to five minutes it has become universal. There is an occasional very short pause between the clonic movements, and not unfrequently at the commencement of their occurrence the animal emits a squealing cry indicating the involuntary expulsion of air through the larynx as a result of abdominal rnuscular compression. There is often gaping of the lower jaw. Keflex movement is ir creased for a time. Breathing laboured. If the animal is confined under a funnel or bell jar open at the top the vessel becomes covered internally with foam. In ten to fifteen minutes the jerking move- ments become continuous, that is to say, not that they alter their individual character, but that they do not show any lasting intermission or rest pauses. The animal is unable at the maximum of this condition to perform any coordinate * 'Arch. f. Anat. u. Physiol.' (Supp.-Band 1879), and ' Centralblt. f. d. Med. Wiss.,' 1880. Digitized by Microsoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 5G7 movement, whilst at an early period in the action of the drug all attempts at movement at once provoke and increase the clonus. The jerking stage may last from one to five hours, or even longer. In the case of small doses it continues longer than after larger doses, which tend to cause paralysis. During this paralysis or semi-paralysis the extended legs are no longer drawn up on stimulating, though from a slight thrusting-out movement the reflex function of the cord evidently exists to some extent. There is more reflex activity in the anterior part of the cord than in the posterior part ; occasional twitchings of individual muscles or groups of muscles still take place, but these are fainter than before, and scarcely affect the position of the limbs. Recovery may occur, though it is rare, excepting in the case of large Frogs, after "003 grm. has been injected ; but with smaller doses, before this paralytic condition has developed far, or after it has done so, the return to voluntary movement is often surprisingly rapid, though for some time jerkings and twitchings occur. More usually the paralysis increases, and the legs remain extended in a semi-rigid condition, when all sign of life has disappeared. If the dose administered hypodermically is as small as "00025 grm., very definite symptoms still appear in the case of small Frogs of 15 grms. weight. The power of voluntary movement is retained, but all movements become tremulous and jerking, and there is some tremor and incoordinate muscular contraction when the animal is not making any effort to move. The spring remains fairly strong, and slight hyper- sesthesia is to be recognized. In the course of seven or eight hours after the injection the animal is again practically normal. We have observed curious variations of reaction of individual Frogs equal in size, and which had been kept under exactly similar circumstances, towards resorcin, one animal appearing sometimes to be readily influenced by half the dose which produced little effect upon another. Larger doses than 3 mg. accelerate the twitching and paralytic stage, absorption occurring readily. Complete flaccidity with loss of all movement takes place. On destroying the brain and upper part of cord there may be total quiescence of all the muscles of the limbs and trunk during the operation, and frequently strong stimulation of the cord also fails to cause contraction. This shows that the power of the cord to conduct longitiidinally is destroyed. The heart is generally arrested in diastole, but usually remains irritable, contracting two or three times after each mechanical stimulation. In advanced poisoning, which has not, however, taken place too rapidly, the function of the motor nerves is much impaired, and frequently that of the muscles also, and direct stimulation produces a stronger contraction than indirect. The noticeable feature in the poisoning by dioxybenzene is the rapid development of muscular contractions, often occurring at very regular intervals of time, not passing into a tonic or tetanic contraction. Digitized by IVIicrosoft® T)RS. T. L. BRUNTON AND J. T. CASH ON THE CONNECTION o be c8 O g OQ 1^ p0:)Oafvi M O CO O M o CO ^ ■upjosd'U- fO-O > 9 ri • i. P^ o ■^ • ^ „, a s ? El cs O o s.-^^ ^ X =ft o r^ -O -fJ ^ <1 s ^ o ■ "^ S 60 M CS t>^ .2 ^ ^ g .- a g. 1 th :hed e sa: the ^ ji ^ a g^-s^ rJ^ « 'S O -^ 3 -S -^ d and Ach as inje amplit ture tend •e w! in tS h^ CD lig: the cnra eel in tn rrt ^H T3 g « ° t>. (> C3 CD O ^ 45 60 S P O ^H f-l cS c3 ;i c3 ^ o ^ .9 XX ° ^ '^ -e o ■35 N o JO CD CO CD ^ CO ^" "ff S m c3 g •- .2 _a ^ ■» CD a, H ^ ^ pi t. Oh -t-^ O !=| a fi ° CD =4.- .^ ^ - fa j3 S ce cere!: . T le do ;ous. he tr 1 — 1 M c c: O ^ ■+i ^ .s g §• 37 grms. he soiatic solution 3ns are sp llims. =:: 2 -tJ cu .;:; .r-j ^"^^ go a • 3 O CD f3 rH ■r .2 §" g - ^ U.S "0 Frog the exce injected All th, cord. T Digitized by IVIicrosoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 569 This movement has its origin in the cord. The action of the drug eventually destroys the power of the cord to manifest increased reflex irritability by tetanic spasm when strychnine is injected, provided that this injection succeeds the full development of the symptoms produced by resorcin. If these, however, are but partially developed, tonic spasm results after strychnine. Curare injected into the dorsal sac abolishes these movements, the disappearance being noted first in the unligatured and later in the ligatured leg. Dioxi/hcu-cnc 1 : 3. [Rcsorcm.) Action on Fjiog Experiment. Frog of 24 grms. 0'' 0™. Injected '002 grm. dissolved in salt solution under skin of back. 6™. Restless. Slight jerking. 8™- Jerking active and universal on movement. 12™. Short pauses only between jerking spasms. Frequent squeal. Eeflex irritability is increased. Breathing laboured. Gaping. 24"^. Much froth round funnel from constant movement of animal. Twitching and fibrillation of muscles. 1\ Does not leave position, limbs chiefly' in extension. Jerking almost continuous. Z^. Jerking diminished. More successful effort at spontaneous movement. From this time improvement rapidly occurred. Experiment (in bi'ief). Frog of 1 5 grms weight. 0''0™. Injected -002 grm. 8"°. Movements are distinctly tremulous. Restlessness. l?"". Jerking of head, trunk, and limbs, legs flat at side of body, tlie animal resting on its ventral surface throughout. Froth in jar. Cannot direct spring. This animal is far more affected than a Frog which has received twice the dose of trioxybenzene. 37™, Legs extended, and if pushed up revert to this position. Also thrust out from time to time. Movements getting feebler, heart still beating. No distinct eye reflex, but on touching eye there is a twitch of the rest of body. 67". No eye reflex, legs out. Feebler movement of trunk and leg muscles still continue. Increased by stimulation and by putting in dorsal position. Heart beating. 267"'- No marked change of condition but twitching is now very feeble. MDCCCXCI. — E. 4 D Digitized by Microsoft® 570 DES. T. L. BRUNTON AND 3. T. CASH ON THE CONNECTION Experiment. Frog of 18 grms. 0''0". Injected '003 grm. resorcin into anterior lymph sac. 6™. Violent jerking. Ducking and squeaking now present (from contractions of abdominal muscles). Frequent extension of limbs. Movement constant. 15'". All eye reflex is gone. Legs extended, there is twitching of groups of muscles, but the legs are but little moved. 65". There are still twitohings of muscles but legs are not moved. 120™. All jerking ceased, legs appear to be in semi-rigor and yield no response to electrical stimulation. Action on the Nerves and Muscles. — -Resorcin is shown, by the rigor which occurs, to be a muscular poison, but it appears to weaken the peripheral terminations of motor nerves before affecting the muscles. This is shown by the following experiments. If the brain is destroyed in the first instance and the iliac vessels on one side ligatured, reflex movement continues for a time more active upon the side of ligature, and the leg of that side reacts more powerfully to stimulation of the other, than the latter does itself. The tetanus which the muscle yields on the unligatured side is feebler than on the other, the difference being more marked for indirect than for direct stimulation. Trioxyhenzene. CgH3(OH)3 1 ; 2 : 3. [Pyrogallic Acid.) (Pyrogallol.) This substance we found to differ decidedly, in its action towards Frogs, from resorcin. But the symptoms produced bj it are not merely different in degree, but also in character. The tendency to the production of spontaneous rhythmical movements, which is so strong in the case of resorcin, is here much less marked. If, after a dose of '003 grm. has been injected an hour, the legs be gently extended, they are still drawn up, though with a somewhat tremulous movement. But little tremor or spontaneous jerking occurs if the Frog is not touched. Even when the brain is intact, there is not the same restlessness but rather a lethargic state, during which all reflexes are preserved for a time and then disappear, the eye reflex and that from the fore limbs being the first to go. One of the most striking differences between resorcin and pyrogallol is that the former produces severe symptoms at first, from which the animal partially recovers, while the latter produces slighter symptoms at first but afterwards kills. (Thus an animal, poisoned by resorcin, may at first appear as if it would certainly die and yet recovers, while another poisoned with pyrogallic acid, may seem so little affected that one thinks it is in no danger, and yet it will be found dead next morning.) The function of the cord does not appear to be quite so rapidly and profoundly Digitized by IVIicrosoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 571 affected as in the case of resorcin, but the nerve was equally impaired in function. The muscle curve was usually well maintained but somewhat less extensive than before. Whilst the immediate effects of the drug are much less marked than in the case of resorcin, it is certain that doses of over '002, though acting slowly, produce a highly deleterious effect on nutrition, as after them on the succeeding morning the animal was often found dead. According to Judell, Pejisonne, and Zeissbk, the death in warm-blooded animals is dvie in large dose to action on the central nervous system, in smaller dose to the solution which is effected of the red blood corpuscles. Experiment. Effect of a Small Dose of Pyrogallol. Frog of 15 grms. weight. O'lO™. Injected -001 grm. trioxybenzol. (1:2:3, pyrogallol.) 10™. Restless. Movements rather tremulous. 15"". Springs well. But tremor on movement. 35™. Reflex is increased. There is no " huddling " movement. 65™. Is lethargic, but reflex increased. There is slight " squatting " or " huddling " movement occasionally. 185™. Spring rather short. Lethargic, tremulous on movement, but not when at rest. Reflex increased. 300™. Tremor less. Decidedly lethargic. Next day, perfectly normal. Experiment. Effect of a Moderate Dose of Pyrogallol. Frog of 15 grms. CO™. Injected '002 grm. pyrogallol into dorsal lymph sac. 7™. Restless. Movements somewhat tremulous. 29™. Crawls stiffly and with a little tremor. Springs. Has slight " hunching " or ducking movement of head. No foam in jar. 42™. Sitting up, springs well, though especially after movement there is tremor and "hunching" with bending of head ; closure of eyes, apathetic. 72™. Crawls stiffly, more tremulous. Very little ducking or tremor when not attempting movement. Reflex is increased, striking bench originates movements. Gets off back with perfect ease. Is apathetic. 232'°. Condition continues much as at last report. It is only on movement that tremor and ducking occur. Spring short. Reflex increases. Is apathetic. 353™. Crawls well if roused and with less tremor, but is apathetic. No jerking if at rest. Next morning the animal was dead. 4 D 2 Digitized by Microsoft® 572 DRS. T L, BRUNTON AND J. T. CASH ON THE CONNECTION Experiment. Effect of a Large Dose of Pyrogallol. Frog of 15 grms. 0'^ 0". Injected '0075 grm. pyrogallol into dorsal lymph sac. 4™- Restless. Movements already tremulous. II™. If roused makes rapid and violent series of springs, but only progresses \~1 inch at each, move- ment. After movement some involuntary extensions of legs and ducking of head. 21™. Resting on ventral surface. Rarely starting occurs. Reflex is increased. Is lethargic. Legs drawn up to body, and do not show rhythmical extensions as in case of dioxybenzol. Still springs short distance, but feebly. 