Oct. 26, 1372.]
`
`THE BRITISH MEDICAL '}0UR.YAL.
`
`457
`
`LECTURE
`
`THE !\NT.«'\C}OZ\'lS.\I BET\l’EEN THE ACTIONS OF
`ACTIVE SUBSTANCES.
`
`.Dt’l2':w't‘rz’ [u;{}>"¢' Z.-it Ifiiyal C0//cgt‘ 0}’ I’/:yJ':i‘r'rms', Er/:':rdrrr;g}t.
`DY
`
`T}IO.\l.5LS R. FRASER, i\I.D., F.R.S.E., F.R.C.l‘.E.
`
`LECTURE II.
`
`I was honoured by the
`MR. PRESIDENT AND GENTLEMEN,—wh€n
`request to bring under your notice some subjects bearing upon pharma-
`cology, I found myself placed in the difficult position of having too
`many good things to choose from. Vllithin my reach were the fruitS—-
`seldom altogether ripe, but without exception temptingly attractive—of
`numerous investigations, conducted both in this country and abroad, in
`the field of pharmacological research. At my disposal, also, were the
`methods by which these fruits had been cultivated—-the refinements of
`experimentation, and the mechanical appliances by whose aid, within
`recent years, results of surpassing beauty and interest have been ob-
`tained, and much progress has been made in the establishment of a
`sound basis for therapeutics. The consideration of either of these sub-
`jects, however, would have required much more time than could be
`found within the limits of two lectures.
`It was for this reason that I
`selected two subjects that admit of briefer discussion, while at
`the
`same time they possess a sufficiently independent interest to allow of
`their being treated apart from the general subject
`in which they are
`included.
`Dt_'fim'r.r'u:: of .r-l;n'.:g'o:::3rrrr.~—The connection between the chemical
`properties and the physiological action of active substances occupies a
`position on the border-land of pharmacology, for it
`is placed between
`pharmacology and one of the sciences most
`intimately related to it.
`The subject which I propose this evening to bring before you is placed,
`on the contrary, in the centre of this region, seeing that it is chiefly
`concerned with the relationships that exist between different groups
`of well defined pharmacological facts.
`Presupposin a definite knowledge of the modifications produced in
`normal physio ogical conditions by a certain number of active sub-
`stances to have been ac uired, antagonism is concerned with the
`opposing intlucnce which tclte action of one or more of these substances
`is able to exert upon that of any of the others—with the opposing
`actions, for example, of morphia and atropia on the pupils and minute
`blood-vessels, of rnorphia and quinia on the circulation, of prussic acid
`and atropia on the vagi nerves, and of physostigma and atropia on
`the iris and on visual accommodation. When several of the actions of
`one substance are counteracted by those of another,
`the antagonism
`becomesamore general one than in the examples I have cited; and
`when, among the different counteracting actions that occur in general
`antagonism, there are included any by which the fatal effect of one or
`other of the substances is usually produced, the one substance may act
`towards the other as a physiological antidote.
`thing from
`Physiological antidotism is,
`therefore, a very different
`chemical antidotism.
`In all probability, however, the origin of the
`one may be referred to the same cause as that of the other. Soon after
`it become known that injurious elfects follow the introduction of cer-
`tain substances into the system, attempts were naturally made to remedy
`these elfects, and also to discover counteragents or antidotes to the
`hurtful substances. The success attending these attempts was of
`necessity closely related to the existing state of lmowleclge regarding
`the physiological action and the physical properties of active sub-
`stances. When the effects of poisons were referred to supernatural
`manifestations, it was chiefly charms and superstitious rites that were
`-trusted to as protectives and remedies.‘ At a somewhat more advanced
`period in the progress of human knowledge, vague notions of physiolo-
`gical laws and processes supplied the indications of curative treatment ;
`and bezoars, alexipharmics, Mithridates, and theriacze, were employed
`almost indiscriminately as universal antidotes. Still later, chemistry
`suggested that, as the physical properties of poisons may be modified
`by various reagents, so may their effects be prevented by the adminis.
`tration of suitable substances.
`The recommendations derived from chemistry were at first only of
`
`the crudest description; but, as the science advanced. many valuable
`hints were obtained. and now the class of the chemical antidotes in-
`cludes a large number of efficient counteragents to poisons. Their
`operation, however, appears to be limited to the chemical changes which
`they produce on the poison while it remains in the alimentary canal.
`As soon as the poison becomes absorbed into the blood, it seems to
`pass beyond the autidotal influence of the chemical couuterpoison; for
`no example exists of :1 chemical antidote neutralising a poison after
`absorption. This may be explained by the fact that the chemical unti-
`dotes known to us are never sufficiently stable bodies. Their affinities
`are numerous; and so. after their entrance into the blood, they dissi-
`pate the chemical energy on which their value depends by forming
`combinations with the elements of the blood and tissues, in- place of
`tra is
`.
`respryilng that energy until
`the absorbed poison is reached and neu-
`Reprm-if ¢E'xnn:,g}fe:.—-In order perfectly to neutralise the injurious
`etfects that follow the introduction of active substances into the living
`economy, it would appear to be necessary that the physiological func-
`tions of the affected organism should be modified. The early though
`undoubtedly crude notions that originated the employment of alexi-
`pharrnics, Mlthrldates, and theriacae, to a certain extent recognised this
`principle. The two latter of these compounds contained opium, along
`with an immense number of other ingredients; and so their indis-
`criminate employment as antidotes may have led to the first sug-
`gestion, or at least to one of the earliest applications, of an antagonism
`whose recognition dates from a remote period of medical history.