54™. Sits with head raised, and shows but rarely jerking or starting except when roused ; can still crawl. Cannot resume ventral position if placed on back. 105™. Weak, lethargic. 160™. Ducks and starts if roused. Refl.ex is increased. 276™. Cannot get off back. Much jerking if roused. 400™. Lies on belly, legs drawn up. Attempts to spring, but hardly moves body. Cannot rise from back. Next morning was dead. Experiment. Action of Pyrogallol on the Spinal Cord, Nerves, and Muscles. A brainless Frog with vessels ligatured in right leg. About '012 grm. injected into lymph sac. After all reflex had entirely ceased the cord was exposed and stimulated by a faradic current. It was found that at 15 centims. distance of the secondary coil there was jerk of the right leg, and that on approximating the coil to 10 centims. there was distinct tetanus on this side. The left leg, which had been exposed to the action of poison, was not moved till the coil was more nearly approximated (3 centims.). The tetanus of the ligatured leg was distinc(;ly better than that of the unligatured from indirect, and slightly better from direct, stimulation. (In testing the effect of medullary stimulation, all the tissues connecting the legs with the trunk were divided excepting the sciatic nerves.) Comparison betweeiV the Activity of Kesorcin and Pyrogallol. In Frogs the activity of pyrogallol in the production of immediate symptoms appears to be only one-quarter to one-fifth as great as that of resorcin ; ultimately, however, it is almost exactly equal in its lethal effect. Action of Amidobenzbne. Amidohenzene. CqHj.NH^. [Anilin.) In considering the action of benzene, in v^^hich one atom of hydrogen has been replaced by amidogen, we must remember that this substance, viz., anilin, is capable Digitized by Microsoft® BETWEEN CHEMICAL CONSTITUTION AND PHlfSIOLOGTCAL ACTION. 573 of being regarded from two points of view : (a) as amidobenzene, or benzene in which one atom of hydrogen is replaced by amidogen, NH^ ; or (b) as phenylamine, i.e., ammonia (NHg), in which one atom of hydrogen is replaced by phenyl (CqHb). In correspondence with this constitution we find that we may regard the symptoms produced by it either as those (a) of benzene modified by ainidogen, or (h) of ammonia modified by benzene. Thus we find the symptoms differ from those of benzene and resemble those produced by ammonia, in the tendency to more violent spasm and to greater paralysis of muscle and nerve. They differ frona those of ammonia in the fact that the convulsions never assume the form of true tetanus, the tetanic spasm which the ammonia group would produce being broken up, so to speak, by the action of the phenyl. As contrasted with the compounds aheady discussed, witli exception of the hydroxyl compounds, it will be at once apparent that the accession of symptoms produced by the action of amidobenzene is decidedly more rapid. Within 5 to 7 minutes of subcutaneous administration a distinct muscular twitching with incoordi- nation of movement makes its appearance. The movements, whilst in the main purposeless and frequently confined to one side, have sometimes a regular speed of recuiTence, one form of motion being repeated again and. again at short intervals. Occasionally the thrusting out and flexion of one leg may cease and the corresponding limb will take up the same action and repeat the movement at a similar rate. Less frequently a group of movements more distinctly coordinate occurs, usually those observed in swimming, and they may persist for several minutes. The eye reflex appears usually to outlast limb reflex. As the notes of the case quoted show, the longitudinal conduction of the cord is evidently diminished, and the effects of nervous stimulation are relatively to those of direct (muscular) stimulation greatly lessened, though the muscle is itself considerably affected by the poison. It was evident from the examination of other animals which had not been so completely poisoned, that, even if the initial stimulation of the nerve yielded a moderately good contraction, whether stimulation was repeated once or twenty times per second, the succeeding contractions became feeble and the muscle soon ceased to respond altogether to indirect stimulation. When decerebration and ligature of the iliac artery had been practised before the introduction of -the poison, it was found that reaction of the corresponding limb both to direct and indirect stimulation was stronger than on the side to which the poison had access by the circulation. (Fig. 9, A, A'.) At the same time tremor was observed in the ligatured leg, evidently as a result ol central action of the drug, and the reflex from it was not longer maintained than on the uuligatured side. Digitized by IVIicrosoft® 574 DBS. T. L. BRUNTON AND J. T. CASH ON THE CONNECTION Fi"-. 9. Action of Amidobenzene (Anilin) on Muscle and Nerve. A, tetanus from unligatured (poisoned) leg by direct stimulation for 5^. A' ,, „ „ indirect ,, „ (i.e., stimulation of nerve). B, thirty contractions at intervals of 2^ from direct stimulation. B' ,, ., „ indirect „ Tte Frog weighed 30 grms. It vyas decerebrated ; the left iliac vessels ligatured ; and 1 minim of amidobenzene injected into the dorsal lymph sac. The examination was made after 2^. B and B' were taken before A and A'. The ligatured (unpoisoned) muscle gave on both direct and indirect stimulation a much more powerful and sustained contraction on tetanising, and the curve from single induction shocks did not elongate and fall in altitude as on the poisoned side (B'). Experiment. Action of a Small Dose of Amidobenzene. (Anilin.) Frog of 45 grms. IP 53™. Injected one minim of anilin into the dorsal sac. 12'' 3™. Active, but movements are tremulous; occasional quack. 7". Head tends to bend forward with jerk. All movements are now very tremulous. Moves round in circle, quacks. No springing spontaneously, but, if stirred, can still spring three or four inches. Breathing more laboured. 25™. Spasm chiefly in muscles of trunk at present. Crawling movement slow and tremulous; seems to feel ground with feet before resting on them. Still tends to creep round in circle. Can still spring five or six inches with great efiort. Legs are drawn up slowly, and there is great trembling on alighting. The body gives a lurch when table is struck, but no tetanus. 40"- Quiet. All limbs drawn up normally. Seems more sensitive to cutaneous stimulation. Ih 0". Quiet. Tremor on movement of body. Circumrotation. By rapidly approaching an object towards the eye, tremor of the whole body was produced, with or without a quack. 15™. Crawling is very slow and tremulous, and occasional spring of three to six inches. 2'' 10™. No farther symptoms. Crawl very tremulous, but stronger. 35™. Do. do. B*" 10™. Hops better ; is less tremulous. Next morniag, perfectly normal. Digitized by IVIicrosoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 575 Experwieiit. Medium Dose. Frog of 29 grms. Eoom Temperature, 63° F. 0^ 0"- Injected two minims amidobenzene into dorsal sac. 7™. Hind legs sprawl, toes spread out. Twitchings in muscles. Appears more paralysed in fore than hind legs. Breathing laboured and accompanied bj protrusion of eyes. Leg at once drawn up if extended and gently touched. Striking the bench on which the Frog rests provokes tremor of legs and all body. 25"". One leg extended, with twitchings and separation of toes, but devoid of rigidity. The other leg and arm only show movements and twitchings, which are incessant. Eye reflex still present. (There is more movement here than in any other of the series.) 27™. Alternate extension and drawing up of right and left legs, as if in crawling, but no progress is made. All movements are very jerking. 33™. Extremely active waving of arms; thrusting out of legs and jerking of body set in without any true tetanus, lasted 2-3™. After this, slower swimming movements, which lasted 15-20™ Thereafter movement (spontaneous) declined. 137™. Legs yield no reflex now. Arms faint reflex. Eye reflex still present. Occasional spontaneous contractions of muscles of trunk and extremities still occur. Examined. There appears a slight coagulation at one part of dorsal sac. Tetanic stimulation of cord produces a hardly observable effect. Stimulation of the nerve gives broken tetanus. Faradisation of the muscles gives sustained but small tetanic contraction. The muscle gives a feeble curve. Nitrobenzene (Mono). We have examined the action of only one nitrobenzene, namely the mononitro- benzene, C6H5(N02). Its action upon Frogs is that of causing lethargy, with increasing tremor on move- ment. The power of voluntary movement disappears ; touching the foot, however, may cause tremor of limbs. Even when the Frog shows no reflex of any kind, a series of jerking movements of the legs may be made, apparently spontaneously, and these may be accompanied by muscular fibrillation. The circulation in the web is slow and feeble, the pigment cells contracted. Recovery may occur from this condition. In 24 hours there is ability to crawl for a short distance ; the movements, however, are distinctly tremulous. When the symptoms of poisoning are fully developed, strychnine injected into the Digitized by Microsoft® 576 DRS. T. L. BRUNTON AND J. T. CASH ON THE CONNECTION dorsal sac no longer produces tonic spasm, nor anything approaching it, but there is increased tendency to a diffused twitch in response to local stimulation. When the nitrobenzene is introduced into the stomach the same symptoms are •induced, though more slowly than when the injection is subcutaneous. Experiment. Action of Small Dose of Nitrobenzene on Frogs. After the injection of 1 minim of nitrobenzene into the lymph sac, in — 15™ to 20™. Movement is tremulous, legs more slowly withdrawn. Occasional starting in limb when lying quiet, but usually no tremor during rest. Occasionally a series of rapid extensions of legs, as in swimming, occur. Reflex decreases till at 80™ there may be only twitching without withdrawal of foot. If 2 minims are injected, the symptoms may develop more rapidly. Eye reflex may disappear in 40™ to 60™. It may be outlasted by extension of legs as a reflex act. Effect of Beat, .30° C. In a Frog poisoned by nitrobenzene and kept at 30°, the symptoms were as follows : — 5™. Tremor well marked. 10™. If leg is pinched it is thrust out and drawn up. There may be a coordinate kick with both legs. No withdrawal of arms if pinched, but legs are moved. 36™. All reflex is entirely gone, except the faintest tremor on pinching either of the feet. If taken out and placed on the bench there may be soon slight return of reflex, but this is usually very slight. EffW,t of Cold, T G. 60™ After injection of 1 minim, still hops. Some tremor and slowness in drawing leg up after spring, 80™. All reflexes present. Has quite ceased to crawl. 200™. All refl.exes present. No tremor when not attempting movement. From this condition complete recovery occurs. Effect on the Spinal Cord, Nerves, and Muacles. When vtflex has almost entirely ceased it is usually found that stimulation of the upper part of the cord causes a very faint twitch in either leg (even if the sciatic artery has been previously tied in one). On the unligatured side indirect stimulation caused a very feeble contraction, if any ; direct stimulation a relatively stronger, though imperfect contraction, which becomes rapidly prolonged on frequent repetition of stimulation (fig. 10). On the ligatured side both direct and indirect stimulation yielded good contractions. The chief effect is ou the cord, which is markedly paralysed by this drug, especially in its conducting power. Next to this the end plates of the nerves are paralysed, and lastly, the muscular tissue is affected. Digitized by IVIicrosoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 577 Action of Nitrobenzene on Mnsclo and Nervo. Decerebrated Frog woigliiug '24 grms. Right iliac vessels ligatured. 0'05 c.c. nitrobenzene injected into the dorsal lymph sac. Curves taken 6'' after the injection. Fig. 10. Muscle of ligatured (unpoisoned) leg. Stimulated by opening shock of induction coil every 2^ Curve obtained by stimulation of the nerve was nearly equal to that obtained by direct stimulation. Fig. II. Muscle of unligatured (poisoned) leg. Stimulated in the same way. The muscle relaxes imperfectly during the intervals between the contractions. There was no response at all of the muscle when the nerve was stimulated. Tiine lOn DVin I second Experiment. Medium Dose of Nitrobenzene. Frog of 29 grms. Injected 2 minims of nitrobenzene into dorsal lymph sac. Torpid and slower in movements. Rests on belly, does not sit up, crawls and springs, but movements aie tremulous and legs not rapidly drawn up. Repeated springing movements. All reflexes present, but the leg is drawn up slowly and jerkily. No tremor on movement whilst lying still, except an occasional starting of limb. Suddenly executed series of 10 to 12 rapid extensions of legs as in swimming. No eye reflex. Sharp twitch of both legs without withdrawal on pinching foot, but no movement of arms or trunk. Yery faint reflex of each arm on stimulation of itself. Circulation very active, pigment cells not markedly altered. Movements of leg muscles very faint. Action on Spinal Oord, Muscle, and Nerve. C^O™. 24™. 34^. 50™. 79™. 84™. 109™. Exposed the brachial cord. Left leg entirely divided except sciatic nerve, no contraction on tetanising nerve or cord. Response to direct stimulation of the muscle was extremely feeble, stronger in the other leg, from which 90 contractions were taken. MDCCCXOI. — B. • 4 li Digitized by IVIicrosoft® 578 DRS. T. L. BRUNTON AND J. T. CASH ON THE CONNECTION Exposure to Vapour of the Benzene Compounds. The original experiments of Briegeb,* who showed how readily poisoning in Frogs might be induced by placing the animals in solutions of resorcin and its isomers, demonstrated the fact that by cutaneous absorption these substances are highly lethal. CHRiSTiANit has demonstrated in the same manner the poisonous action of benzol. The literature of pyrogallol abounds with instances of poisoning produced by the application of the drag applied in the form of ointnjent to the human body. The inhalation and cutaneous contact of the vapour of nitrobenzene have caused poisoning, and anilin when brought into contact with raw surfaces, as in the treat- ment of skin diseases, and more especially when its vapour has been inhaled, has produced its characteristic poisonous effects. Exposure of Frogs to the vapour of the anilins and their alcoholic combinations has been found by Jolyet and Cahoues;{: and other observers to cause poisoning. In confirming these and other experiments, we have found that exposure of Frogs to the vapour of benzene, its haloid compounds, its alcoholic compounds, to anilin, and to nitro-benzene, produces the characteristic symptoms of poisoning with great rapidity and completeness. We introduced Frogs into large funnels, the lips of which were covered with vaseline, so that they fitted air tight upon glass plates. In the neck of the funnel a fragment of sponge was contained, and into this the body to be tested was dropped. There was by this method no actual contact of the substance with tire Prog, merely the exposure to the vapour liberated from the sponge. We will merely quote one or two of such experiments in this place. E;v perimcnt . Action of the Vapour of Monochlorobenzene. Frog of 1.5 grms. m large funnel as above described. Temperature 15° C. 0''0". Dropped three drops of monochlorobenzene into the sponge contained in mouth of funnel. 20™. Violent springing alternating with crawling movements, great frothing on sides of funnel. Legs are strongly withdrawn. 45"". Movements, much less powerful, are jerky and broken. SS"". All reflexes are jerking. Start of body and limbs on striking bench. Lies still if not roused, legs extended. 95". All movement completely gone, ¥wg taken out of the funnel. ISi™ There is a very faint twitch of toes on stimulating fore foot or hind foot. On decapitating, a * Beieger, 'Arch. f. Anat. u. Phys.,' 1879. t ' Comptes Rend.,' vol. 56, p. 1131, t ' Zeitschvift f, Physiol. Chemie,' vol. 2, p. 282, Digitized by Microsoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 579 weak movoment of avnis and legs ocruiTed. On stimulating tho spinal cord, contraction in U\os was very impcrl'cct and unsteady. Nerve distinctly impaired in function. Muscle gives I'eoble tetauns. Heart still beating slowly. Action of tlie Vapour of Diniethylbenzene. The symptoms priidueed by diinetliylbenzene wore much less marked, i^liiefly characterised by motor paresis. Action of the Vapour of Amidobenzene. (Anilin.) Auilin caused, after an initial period of excitation, great tremor and twitching, and after exposure to vapour for -tO minutes, the animal hardly possessed the power of crawling. Appearances like those of paralysis agitans. Experiment. Action of the Vapour of Nitrobenzene. Placed a Frog under glass on filter paper. Temperature 1 5"-5 C. 0'' 0™ At upper end of glass, five drops of nitrobenzene dropped on sponge. 20™. Cannot hop, all reflexes present, but slow and jerky. Breathing rapid. 60™ Decerebrate. Thereafter no spontaneous movement causing tremor occurred, but on irritating foot, withdrawal was very slow and still tremulous. 420™ All reflex gone from legs. Very weak reflex from arms. Circulation active, strong. Condition of Spinal Gont, Muncle, and Nerve. Decapitated, prepared upper part of cord and cut through all tissues but nerve of one side. Con- traction in gastrocnemius of this side, though not so strong as of the other on stimulating cord. After contraction occurred, fibrillation lasted sijme time. Although it may seem almost superfluous after what we have already said, yet we shall now give, in the briefest possible manner, the most prominent results obtained, which may serve to contrast the bodies we have examined. Benzene (aromatic) causes relatively but little tremor, except on movement, and whilst it may for a time increase the reflex function of the cord, in the end it causes paralysis. The central nervous (cerebral) apparatus is somewhat specially afiected by hromobenzene, whilst spontaneous jerkings, with tremor on movement and increasing lethargy, characterise iodobenzene. Monochlorohenzene tends to cause more pro- nounced spasm than the foregoing. There is great tremor, with ataxic movements. The circulation is but little affected. The methyl compounds abolish voluntary movement and ordinai;y reflex, but some- times after the ordinary reflex response has disappeared, touching may cause other movements which are not usually induced, as touching eye causing extension of limbs, but no eye reflex (as in case of trimethylbenzene), occasional clonic convulsive movements of limbs and trunk have been observed to occur spontaneously (as in case of methylbenzene). There is more tremor after dimethylbenzene than after methyl- benzene. The eye reflex disappears relatively soon. The trimethylbenzene is distinctly the most active of the three. 4 E 2 Digitized by Microsoft® 580 DES. T. L. BRUNTON AND J. T. CASH ON THE CONNECTION Ethijlherizene is stronger than methylbenzene in producing paralysis, but not so strong as the trimethyl compound. Some amount of tremor is observable on attempted movement. Dihijdroxyhenzene meta (resorcin) is distinct from all the others in the spontaneous, rapidly occurring, and somewhat rhythmical movement which it occasions. This symptom, whilst rapid in making its appearance if the dose is small, lasts for a long time before paralysis of the cord ensues. PyrogaUol has not the same tendency to cause clonic spasm, but tends rather to produce a lethargic state with gradual decline of reflex. Amidohenzene causes the most rapid occurrence of motor phenomena, the hydroxyl compound excepted. There is great tremor after a spring. Very active incoordinate movement is made, but tonic spasm is absent. Nitrobenzene causes lethargy with increasing tremor on movement. The reflex is abolished somewhat early, but after this time a series of jerking movements of the legs, perhaps with fibrillation, may be observed. SECTION II.— ACTION OP BENZENE AND ITS COMPOUNDS UPON REFLEX. An extensive series of observations was made with the view of testing the effect apon reflex action of the various bodies entering into the series under discussion. Decerebrated Frogs, prepared some time previously, were used for this purpose. Immediately before the experiment commenced, the right iliac artery and vein were ligatured, in order that an estimate might be formed of alteration of reaction originating, not in the cord itself, but in the muscles and peripheral nerve terminations. The foot of the suspended Frog was stimulated by dilute acid of various strengths, from 1 per 1000 to 1 per 6000 (by measure). The reflex was tested every 10, 15, or 20 minutes, according to circumstances, and estimated by means of a metronome beating half-seconds. The time of withdrawal was recorded, and from the figures obtained the diagrammatic charts were constructed. One difficulty peculiar to the substances under consideration was met with, namely, that from the action of certain of them, a condition of spon- taneous jerking was developed, which was aggravated by immersion, even in pure distilled water, at the moment the application was made. This action, which occurs when the foot is very suddenly immersed, but not nearly so much so when gradually, was specially pronounced in the case of benzene, monochlorobenzene, and amide- benzene (anilin). The difficulty was overcome by a more gradual immersion, and by repeating the test until the uniformity of time of withdrawal clearly indicated that this was due to the stimulation by the acid. On account of the motor symptoms produced by the hydroxyl compounds, we found them unsuited to this form of experiment. Digitized by IVIicrosoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 581 The ultimate effect of many bodies in the series is to render the withdrawal of the foot highl}^ tremulous and jerking. The flexion of the leg is followed by an extension, and this again by another flexion, so that instead of a sustained withdrawal from the irritating acid fluid, the foot is splashed in and out, and the action is continued until the foot is washed with pure water, and sometimes even after washing. After use the animals were placed in the cold and kept moist. The doses employed throughout the series of over 70 experiments were either the -3-^ of a cubic centimetre, or exactly double the quantity. The measurement was made in an accurately graduated capillary tube. Twenty-four hours after the larger dose reflex was still active, chiefly in the case of Frogs receiving the monoiodobenzene, dimethylbenzene, and benzene, though with the smaller dose it was usually retained, excepting after trimethyl- benzene. Benzene. CgHg. This body in larger dose, -^g- c.c, rapidly lengthens the time elapsing before reflex reaction to acid solutions, which were previously strong enough to cause rapid with- drawal of the foot. The curve which may be obtained by placing verticals, repre- senting the time elapsing before reflex withdrawal of the foot, upon an abscissa, which is divided into equal time intervals, shows a parallel change of responses on the ligatured and unligatured sides, allowance being made for the slower reflex in the former owing to blood stasis. With a smaller dose, 3-g c.c, the failure of reflex is much more gradual ; in the experiment from which the curve is formed it varied only from 1"5 second to 7'5 seconds in the course of 4^ hours. There was no certain indication of shortening of the reflex phenomenon even at an early stage of the poisoning. We quote the results of two experiments.* * In recording the reflex time we occasionally give two speeds, as 1 second to 1-5 second, indicating at that particular time a withdrawal, sometimes at I second, sometimes at 1-5 second. In the figures we have drawn up the mean is given between these numbers. Digitized by Microsoft® 582 DRS. T. L. BRUNTON AND J. T. CASH ON THE CONNECTION Experiment a. (4.) Frog of 32 grms., pegged some hours previously. Ligatured Right Ihac Vessels. Acid Solution 1-4000 (by measure). Reflex three times tested at short intervals. Injected -^ cc. Benzene into Anterior Lymph Sac. Time. Unligatured leg. Ligatured leg. Remarks. minutes seconds seconds 1-6-2 2-5 10 1-5 2 20 3 3-5 Jerking of feet and spreading of toes commenced 40 10 9 Change to 1-2000 acid 50 2-5 2-5 Jerking exaggerated on instant of immersion 60 3 3-3-5 120 6-6-5 6-6 Legs jerked out sharply, but thrust in again ; the movement is exaggerated for some time after falling in water 180 8-9 8-9 In 24 hours the reflex of this Frog was good, and bnt slightly tremulous Experiment b. (Fig. 12, a.) Frog of 36 grms. Preparation as before. Time. Unligatured leg. Ligatured leg. Remarks. minutes seconds seconds 1-5 3-5-4 Tested four times at short intervals. Acid solution 1-2000 Injected Jg- cc . aromatic benzene 10 1-5-2 3-5-4 30 2-2-5 4-4-6 45 3 4-5 60 3 4-5 Withdrawal tremulous 86 3-5^ 5-5-5 115 5 6-5-7 All movements are flapping and unsustained 130 4 5-6-6 150 6 8 166 7-8 10 190 8-5 Not in 20 Next day reflex from both legs was good to mechanical stimulation Digitized by Microsoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 583 Sao 'r-t Digitized by IVIicrosoft® 584 DRS. T. L. BRUNTON AND J. T. CASH ON THE CONNECTION MonocMorobenzcnc. This compound causes a powerful effect upon reflex ; it is, in fact, one of the most active bodies in the series. In about one-half of the experiments a shortening of the reflex period was produced immediately after injection. The reduction varied from •5 second to 1'5 second, and was never present for more than 30 minutes after the injection had been made. After this temporary reduction, or an alternative equality or slight lengthening of reflex, a very rapid change took place, the period of reflex increasing considerably with every estimation. Spontaneous spreading of toes and jerking of feet and legs were developed in all cases, and this condition w^as increased by immersion in the acid solutions, and sometimes persisted for a time in exaggerated form after w^ashing with cold water. Immersing suddenly in water caused an active instantaneous jerk. In several experiments the ligatured leg, though as much affected in this respect as the unligatured, was stronger in its reaction, and, spite of diminished irritability from stasis, came to res23ond by withdrawal more rapidly than the other, indicating a direct paralysing action of the drug on the side of free circulation. Exjjeriment c. (Fig. 13, ;S.) Fkog of 28 grms. Usual Preparation. Time. Unligatured leg. Ligatured leg. Remarks. minutes seconds 1-1-5 seconds 2 Acid 1-2000 (measure) . Tested reflex four times at intervals Injected yig- o.c. monocliloro senzene into anterior lymph, sac 10 20 30 40 60 -S-1 -6-1 2 2-6-3 8 1-5-2 1-5-2 3 3 5 Twitching of toes has commenced Twitching of toes and feet active 24 tours. All reflex gone Digitized by IVIicrosoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 585 Eig 13, ft a.iul 7. 10 SO' 30 40' Mo I/O C/t/oi-o Jif //^( ne ///Jfct-/-^ r.r — I.f'rftj} leq Ar/r7 /~^'Ooo (Mr as/ar) 13 Moi/o C/il oro — V/ilia^j^- Icid 7- 4 000 iiiiiiiiiiiiiiiiimiii iiHimiiiiipaiiiiiii IllllliiiiiiilliiiiiiiimiiiimiKfiiimii maiBiiiiiiiii !!lii!ii!il!!iilll m iiiiiiiiiimiiiiiiiiiiiiiiiiiiiiiiiiiio^^^^ iniiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiisiiiiiiii !!!!!!!!!n!!!!n!!!!!!!!H!!!!!!!!!n!!!!!!lSi!!rfm .__.../ h ..._L / T/ " 1 miiMiniH .-: 1 IIIKIIIIIIIII IllllllllllllllllllllllisSilllllllll" ! iillllllllim llllllliiililllllll!SillM'!i iiillll 1 lllllllll III !E!!!!!!IJJ!M!BKiiillim 1 l!!!!!!ll III Hiiiinniiinmiiiiiiiiiiiiiiiiii iiiiiiiiiii III Experiment d. (Fig. 13, y.) Frog of 46 grms. Usual Preparation. Time. Unligatured leg. Ligatured leg. Remarks. minutes seconds 2-2-5 seconds 2-5 1-4000 acid. Tested reflex thrice Injected -gig- c.c. moiioclilorobeiizene into anterior lymph sac 1 10 20 30 50 70 90 2-2-5 2-5 3 4 5 13 3 3-3-5 4-4-5 6 9 Not out in 20 sees. iVIovement broken and tremulou.s Active jerking before withdrawal On changing the solution to 1-1000 (nothing weaker caused withdrawal), the reflex of the unligatured limb was reduced to 5 seconds, but lengthened again with moderate rapidity to 10 seconds. The Hgatured limb yielded no further response. In 24 hours there was feeble reflex on the unligatured side, and in 48 hours this had become moderately active. MDCCCXCI. — B. 4 P Digitized by IVIicrosoft® 586 DR3. T. L. BRUNTOX AND J. T. CASH ON THE CONNECTION Monohromobeiizene. The action of this body upon reflex is considerable and moderately rapid, though it is distinctly less than that of monochorobenzene. There is during the course of the experiment an almost entire absence of the motor phenomena which are so prominent in the former. No distinct reduction in the time of reflex was observed. The curves obtained from the ligatured and unligatured limbs ran fairly parallel. In the expei'i- ment quoted the latter at first was slightly slower than the firmer, but the position became in time reversed. Experiment e. (Fig. 14, 8.) Frog of 32 grms. Usual Preparation. Time. Unligatured leg. Ligatured leg. Remarks. minutes seconds secunds ■5-1 ■5 Tested tlirioe at intervals. Acid, 1-2000 Injected Jg- c.c. monobromobenzene into anterior lymph sac 10 1 -6-1 ! 20 1-1-5 1 40 1-5-2 1-5 60 2-25 1-1-5 Withdrawal tremulous, but no spontaneous jerking 80 25-3 1-5-2 100 2-5 3-6-4 120 4 7 140 6 8 175 7 10 200 8-5 12 275* 12 18 From 1-4000 acid solution 24 hours. Reflex entirely disappeared to all stimulation * Not sbo-vvn in fig. Monoiodohcnzene. Of the haloid compounds, iodobenzene is the least active upon reflex. Although it does not appear to reduce the reflex period in the first instance, the prolongation caused as a rule develops slowly. In experiments extending to 4 and 5 hours it was found that the ligatured leg, at the conclusion, usually had a distinctly shorter reflex latency than its unligatured companion ; from which circumstance a direct effect of the drug upon the terminal nervous filaments or the muscular tissue, impairing their function, is to be inferred. The spontaneous jerkings appear like those caused by chlorobenzene. A persistence of reflex on the day after the experi- ment appeared more usual than with the other haloid compounds for equal doses to animals of equal weight. Digitized by IVIicrosoft® BETWEEJf CHKMIOAL CONSTITUTION AND PHYSLOLOGICAL ACTION, 587 4 V 2 Digitized by IVIicrosoft® 588 DBS. T. L. BRUISTTON AND J. T. CASH ON THE CONNECTION Experiment f. (Fig. 14, e.) Frog of 30 grms. Usual Preparation. Time. Unligatured leg. Ligatured leg. Remarks. minutes seconds seconds lo 1-1-5 Tested thrice at intervals. Acid 1-2000 lujeoted Jg- r.c. monoiodobenzene into anterior lymph sac 10 1-5 i-1-6 20 2 1-1-5 40 2 1-5 60 2-2-5 2 80 100 .3-6 2-6 Withdrawal becoming tremulous on both sides 125 3-3-5 140 2-5 2-2-5 No spontaneous jerking 170 4 3-5 19.5 4 3 260 9 I,- 5 24 hours. Moderately good reflex in both legs The action of methylhenzene is apparently identical with that of the dimethyl compound, -which we shall now consider. Dimethylbenzene. The effect produced by this compound upon the time of recovery is neither rapid nor powerful, and this statement holds even when the larger dose, -j^ c.c, is employed. A reduction of the latency has been observed in a considerable proportion of the experiments made with this drug, and this phenomenon has occasionally been seen to last for 40 minutes. Failing a positive reduction, the speed of withdrawal remains for a time unaffected. When the reflex does begin to lengthen the increase is gradual. There is no spontaneous movement. The reflex after the lapse of 24 hours is good and destitute of tremor. Digitized by IVIicrosoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 589 KxpfniiU'iU g. (Fig. 15, {.) (The time of reflex was identical for a considerable period in the two legs.) Fbog of 3 1 grms. Usual Preparation. Time. minutes Unligatured leg. seconds 1-5 Ligatured leg. seconds 1-5 Remarks. Tested four times at intervals. Acid solution 1-2000 Injected -Jj c.c. dimethylbenzene into anterior lymph sac 10 1-5 1-6 20 1-5 1-5 ■iO 2 2 60 2 2 80 2-2-5 2-2-5 100 2-5 2-5 120 3 3 145 3 4 170 3-3-5 4-4-5 195 3 4 260 3-5 4-5 24 hours. Reflex moderately good, devoid of tremor Trimethylbenzene. This compound is markedly stronger in its action upon reflex than the dimethyl compound. No shortening of reflex has been noticed, but a steady prolongation of the time elapsing between immersion and withdrawal of the foot. As a rule, the curves obtained from the ligatured and unligatured legs respectively run fairly parallel, but occasionally the unligatured drops behind the other, as if eventually a direct effect was produced upon the muscle substance and nerve terminations. In 24 hours after the smaller dose reflex has, as a rule, entirely disappeared. Digitized by IVIicrosoft® 590 DBS. T. L. BRUNTON AND J. T. CASH ON THE CONNECTION a c3 JV5 r-( ti) Digitized by IVIicrosoft® BETWEEN CHEMICAL CONSl'ITUTlOX AND PHYSEOLOGLCAL ACTION. 591 Ea-pcrinienf K (Fig. 15,17.) Frog of 30 grms. Usual Preparation. Time. Unligatuved leg. Ligatured leg. seconds Remarks. minutes seconds •5 -5-1 Thrice tested at intervals. Acid solution 1-2000 Injected ^V '"•C- trimethylbenzene into anterior lymph sac 10 ■5-1 1-1-5 •20 1 1-5-2 30 1-15 2-3 40 1-5--2 2-6 60 2 4 70 2 3-5 90 2-3 3-5-4 110 3-4 6 Well -withdra-wn. No tremor 130 4 6-5 150 4-4-5 6-5-7 170 2-5 3-5 A most distinct acceleration of reflex, regular on every immersion 190 3-5 4-5 210 6 7 24 hours. All vitality gone. Ethylhenzene. Although the effect produced upon reflex is moderately rapid and extensive when large doses have been administered, with smaller doses the result is much less marked, so that this compound is to be regarded as amongst the feebler in its power of reducing the reflex activity of the cord. As a primary result of its action the time of reflex is usually reduced, sometimes by as much as 1 second. This stage of acceleration may persist from 10 to 30 minutes. Thereafter a lengthening of the period occurs and develops slowly or rapidly according to the dose. There is no protraction of spontaneous tremor and jerking, though the withdrawal of tlie legs becomes ultimately tremulous. The day after the experiment, when the smaller dose had been used, the reflex was usually found to be good and unaccompanied by tremor. Digitized by Microsoft® 592 DRS. T. L. BRUNTON AND J. T. CASH ON THE CONNECTION Experiment i. (Fig. 15, 6.) Frog of 33 grms. Time. Unligatured leg. Ligatured leg. Remarks. minutes seconds seconds 1-5 1-5-2 Tested four times. Acid 1-2000 Injected -^ c.c. ethylbenzene into anterior lyraph sac 10 1 1-5 20 •5-1 \ 1 ! 30 1-1-5 2 1 1 40 1-5 2-6 50 2-2-5 ! 3-3-5 60 2-5 1 4 70 1 80 90 3-3-5 6 100 4-5 6-5 no 4-5 6-5-7 130 4-5 7-5 150 5 170 190 5-5 8 In Experiment k, in which a Frog of 38 grms. received -g-g c.c. of ethylbenzene, the time of reflex, -when tested with 1-2000 acid, increased in 1 40 seconds by less than 2 seconds, and in 2 hours later it had increased only one addition^-l half second. The day after the preparation showed good reflex in both legs ; no tremor -was present. Amidobenzene. Aniliu has considerable power in causing spontaneous movement in a pegged Frog. The movement is spontaneous, but it is exaggerated on dipping the foot into acid solution or even into water. No reduction of the reflex period has been observed. The time occupied in withdrawal lengthens materially, Avhilst the increased jerking immediately after immersion shows it is a case of slow s\immation of stimulations centrally rather than of a failure of peripheral motor and sensory apparatus. The curves of response of the ligatured and unligatured legs are very parallel throughout. If the acid solution used is of the strength of 1-2000, and the amount of anilin injected does not exceed yg- c.c, reflex may still occur within three or four seconds of the original speed, even after the lapse of three hours. Digitized by Microsoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 593 Experiment 1; la. (Fig. IG, i) FroCx of 'J!) o-nns. Usual Pi'eparation. Time. min\itcs. 10 20 40 50 60 7o 95 120 175 Unligatiived leg. seconds. •5-1 1-5 2-5 LiQ'iituvod log'. soi'oikU. ■5-1 Re Thrice ivpciitcd at iiitcrviils. Acid 1-2000 Injected -jig- c.c. amidobenzenc 3-3-5 4 4-5 1 i-r, 2 2-o-y 3-3-5 4 4-5 Withdrawal tremulous Twitching of toes increased even after acid removed by washing Are only just drawn clear of the solution. The ligatured leg is the stronger of the two Withdrawal very weak and tremulous. Jerking and spreading of toes after washing Same preparation tested at same time with 1-4000 acid solution , 2 Time of injection 10 20 40 50 60 70 3 4 5 4 4-5 Not out in 10 4 4-4-5 5-5-5 4-4-5 4-5 7 Kg. 16, MDCCCXCI. — B. 4 Digitized by Microsoft® 594 DRS, T. L. BRUKTON AND J. T. CASH ON THE CONNECTION Nitrobenzene. Little or no movement of the reflex frog preparation is observed independently of the stimulation. If the dose- of nitrobenzene injected is a moderately large one {ys cc. to frog of 23 grms.), great prolongation of reflex is observed usually -within an hour. Thus, in the case referred to, in 60 seconds after injection neither leg -was removed •within 20 seconds, thouo-h at 20 minutes the reflex stood at 3 seconds and 4 seconds for the t-wo legs respectively. A dose propoi'tionately much smaller, as in the case quoted (-^ cc. to frog of 41 grms.), shows a comparatively slight effect upon the cord, the reflex remaining active, with but little tremor on stimulation. After the smaller dose recovery frequently takes place, so far that reflex next day is good on the side of ligature, and the withdrawal of the protected foot occurs more powerfully on stimu- lating the unprotected than the withdrawal of the latter itself. It is evident, therefore, that sensory nerves are no more aflfected than motor, if as much, by the action of this drug, which has a direct effect upon the exposed limb in addition to its action on the cord. Experiment m. (Fig. 17; k.) Frog of 23 grms. Usual Preparation. Time, Unligatured leg. Ligatured leg. Remarks. minutes seconds 3 seconds 4 Tested thrice. Acid 1-2000 Injected -Jg cc. nitrobenzene 10 20 30 40 60 3-5-4 3 3 4-5 Neither c 5 4 4-5 8 mt in 20 £Ia?p. m (Ft^ KJ JVttro Benzene F'rog of S3 ^rms Irr/ec(- j^ cc Actd J~2,o6o Fig. 17, .. >-•-'• Digitized by IVIicrosoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 595 Expei'iment n. FliOG of 41 grins. Injected -^^ c c. Nitrobenzene. In this experiment rittox on immersion in 1-4000 acid solution became gradually slower, but afttr 3'' the ligatured leg was still withdrawn in 4= (instead of 1» before injection) and the ligatured in 5-.5'' (instead of 1-5^). When a reflex Frog poisoned with nitrobenzene is laid on a flat surface, the legs, if flexed, are not violently extended with jerking and tremor, as in the case of monochloro- benzene, amidobenzene, &c., but aie retained in a flexed position. SECTION III.— THE ACTION OF BENZENE COMPOUNDS IN CAUSING MUSCULAR RIGOR. It had been frequently observed tliat local coagulation of muscle was produced at parts with which the benzene compounds had come into contact ; it seemed advisable therefore to determine whether the activity of these bodies was uniform or whether some were more active than others. With this object in view the compounds were either brought into direct contact with the muscle by filling the muscle chamber already described ('Phil Trans.,' Part I., 1884) with them, so that the muscle was completely immersed, or else measured quantities were introduced into a muscle chamber which was specially constructed so as to be absolutely air-tight, and thus without bringing the liquid into direct contact to allow of its action during volatili- sation upon the muscle. By the first method it was found that powerful rigor was rapidly induced by all the members of our series. The contrast between the three halogen compounds showed that in the case of — Monochlorobenzene, the active shortening of the muscle 30 minutes after application of the drug was ... 3'1 millims. Monoiodobenzene, the active shortening of the muscle 30 minutes after application of the drug was . . . 3'4 ,, Monobromobenzene, the active shortening of the muscle 30 minutes after application of the drug was . . . 2'5 ,, In each case contraction commenced within one minute of contact with the benzene compound. As this method however involved the use of such large quantities of the compounds the series was not completed, but the second plan [i.e., the spontaneous volatilisation of carefully measured amounts of the compounds in an air-tight chamber, into which a muscle had previously been introduced) was followed. 4 G 2 Digitized by Microsoft® 59G DRS. T. L. BRUNTON IND J. T. CASH ON THE CONNECTION The contrast was made at equal temperatures. By following this plan it was soon determined that variations occurred between the various benzenes. Shortening of the muscle did not immediately occur as in the case of immersion which has been already described. It was even found that when stimu- lation of the muscle was practised before and after the admission of the benzene compound, the contraction occasionally remained as powerful for some time under the latter conditions as it was before, but this was always in absence of any material shortening. The variation between the bodies with regard to this as well as to the shortening was, however, considerable. Some proved themselves distinctly more active than others. When Yo c.c, exactly measured, of the halogen compounds was introduced, it was found that monochlorobenzene was much the most active in causing rigor, then mono- bromobenzene, and monoiodobenzene was a good deal weaker than either of them. When the strongest of these bodies (monochlorobenzene) was contrasted with the alkyl compounds it was found to take an intermediate place between methyl-, which is the strongest, and dimethylbenzene which stands next to it ; when contrasted with the third of the methyl compounds, trimethylbenzene, monochlorobenzene shows itself itself later in producing shortening, but its ultimate effect is more powerful. The activity of the methyl compounds is therefore inversely to the extent of methyl substitution in the benzene molecule. Ethylbenzene is not far removed from methylbenzene in the total effect of the shortening it produces. In each of four experiments the latter was strongest. It is generally quicker in causing shortening than methylbenzene. Ethylbenzene is distinctly stronger than the di- and trimethyl compounds. With such small quantities as ^ c.c. of these compounds a very distinct and moderately rapid shortening was induced, as the following figures, illustrative of a few experiments only, suffice to show, the contrast in each instance being between com- panion muscles of the same Frog at equal temperatures. Two slow drums were employed, having a slightly different speed of rotation. No. 1 has a rate of 33 millims. in 10 minutes. Figs. 18 and 19. No. 2 „ 39 „ „ „ Fig. 20. Nitrobenzene and amidobenzene showed themselves much less effective than the other compounds when muscles were exposed in air-tight chambers to their action. In experiments in which only the -^q c.c. of these bodies was tested, it was found that after the lapse of 15 hours no shortening nor rigor were observable. When the muscles were exposed for many hours in the presence of a large amount of these bodies, mononitrobenzene was earlier in producing its effect than anilin. Digitized by Microsoft® BETWEEN CHEMICAL CONSTITUTION AND PHISIOLOGIOAL ACTION. 597 Digitized by IVIicrosoft® 598 DRS. T. L. BRUNTON AND J. T. CASH ON THE CONNECTION .a «> o be 2 rJd •n-^ ^ • ^^ p Exten minu after ixposui a 00 r— 1 6i -^ CO CD 00 6q CO CO 1^ ; ■ CO o -P O Pt c3 o.SP-p g en a O CO O CO O CO )0 o o 03 03 a o O r0 &0 bo o a o o ^< -p C2 a, O (DO,-; o, f-l O 13 O S a c3 -p 03 a or ca o a ra i: ii 01 § be en » CD ,a jQ CD >^ Eh g ,d a 'Si ra H H a CD N a ra CD a C1> ID CSl a a CD nO a o rO TS o a ■S <4 ^ Digitized by IVIicrosoft® BETWEEN CHKMIGAL CONSTITUTION AND PHySIOLOGICAL ACTION. 599 This result would not seem to point away from the theory which might possibly be advanced, that we have here to do to a large extent with a question of varying volatility between the various benzenes. The boiling-points of amidobenzene and nitrobenzene are 184 and 209 respectively, and the only body which at all approaches them in the slowness of its action is monoiodobenzene, with a boihng-point of 188. Ethylbenzene, with a boiling-point of 134, comes after methylbenzene (111), but before dimethyl- (146) and trimethylbenzene (163). SECTION IV.— EXPERIMENTS UPON RATS. Benzene, and the compounds of the benzene series, together with resorcin, were administered hypodermically to Rats, the animals chosen for experiment being as nearly as possible of the same size. Aromatic Benzene Produces lethargy, with some exaggeration, however, of reflex, and occasional spontaneous jerking, with great impairment of mobility. Expe7'iment. Injected 5 gtt. into right groin. 19™. Is torpid, tnt can run easily if roused. 31™. Is hypersestlietic and jerks away, if touched, to another place. 36". Starts if touched. There is an occasional spontaneous jerk. 60™. Much less affected than either of the others (nitro- and amidobeazene) examined at the same time. 80™. Falls over on one side if touched. 260™. Sitting up and beginning to run. 300™. Normal. Nex t day perfectly normal. Small doses of monochloro-, monobromo- and monoiodobenzene (2 minims) injected beneath skin of three Rats of equal medium size, caused in each case slight lethargy without any special symptoms. This lethargy continued for from 60 minutes to 90 minutes, after which time complete recovery occurred. Larger Doses. GJdorohenzene.—e minims injected beneath skin caused some tremulousness in movements in 30 minutes. The animal became lethargic, and if not roused remained sitting in corner of cage. It was, however, easily roused by touching or noise, and then ran well, though its movements were somewhat unsteady. This condition lasted Digitized by IVIicrosoft® 600 DRS. T. L. BRUNTON AND J. T. CASH ON THE CONNECTION for three hours after administration of chlorobenzene, and thereafter a return to normal took place. Bromobenzene.— After a similar dose of this drug a Eat of equal size became very lethargic, and though sitting up and possessed of all its reflexes, it could hardly be roused to movement. When recovering it walked slowly with a rolling or rocking movement, its balance appearing Tincertain. lodobenzene. — Was distinctly more active than either of the other haloid compounds (6 minims to animal of equal size to other two). 12". After administration it was observed to jerk five or six times in succession, became rapidly weak, tending to sink on its side. 27™. Resting on side. Very lethargic. All reflexes are present. .37™. Breathing much accelerated. Rocks as if attempting movement, but lies in any position in which it is placed. 2'' 42™. Symptoms are more marked than at the last report. The animal cannot move trunk or limbs. The eye reflex still persists. No tremor. Breathing rapid. The conditions remained much the same till death occurred in 5 hours from failure of respiration. Post-mortem. Right heart contains much dark blood. No other special appearances. Subcutaneous injection of 6 minims of ethyl-, methyl-, and dimethylbenzene respectively, caused a condition of lethargy which lasted from three to four hours. The animal could be roused at any time. No special motor symptoms were produced, but a certain degree of anaesthesia was observable in each instance. Trimethylbenzene of the same dose caused closely similar symptoms, but terminating in the death of the animal. Dioxyhenzol on Rats. 0*03 grm. of metadioxybenzol, dissolved in five drops of salt solution, injected sub- cutaneously into large Rat. 3™. Shuddering and jerking of body, shaking of head. 9™. Above symptoms much more marked. 12™. Still walks, but very ataxic. B]*eathing accelerated. 18™. Resting on side and back, cannot rise, all limbs in clonic spasm. Abdominal, thoracic, cervical, and facial muscles also contract sharjjly at intervals. No fixed or tonic spasm. 41™. This condition continued until 41™ after the injection, when jerking became less, and the power of spontaneous movement began to return. Washed face and walked a few paces. 51™. Reflex is still rather exaggerated, but spontaneous jerking has almost disappeared. 80™. Quite normal. Doses of 0'05 to O'l were fatal; death occurred from paralysis of the respiratory muscles. The heart appeared to be relatively not much affected, its action outlasting the respiration. (Pyrogallic acid was not examined in this series.) Digitized by Microsoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 601 Amidohenzene on Hats. Eapidly developing weakness, with jerking and marked dyspnoea, is observed. Injected 4 minims into right groin, lo". Tends to sink on belly. Hind legs weaker than fore. IS™. Breathing over 200 per miniite. An occasional start or jerk is noticed. Can still crawl very slowly, but usually lies with legs extended behind it. 57". Is much more affected than the benzene or nitrobenzene Rats. 87™. A good deal of jerking as it lies, both of fore and hind limbs. Much dyspnoea. 107™- Breathing very hurried ; great dyspnoea. 262°i. Quite insensible ; no reflexes. Jerking of limbs at intervals, as 2', 5», 6», 3», 2», &c. Respiration rapid and laboured, 150 per minute. Body not very cold. Breath smells of amidobenzene. 342™. Died. Only very slight twitoh of toes occurred on crimping sciatic. Post-mortem. — Limp ; cortex of kidneys and brain surface congested. Right side of heart very full. Nitrobenzene on Rats. Torpidity, weakness, failure of reflex, absence of motor symptoms. Failure of respiration. Injected 5 minims into right groin. 38™. Runs, but is weaker and somewhat torpid. 53™. Rnns a step or two and falls on side, but soon recovers itself. 83™ Rises with difficnlty if turned over on side. 130™. No marked reflex from body or limbs, but from eye still present. Breathing quiet, not hurried. 258™. More nnder influence of drug. Is now profoundly insensible to all stimulation. Breathing and pulse feeble. Surface very cold. 358™. Breathing slower ; no twitching; no reflex ; quite insensible. 500™. Died. Post-mortem. — Lungs congested. Right heart contracted, also left. Kidneys not markedly hyperesmic (in these respects differs from amidobenzene). SECTION V. ACTION OF AROMATIC BENZENE AND ITS COMPOUNDS ON PULSE, BLOOD-PRESSURE, AND RESPIRATION OF MAMMALS. In all cases ether was the anaesthetic employed during the experiments. This was administered from a bottle which was connected with the tracheal cannula by means of a short tube. By turning the stop-cock (Dr. Brunton's*) with which the bottle was provided, atmospheric air was substituted for ether. The animal was kept thoroughly anaesthetised, but never profoundly narcotised. Aromatic Benzene. Experiments made with this substance yielded fairly similar results. The blood-pressure was for some time but little affected (in one instance slightly increased), and the character of the pulse was not materially altered, although it was considerably reduced in frequency. The respiration showed at first a slight acceleration, but this soon yielded to a * 'Brit. Med. Journal.' MDCCCXCI. B. 4 H Digitized by IVIicrosoft® 602 DRS. T. L. BRUNTON AND J. T. CASH ON THE CONNECTION marked slowing, with a slowly developing and relatively prolonged inspiratory phase. The heart became irregular, with incomplete diastole. As the amount of the drug injected was increased, the respiratory waves became more marked in the blood-pressure curve. Section of the vagi caused a distinct rise of blood-pressure and an acceleration of the pulse. The respiration was reduced to about one-half of its previous frequency. In the experiment which we shall now quote, death took place suddenly after injection of benzene into the intestine. Both vagi had been previously divided, and death was due to cardiac arrest. Cat of 6 lbs. weight. Etherised. Cannulse in Trachea and Eight Carotid Arteries, Both Vagi prepared Loose on Threads. Animal placed in Warm Box. Arrange- ment of Apparatus as usual. Time. Remarks. Pulse for 1 minute. Blood- pressure. Respiration. minutes 10 18 38 43 60 70 75 93 115 120 155 165 175 192 194 205 210 215 230 233 10 minims benzene injected subcutaneously . . 110 112 143 108 132 120 1.S2 110 111 126 118 120 132 120 21 26 15 18 9 20 minims benzene injected subcutaneously Respiratory waves of blood- pressure very exten- sive, causing variation of 9 millims. . 20 minims benzene )) )? Inject 30 minims as before Systole incomplete. Fluctuations owing to respiration irregular. Groups of two or three hurried cardiac contractions may be followed by a somewhat longer diastole Ligature of left vagus causes rise of 22 millims., which persists for few seconds, then a return to previous level Ligature of right vagus causes temporary rise of 19 millims., and a more permanent rise of 6 millims. Stimulation of peripheral end causes fall of 20 millims. Shows great irregularity Opened abdominal cavity, exposed loop of intestine Injected 10 minims benzene into loop of intestine Rapid fall of pressure, heart having stopped. Attempts at respiration continued 3™ after heart had ceased Post-mortem.— The right auricle and ventricle were dilated and full of dark blood. Left ventricle firmly contracted. Lungs slightly congested, but otherwise not abnormal. Intestine very full of flatus; irritable. Stimulation of sciatic nerve gave firm tetanus of gastrocnemius. Digitized by IVIicrosoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 603 Monochlorohenzene. When injected subcutaneously iil an emulsionised condition, monochlorobenzene was found at first to raise tlie blood-pressure and to accelerate the pulse and respira- tion. The blood-pressure remained high throughout the first two hours, during which time one drachm had been injected (in experiment quoted below). The pulse rate was also increased. Some slowing of the respiration was produced eventually. Whilst large doses injected subcutaneously did not produce more marked action, small doses, in a fine state of emulsion, injected into the femoral vein caused cardiac arrest, respiratory efforts outlasting the heart's action. After the injection of this drug, ether appeared in one case to have an unusually depressant action on the heart. MoNOCHLOBOBENZENE. Cat 5 Ibs. Etherised. Cannulse in Trachea and Femoral Vein. Animal in Warm Box. Time. Remarks. Pulse for 1 minute. Blood- pressure. Respiration. minntes 0-20 20 38 60 67 77 85 105 120 125 140 158 172 173 178 183 Injected 20 minims monochlorobenzene (emul- sionised) subcutaneously Injected 20 minims monochlorobenzene If anaesthesia is not profound there is con- siderable tremor of limbs On giving ether, first a fall, then rise, then rapid fall of blood-pressure to 9 millims. Division of both vagi and artificial respiration caused recovery Injected 20 minims as before V 51 >> Clot formed in right carotid which could not be renaoved. Changed cannula to left carotid. Unusual tendency to clotting throughout the experiment Pulse somewhat dicrotic . . Injected 20 drops (emulsionised) into femoral vein Heart ceased Respiratory eilorfc ceased 12.3 132 168 164 134-162 165 181 156 124 116 25 30 22 22 Post-mortem. — Heart. Auricular appendix beating actively. Right ventricle in diastole, smelling strongly of monochlorobenzene. Left ventricle in strong systole. Lungs healthy, contain much mucus, but do not, on naked eye examination, show haemorrhages or infarction. Gastrocnemius contracts well both to direct and indii'ect stimulation. 4 H 2 Digitized by IVIicrosoft® 604 DRS. T. L. BRUISTTON AND J. T. CASH ON THE CONNECTION Monohromohenzene. Like aromatic benzene and monochlorobenzene this substance (monobromobenzene) was found to act very feebly when injected subcutaneously. Administered in this way some increase of blood-pressure with acceleration of the pulse was produced. When injected into the jugular vein, very largely diluted, a small dose of 1 to 4 minims caused a slight rise of pressure if the injection was slow, but a fall if it was rapid. The respiration became greatly accelerated, sometimes irregular and gasping. When the pure drug was slowly injected without dilution, gasping respirations succeeded and ultimately complete paralysis of respiration. Even when the pure drug was employed very large doses were injected before death took place. Death was due, in the experiments made, to failure of the heart. Cat of 8 lbs. Preparation as usual. Injection was made into the Jugular Vein. Time. Remarks. Pulse for 1 minute. Blood pressure. Respiration. minutes (Fig. 21) 144 114 24 25 Injected 1 minim of monobromobenzene, thoroughly emulsified into the jugular vein 60 83 148 111-115 Injected 1 minim as before, but more rapidly. There is a fall of 18 millims. for a few seconds followed by rise of 4 millims. 90 Injected 2 minims, shaken up in 3 c.c. salt solution, slowly. Rise of 3 millims., but if injection was made more rapidly there was at once a fall ... 118 92 Systole well maintained 126 110 46 105 Injected 4 drops a's before, with a fall of pres- sure succeeded by a rise (fig. 22). Respi- ratory curves in blood pressure increased in extent 120 (Fig. 23). . . 144 94 44, rather irregular 130 Injected very slowly 8 drops . ..... . (Injection occupied 9 minutes) ... •• 104 82-92 140 (Fig. 24) 150 Slow injection of 20 minims in 30 c.c. salt solution yields faint rise of pressure succeeded by gasping 155 140 100 162 110 165 Injection of 4'5 minims unsuspended into vein. Succeeded by salt solution. Respiration occasional and gasping. Pause in expiration. 120 minims undiluted in all, injected in 3 doses . .... .... 100-32 175-190 After first dose of 30 minims (fig. 25) .... 131 43 5-6 195 Blood pressure falling, vagi are cut. Rise of pressure for few seconds, and the heart ceases Post-mortem.— Lmgs engorged. Some ecchymosis observed on section. Left heart simply contracted. Right heart dilated. Blood smells much of monobromobenzene. Kidneys congested, bat showed no hemorrhages. Intestine exhibits peristalsis. Digitized by Microsoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 605 a o 56 Pi ri4 o •H a bp s o 00 o .a Ph a pi u n '3 in CM ca a .2 a 0) *-+3 03 QQ ^tn ^ .a 'a. H P Th a g PI c8 4M a ■J '0 Pi o _fl a5 '5 •^ n ^ p; 10 ES3 C4-I j:3 en s a) P5 -^ •M-l rJd O tiD d •g o CQ a • 1-1 P QQ gg a' O ^ ^ I— 1 &0 I— 1 f=l •r-l O o 1 CO sb - « S E-! MDCCCXCI. — B. 4 1 Digitized by IVIicrosoft® 610 DRS. T. L. BRUNTON AND J. T. CASH ON THE CONNECTION ] 6 to 10 per minute. The succeeding injection of 10 minims completely paralysed respiration. The heart continued to beat so long as artificial respiration was kept up, and then failed. Post-mortem. — In case quoted, showed great pulmonary oedema. Action of Dimethylbenzene on Circulation and Respiration. Pig. 32. Quick drum. Time 0. Normal pulse and respiration. Fig. 33. Pulse and respiration 62", Fig. 34. QS^. Vagi not yet divided. Fig. 35. Time 99". The vagi have been divided. Speed of quick drum 31 millims. equal to 5». Digitized by Microsoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 611 ^3 i d o O a o c A a p CD 4 I 2 Digitized by IVIicrosoft® 612 DRS. T. L. BRUNTON AND J. T. CASH ON THE CONNEOTrON Cat of 7 lbs. Dimethylbenzene. Animal in Warm Box to maintain Temperature. Time. Remarks. Pulse for 1 minute. Blood- pressure. Respiration. minutes. (Ma- 32") 192 144 25 16 Injected 6 minims diraethylbenzene into intestine 30 Respiratory waves well marked in manometer . 168 140 20 50 62 136 Very distinct wave in descent has developed itself, though, it was already discernible at 30™ to a lesser extent. (33) 168 131 27 65 Ether causes fall of pressure of 33 raillims. 6V 69 •• 128 Injected 2 minims suspended in 2 c.c. salt solution into femoral vein 70 Rise of pressure of 8 millims. succeeded by fall to such level 76 Rise to . . . . . . 130 11 Injected 4 minims in 2 c.c. salt solution . . , , 104 87 Systole sharp, and shows a second summit in descent of curve 158 120 23 95 121 96 Injected 8 minims suspended in 4 c.c. salt solution 98 Blood-pressnre falls very rapidly (34). Both vagi divided (35) . . 140 64 21 100 Prolonged pause in inspiration. Pressure rises rapidly ... . . 170 . , 10 115 143 116 Injected 8 minims in 4 c.c. salt solution. At once a fall (36) 118 All attempts at respiration over , , 13 123 Artificial respiration raises blood-pressure ; when discontinued, death results. Pulse good till artificial respiration discontinued 50 ■' Post-mortem. — Some very dark blood in right ventricle. A little in the left ventricle. No clots here nor in the pulmonary artery. Lungs congested ; contain much oedematous bloody fluid. Trimethylbenzene (1:2:3). Injected under the skin trimethylbenzene causes at first a slight fall in blood - pressure, a decrease in the number of cardiac contractions, and an acceleration in the respiration. The pulse then tends to quicken as a set-off to the reduced pressure, and the respiration becomes slower. Injections of small doses of the drug (largely diluted with salt solution) into the femoral vein cause a slight decline in blood-pressure, an acceleration of both respira- tion and pulse, but this acceleration is only temporary. The fall of blood-pressure becomes more marked as the amount of the drug in the circulation increases. Section of both vagi, as in experiment quoted, rapidly raises the blood-pressure above its original level, an acceleration of the pulse being well marked. The respira- Digitized by Microsoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 613 tion is reduced to half its previous frequency, the long pause in inspiration characteristic of vagotomy being well marked. After further injections the respira- tion became much embarrassed, a bloody oedematous fluid running freely from the tracheal cannula. After the last injection spontaneous respiration ceased and artificial respiration failed to raise pressure, death ensuing. Cat 8 lbs. Trimethylbenzene. T{me. minutes 15 30 35 53 80 82 90 92 100 122 123 135 140 145 148 Remarks. (Fig. 37) ...... . .... Ether causes fall of blood-pressure Injected 3 minims trimethylbenzene subcu- taneously Injected 30 minims Distinct second summit after active systole of heart ... . (Fig. 38) . . . . • .• • Injected 2 minims in 2 c.c. salt solution into femoral vein Injected 6 minims in 6 c.c. salt solution Injected 10 minims in 5 c.c. salt solution Divided both vagi Indications of second rise in pulse very faint. Long inspiratory pause Injected 10 minims trimethylbenzene in 5 c.c. salt solution into vein. Fall of 18 millims. blood-pressnre. Respiration becomes very laboured. Fluctuations of pressure. Red- tinged oedematous fluid begins to run into tracheal cannula, and secretion of this is soon so rapid that animal threatened with suffoca- tion (Fig. 39, slow drum, shows course of pressure to end of experiment) (Fig. 40) Injected 20 minims trimethylbenzene . . . Artificial respiration fails to raise pressure. Death Pulse for 1 minute. Blood- pressure. 204 180 168 192 162 108 168 180 204 142 142 134 134 112 126 56 158 139 111 110 88-100 12 Respiration. 36 33 48 31 42 33 25 13 12 Post-mortem.— -Right heart in diastole. Left in systole. Lungs are congested and oedematous. There is a soft clot in pulmonary artery. Kidneys are fatty, congested. Digitized by IVIicrosoft® 614 DRS. T. L. BRUNTON AND J. T. CASH ON THE CONNECTION a Si a o .a 1 §-S t^ lO m M Digitized by IVIicrosoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 615 Ethylhcnzene. When injected into a loop of the intestine, which was subsequently returned to the abdominal cavity, ethylbenzene caused some increase in blood -pressure and also acceleration in the speed of the pulse. A prolonged inhalation of ether reduced this high pressure to or below the normal. Small doses, 2 to 3 minims, injected into a vein raised the blood-pressure, but larger ones, 5 minims, greatly reduced it, whilst the respiration became much accelerated. The dyspnoea produced by each intravenous injection soon subsided. Section of the vagi only caused a feeble and gradual rise in blood-pressure and produced a very faint acceleration of the pulse. The speed of respiration was reduced to one-half. The respiration and heart both tended to fail, occasional pauses in the former occurring. A few respiratory efforts were made after the heart had stopped. Cat of 8 lbs., anaesthetised by Ether. Cannulas in Right Carotid, Trachea, and Femoral Vein. Vagi prepared. A Small Loop of Ilium Ligatured and Returned to Abdominal Cavity. Usual arrangement of apparatus. 0". Original blood-pressm-e 1.38 millims. Respirations 14. Pulse 168; there is a considerable pause in inspiration, breathing appeared to be for time altered, owing probably to irritation of vagi. (Fig. 41.) 10™. Injected 10 minims ethylbenzene into loop of intestine. 12". Blood-pressure has risen to 140, but rise rapidly reduced by administration of ether. 17™. Blood-pressure 120 to 149 (great variation owing to respiratory waves). Respirations 18 (assuming a more normal form). Pulse 192. SO". Blood-pressure 137. Injected 10 minims ethylbenzene into ligatured loop of intestine. 36". Fig. 42. 42™. Blood-pressure rose rapidly to 144 millims. Fell slightly and again — 50™- Rose steadily to 14.3. 55™. Ether reduced the pressure rapidly to 117. 62™. Blood-pressure 133. Respirations 13. Pulse 162. 8C™. Injected into femoral vein 3 minims of ethylbenzene, shaken up with 2 c.c. salt solution 8L™. Blood-pressure rose rapidly from 117 to 127, and then fell to 119 gradually; the re pira orj waves being very extensive. (Fig. 46 slow drum.) 87™. Slowly injected 5 minims ethylbenzene, suspended in 4 c.c. salt solution, (c.) 89". Blood-pressure fell rapidly to 62, but soon began to recover itself. Respirations 40. Pulse 144. 91™. Ligature left vagus. Respirations 29. Pulse 144. (Fig. 43.) 94™. Blood-pressure 107. IOC™. Blood-pressure steady 109 millims. (c.) Injected 5 minims ethylbenzene in 5 c.c. salt solution. 102™, Blood»pressure fell to 46. Respirations 28. Pulse 150. The right (remaining) vagus was now tied. 5' after ligature : — Respirations 18. Pulse 160. IIS"^. Blood-pressure only rose very slowly and pai-tially, so that at 115™ it only reached 81 millims. Digitized by Microsoft® 016 DBS. T. L. BEUNTON AND J. T. CASH ON. THE CONNECT] ON Fig. 41. Before injection of ethylbenzene. There is probably irritation of tbe superior laryngeal nerve provoked by preparation of the vagi. Pig. 42. 35™. After injection of 10 minims ethylbenzene into a loop of intestine. Fig. 43. 91". *Ligature of left vagus. Blood -pressure is lovr from the preceding injection of 5 miniins of ethylbenzene. Pig. 44. 115™. After ligature of the second vagus. Fig. 45. 139". 10™ before death. Blood-pressure 42 millims. Speed of drum 31 milliins. = 5^. Digitized by IVIicrosoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 617 13 o d o MDCCCXCI. B. 4 K Digitized by IVIicrosoft® 618 DRS. T. L. BRUNTOJSr AND J. T. CASH ON THE CONNECTION and thereafter declined. Respirations 7. Pulse 150. The respiratory curves became very well marked and persisted from this time to end of experiment. (Fig. 44.) 122". Blood-pressui-e 74 millims. Injected 5 minims ethylbenzene in 5 c.c. salt solution. 128". The succeeding fall has not been so extensive as formerly, it has now reached 52 millims. 130" Respiration ceased for 2", its curves in the blood-pressure of course disappearing. 132". Respiration recommenced. 134". Respiratory curves reinstated. Blood-pressure 40 millims. Respirations 7. Pulse 150. There is a much longer pause in expiration than before at 115". The fluctuation of blood-pressure holds a somewhat different relationship to the respiration, the maximum corresponding closely with active expiration, whereas before (116") there was a much more distinct rise before the inspiratory pause had terminated. 139"- (Fig. 45.) 140". Injected 5 minims ethylbenzene quickly. Fall of pressure very slight, respiration slowed, 145". Blood-pressure 34 millims. 148". 6 minims ethylbenzene injected rapidly caused death in a few minutes. Respiration outlasted the heart's action, Dioxyhenzene, [Resorcin.) (l ; 3.) As in the case of experiments made upon lower animals, we confined our attention to rescorcin M-hen studying the action of metadioxybenzene upon Carnivora (Cats). Brieger ('Arch, f Anat. u. Pbys.,' 1879, Sup.-Bd.) has shown that rescorcin is not only weaker in its action upon Frogs than its isomers, pyrocatechin and hydro- chinon, but that this difference obtains with regard to Rodents. He found that .5 grm. of pyrocatechin was fatal to a Rabbit in 30 minutes, which had survived a dose of 1 grm. of rescorcin administered some days previously. We have carefully examined the action of the drug administered subcutaneously and by injection into the peritoneal cavity. Injection into the Peritoneal Cavity. — For this purpose a 5 per cent, solution was made by aid of warm salt solution. Small doses, '75 c.c, and 2 c.c, had but little effect upon blood-pressure. A slight fall of pressure amounting to from 4 to ] millims. was produced, but from this recovery took place to a considerable extent, though on repeated injection a permanent reduction remained. In 3 hours' time, after 7-75 c.c. had been injected in all (-38 grm., resorcin), the blood-pressure had fallen from 126 to 110, or through 16 millims. only. The pulse was reduced from 156 to 144, but the respiration was not materially altered ; faint twitchings of the thoracic muscles were produced. Section of the vagi caused a marked rise in pressure, accelerations of the pulse and the usual type of slowed respiration. The effects of such small doses were therefore very slight. ; Subcutaneous Administration. — Doses of 1 centigrm.. produced no appreciable effect. After TO grm. had been injected, distinct jerking of the extremities was Digitized by IVIicrosoft® BETWEEN CllElMtCAL CONSTITUTION AND PHYfSlOLOGIUAL ACTION. 619 noticed in 15 minutes, but this jerking was abolished by deepening the ansesthesia. This first injection, after causing a slight acceleration of res|>iratinii, produced a steady Ml of 5 per minute, and reduced the pulse by 34 per niiimte. The blood- pressure fell 14 millims. The jerking which takes place in the muscles of the trunk is itself a factor in producing dyspnoea, as it makes the emptying of the lungs irregular and hinders their expansion. So much is this the case that the rhythm may vary 8 or 10 per minute, according to the depth of aneesthesia. When the animal is deeply narcotised, the respiration becomes slow, though often irregular, with a prolonged pause in inspiration, jerking being abolished, kn acceleration in respiration was observed every time that the anaesthetic was relaxed, whilst the returning muscular contractions greatly interfered with the act. The jerking occurred when the animal was entirely unconscious from the action of the ether, and even when the narcotic action which the drug itself causes had been slightly reduced ; but under the deeper action of resorcin a condition of narcosis occurred, in which jerking was only very feeble. There is little doubt, we think, that ether greatly prolongs life in poisoning with resorcin, by reason of the power it possesses of relieving and steadying respiration. In the experiment we are about to quote, we administered to a Cat of 6 lbs. no less than 3 grms. of rescorcin in the course of 3 hours, and at the expiration of 5 hours, when the experiment terminated, the blood-pressure was still 74: millims. iDioxYBENZENE on Blood-pressure of Cat. Cannula in Trachea. Cannula in Right Carotid Artery. Marey's Tambour on Chest. Ordinary Connection with Mer- curial and Tick's Manometers. ()hQm_ Experiment comraerced. 30™. B]ood-pre.ssTire varies from 120 to 128 millims., and is rather easily reduced by ether. The pulse aveiages 184 and the respiration 42 per minute. (Eig. 47.) 35™. Injected 1 grm. of resorcin dissolved in 20 c.c. salt solution subcutaneously. 48™. Jerking of muscles of limbs and trunk has commenced. Blood-pressure 116 millims. Pulse 180. Respiration, 54. A small clot formed in the cannula immediately after taking the tracing. 60™. Blood-pressure 113. Pulse 172 (fig. 48). Respiration about 60, but, owing to jerking, estimation is diflScult. Urine passed, bat has no abnormal odour. Jerking easily subdued by ether, and respiration reduced to 40. (Fig. 49) 67™. Blood-pressure 110. Pulse 156. Respiration 36. 82". Pulse 156 ; appears to be unaltered by ether, whilst jerking abolished and respiration slowed by it. -110™. Blood-pressure 102. Pulse 150.' Respiration 37. J13™. Injected 1 grm. of resorcin in two places as above. 128™. Jerking very powerful, but disappears when deeply anaesthetised. Blood-pressure 96. 150™. Blood-pressure (94) is very steady, except for gradual tendency to fall. 160™. Pulse 146 per minute. 175™. Injected 1 grm. of resorcin in two places as above. 4 K 2 Digitized by IVIicrosoft® 620 DRS. T. L. BRUNTON AND J. T. CASH ON THE CONNECTION 183". Blood-pressure 95 millims. Pulse 140. Respiration 40, irregular. 19.5™. Blood-pressure 90. Pulse 108 (fig. 50). Respiration 30; pause in inspiration. At this time the temperature in the rectum was reduced to 29°-5 C, though the laboratory was warm and the animal had been kept carefully covered by cloths. 210". Though ether has been suspended for 20 minutes, the animal is completely narcotised ; muscular jerking has greatly diminished. No clotting has occurred for nearly three hours. The respiration is superficial. Pulse 108. Pressure 84 millims. Powerful sensory stimulation of sciatic nerve causes a rise of blood-pressure of 4 millims., but on second application had no eSect. ?45°>- Blood-pressure 76. Pulse 108. The respiration is feeble, and is still marked by the twitchinga of thoracic muscles. 270"- Pressure 74. Pulse 96. Respiration very irregular. (Fig. 51.) '475™. Both vagi divided. 278". Pressure 66. Pulse 90. Respiration 14, extremely feeble and failing. 285". The experiment was now terminated. Trioxybenzene. (1:2:3, Pyrogallol.) As this is a soluble salt, no mechanical diflBculty was found in its administration. A 10 per cent, freshly-prepared solution was employed, and the desired dose of this was largely diluted with salt solution, for the purpose of subcutaneous or intravenous injection. Subcutaneous injections of "065 grm. were not succeeded by any great change in pulse or blood-pressure beyond a slight slowing of the former and fall of the latter. The respiration, however, was distinctly slowed. Intravenous injections of amounts varying from 'OSS to "065 slowly made into the femoral vein, were i-apidly succeeded by a marked rise of 6 to 13 millims. of pressure ; this rise, after persisting for 2 to 5 minutes, was followed by a fall to the previous level. The cumulative action of the drug was shown by a gradual, but steady, fall of pressure after a total dose of "12 grm. had been injected. Larger doses of "4 and "6 grm., well dilated and slowly injected, caused also a rapid rise of pressure ; but this rise quickly reached its maximum, and the pressure fell much below the previous level. During this fall respiration was very slow, a long pause in expiration being succeeded by a rapid and incomplete inspiratory movement. The heart beat only at the rate of 19 per minute for some time after the large injection ; the systole was sharp, and succeeded by what appeared to be a second feeble contrac- tion passing into a prolonged diastole. As the immediate effect of the drug passed off, this second cardiac effort developed still further, so as to give a bigeminal character to the pulse, and gradually the previous rhythm was restored. After 1*252 grm, in all had been injected, in the experiment quoted, the blood-pressure gradually fell, the respiration declined and ceased simultaneously with cardiac action. Digitized by Microsoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 621 Action of Dioxybenzene. 1 : 3. Resoroin. Fig. 47. Before injection of Resorcin. Fig. 48. Time 60™. I grm. of Resorcin injected 25"" previously. Fig. 49. Time SS". Deep anaesthesia. Fig. 50. Time 195™. Three grms, of Resorcin have been injected. Fig. 51. Time 270*". Speed of drum, 64 millims. = 5^ Digitized by IVIicrosoft® 622 DRS. T. L. BRUNTON AND J. T. CASH ON THE CONNECTION Cat of 7 lbs. Ether was used as an Anaesthetic. Animal placed in Warm Box. Cannulas were placed in the Right Carotid, Femoral Vein, and Trachea. Immediately after placing the animal in position the Heart suddenly failed, though but little Ether had been given, and Pressure fell from 134 to 22. Artificial Respiration restored Animal. Time. Remarks. Pulse for 1 minute. Blood- pressure. Respiration. minutes 17 35 50 62 73 76 80 82 90 105 110 112 115 118 122 124 130 135 142 146 150 158 179 (Fig. 52) . ;. Injected 10 minims of a 10 per cent, solution of trioxybenzene Much tremor of hind legs Blood-pressure risen under ether. Respiratory blood-pres.sure waves become very large Injected 2 minims diluted with 2 c.c. salt solu- tion. Rise of 5 niillims. in the pressure Injected 5 minims, 10 per cent, solution Blood-pressure risen 6 milHms., falls rapidly to former level Clot far down in right carotid artery. Insert cannula into left carotid. (15™ lost) Injected 10 minims of a 10 per cent, solution as before (fig. 63) Both vagi divided. No rise of blood-pressure (fig. -52) Injected 10 minims of a 10 per cent, solution as before (fig. 54) Injected "1 grm. in 3 c.c. salt solution. Rise of 16 minims, succeeded by fall ..:... Injected '4 grm. in large solution- (fig. 54, d^) . Pressure begins to rise again Injected "6 grm. trioxybenzene (fig. 54, cZ"^) . (Pig. 55): '.'.'.''.'.'.'.'.'.'..'. Heart stopped. For some time before death there was no indication for ether 180 158 181 166 156 150 157 156 165 I9I73 168 124-130 121 102 94 102 93-106 84 96 64 76 76-82 51 79-22 36 23 32 24 15 24 23 19 17 19 23 3-6 11 Post-mortem.— Lungs pale. Heart in diastole; on cutting much dark blood escaped and ventricle commenced active vermicular movement. Intestines pale, peristalsis active. Kidneys congested. Digitized by IVIicrosoft® BETWEEN CHEMIOAIj CONSTITUTION AND PHYSIOLOGICAL ACTION. 623 c3 a o g C3 o u d a 2 o i-H 1=1 bo iration. Benzene and the Halogen Compounds. An alteration of respiration was an early effect of the drugs. This acceleration has been observed to vary in degree with the different bodies. Intravenous injection of aromatic benzene caused a slight acceleration, but ulti- mately a great slowing of respiration, whilst subcutaneous injection caused from the first a steady decline. Monochlorobenzene produced a very decided acceleration of respiration by whichever way administered, followed by slowing, and in all the experiments made, respiratory arrest was not the immediate cause of death. Mono- bromobenzene caused also marked respiratory acceleration in the first instance and then depression, but the respiratory movements outlasted cardiac systole. Monoiodobenzene was not so active in causing acceleration, nor was the retardation of respiration by any means so marked as with the other halogen compounds. In all cases the greatest acceleration occurs after intravenous administration. The Compound Benzenes possessing Alcoholic Radicles. Methylhenzene, whether by intravenous or hypodermic administration, accelerates the respiration in the first instance and then slows it. Pulmonary, oedema was induced probably from capillary embolism caused by the compound in the lungs. Dimethylhenzene acts powerfully also on respiration. A short period of slowing followed intestinal absorption of the drug, then an acceleration, and ultimately, however administered, the respiration became greatly slowed. Pulmonary oedema tended to occur after intravenous injection, but artificial respiration was capable of prolonging life, the heart beating moderately well after all natural attempts at respiration ceased. Trimethylbenzene, by intravenous and hypodermic injection, produced an accelera- tion of respiration, then a slowing which was still further increased after vagotomy. Death occurred here also from pulmonary oedema and arrest of respiration. Mhylbenzene likewise accelerated respiration, and this to a considerable extent when intravenous injection was made, though recovery towards the normal tended to occur soon afterwards. The heart, however, failed before respiration. Hydroxyl Compounds. Dioxybenzene (Besorcin). — Hypodermic administration slightly slowed the respira- tion ; dyspnoea was produced, apparently as a result chiefly of jerking of the thoracic muscles, which the drug induces, as it is to a great extent removed by deepening the Digitized by IVIicrosoft® BETWEEN CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. 631 anaesthesia. A marked slowing of the respiration was ultimately caused by resorcin. Tha T'espiration tended to cease somewhat before the heart. Pyrogallol. 1:2: 3. — Appeared from the first to slow respiration, this retardation being specially marked after intravenous injection. A tendency to an expiratory pause was observed. Respiration ceased simultai-»eously with the heart. Amidobenzene caused some acceleration of respiration with changes in its character, succeeded by a decided slowing. The respiration was greatly reduced by double vagotomy. Feeble respiration occurred during fall of pressure, and thoracic movement slightly outlasted cardiac contraction. Nitrobenzene did not greatly affect respiratory rhythm, though ultimately some slowing with long pauses in inspiration supervened. Double vagotomy caused a marked slowing, but on further injection the respiration again became rapid and outlasted the pulse. Some oedema of the lung was found after death. Pulse and Blood-pressure. Aromatic benzene produced in the first instance but a slight effect in the direction of raising the blood-pressure and slowing the pulse, with a tendency to irregularity and incomplete systole. Section of the vagi was followed by a rise of blood -pressure with' cardiac acceleration. Death was due to cardiac arrest. The Halogen Compounds. Monochlorobenzene showed considerable activity in the earlier part of its action, in raising the blood -pressure and accelerating the pulse. Cardiac arrest was the cause of death. Monobromobenzene in small doses subcutaneously, and in small doses slowly injected into veins, caused an elevation of the blood-pressure with some acceleration of the pulse. Both these effects were weaker than after monochlorobenzene. Rapid injection of even a small quantity occasioned a marked fall in the pressure. Death "was due to cardiac arrest. Monoiodobenzene caused marked cardiac acceleration of the pulse after intestinal administration, the pressure also rising. An increase of pressure and pulse rate was produced by vagal section. Death was due to cardiac failure. Methylbenzene, — A marked acceleration of the pulse with a rise of pressure resulted from the earlier action of this drug. Large doses reduced both and rendered the pulse irregular. The pulse was accelerated by vagotomy. Cause of death, pulmonary oedema. Dimethylbenzene. — Whilst intestinal injection of this drug reduced the pressure to a slight degree, intravenous injection of the emulsified body in very small doses Digitized by IVIicrosoft® 632 ON CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION. produced a very slight rise of pressure, whilst doses of 4 minims and upwards, even freely diluted, caused a marked fall. Larger injections reduced blood-pressure, but the heart outlasted respiration. Trimethylhenzene. — Small doses, both by hypodermic administration and intravenous injection, slightly reduced the pressure, whilst an acceleration of the pulse was observ- able. The pulse by the former method was slowed, by tke latter somewhat accelerated. Section of vagi raised pressure and accelerated the pulse, after the period of depression had been produced. This appears to be the most active of the methyl compounds. Ethylhenzene. — In small doses, both by intestinal and intravenous administration, this drug caused an elevation of blood -pressure and acceleration of the pulse. Large doses produced a rapid fail of pressure with slow recovery. This effect was to some degree central, as division of the vagi caused some rise and acceleration. Dioxyhenzol {Resorcin). — Caused some- fall of pressure and slowing of pulse, but neither effect well marked except with very large doses. A great slowing of the pulse ultimately ensued. Pyrogollol. — Small doses to some extent reduced pulse and blood-pressure. Injec- tions were succeeded by a rise, which suddenly gave place to a considerable fall from which recovery was comparatively slow. The pulse became very slow, of irregular rhythm and peculiar form. Amidohenzene [Anilin). — From the subcutaneous cellular tissue and the stomach this compound produced a slowly developing fall of pressure, the heart being slowed. Intravenous injection, however, caused a rise of pressure if the dose was only a small one, 1-2 minims. After a single large dose, or repeated small doses, a great fall in pressure took place. Nitrobenzene. — Small doses caused a fluctuation in the blood-pressure usually in the direction of a fall. Large doses greatly reduced the pressure and slowed the pulse. Section of the vagi during the effect caused a rise and acceleration, but further injection caused a fall and slowing. Death was from cardiac failure. Digitized by Microsoft® Digitized by IVIicrosoft® Digitized by IVIicrosoft® Digitized by IVIicrosoft® ■''■■^ -■! ', tX^v V*>?."'K ■«*^if^^''. v>. >, j*^^ ^^^> '^'"" ^*^."i ^:^..^^^ ^^fe^-,^.^-' - :5;r^'^"T''^^ k 1 « -^ . -f --I ' '( ' V^>^■■■>■-" i ■_|;i .'i 4 -* W.-.s .•••'([i.f ■>.?< d^Hl""' ■^i ';'ii if ',5V-' ?'..^: •'. ..%' >' «►,>•*