`I
`refer to the antagonism between opium on the one hand, and bella-
`donna, hyoscyamus, and strumonium, on the other. One of the
`earliest records of a belief in the existence of this antagonism is to be
`found in the S.-‘:‘r;)i':rn: A:{:*rr.mr:'rr Ab:-n, published in 1570 by Pena and
`De Lobe], where the statement is made that some Italian pedlers, who
`gained much notoriety by employing the root of the belladonna-plant
`to quench thirst, were in the habit of administering opiates to remedy the
`evil effects that occasionally were thereby produced. Tracing the his-
`tory of this antagonism down to the present time, we find. that during
`the seventeenth and eighteenth centuries, and at the commencement
`of the present century, several cases were reported, more especially by
`Horstius, Faber, Boucher, and Jose h Lippi, in which opium was ad-
`ministered with apparent benefit in t ie treatment of poisoning by bel-
`ladonna. Within more recent times, many modern authors, as Angelo
`Poma, Anderson, Cazin,
`I3en'amin Bell, Behier, Lee, Norris, and
`Constantin Paul, have publis ed evidence, derived from cases of
`poisoning in man, that appear to favour a belief in its existence.
`I need scarcely point out
`that evidence of this kind is usually sur-
`rounded by numerous causes of fallacy.
`It
`is not surprising, there-
`fore, that observers of such recognised ability as Drs. John Harley and
`L. Orfila should have come to the conclusion, after a careful examina-
`tion of the record of each case, that the evidence derived from clinical
`experience is insufiicient to establish the reality of this nut
`onism ; or
`that Dr. Fraignlaud and others should besides assert that t e associa-
`tion of opium with belladonna, in place of producing a diminution, pro-
`duoes an increase. of the toxic power of both substances. For my
`part, I feel inclined to believe that, while the existing evidence is in-
`sufficient distinctly to prove that opium is able to prevent the fatal.
`efiect of belladonna, hyoscyarnus, or stramonium, or these latter sub-
`stances that of opium, it is still sufficient to render it extremely probable
`that a general antagonism does really exist—- to the extent, at any rate,
`of the primary lethal action of morphia being preventable by the phy-
`siological action of the other substances whicn I have named. A
`properly devised series of experiments would in all
`likelihood justify
`the opinion of those who, with no little courage, have practically
`allirmed their belief in the existence of this antagonism.
`The rapid development of pharmacology has led to the acquisition
`of definite knowledge regarding the manner in which many active
`substances influence the physiological condition of vital structures;
`and it has been found that the modifications produced by certain of
`these substances are of an opposite kind to those produced by others.
`In this way the existence of many instances of localised antagonism—-
`to several of which I have already alluded—bave been established.
`The study of pharmacology has likewise led to the difierentiation of
`the special structures by the modification of whose physiological condi-
`tions the lethal action of poisonous substances is
`roduced.
`In a few
`instances, it has been shown that the nature of tlie modification pro-
`duced in the physiological condition of the structure or structures in-
`volved in the lethal action of one substance, is apparently contrary to
`that produced on the same structure or structures by the physiological
`action of another substance. The establishment of such facts has led
`to the suggestion of various instances of antagonism, in which it is sup-
`posed that the lethal action of one substance may be prevented by the
`
`1 of 3
`
`Alkermes, Ex. 1041
`
`

`
`453
`
`THE BRITISH MEDICAL ji“0URNAL.
`
`[Oct 26, 1872.
`
`i‘roi-niiient among these are the anta-
`physiological action of annth er.
`gonism between the lethal action of prussic acid and the physiological
`action of atropia, and that between the lethal action of muscaria and
`the physiological action of atropia. The elaborate researches of Preycr
`and of Schiniedeberg and lioppe proved that both prtissic acid and
`muscaria increase the excitability of the vagi nerves, and in this way so
`seriously affect the cardiac and respiratory functions, that death results
`when sufficiently large doses are given.
`Previous investigator-:.—morc
`especially Von Bczold and Bloebaurn—had already discovered.
`that
`atropia exerts an action that is in a remarkable mariner contrary to that
`of these substances ; for it paralyses the cardiac inhibitory fibres of the
`vagi, and likewise the tei'rniti:I.lions of these nerves in the lungs, and
`thus accelerates both the cardiac and respiratory movements. Guided
`by these facts, I‘reyer made a. few experiments which strongly support
`the opinion at which he has arrived.
`that atropia is a physiological
`antagonist to priissic acid, even to the extent of being able to prevent
`the primary lethal action of that poison; while Schmiedeberg and Koppe
`have made several experiments which induce them to believe that the
`lethal action of niiiscaria may be counteracted by atropia.
`In addition to these, many other examples of general or of lethal an-
`tagonism have been advanced. Their existence, however, has rarely
`been inferred from a knowledge that the substances concerned influ-
`ence the same structures in contrary modes, but has been conjectured
`from a knowledge of merely the general phenomena that are produced
`by these substances. The conspicuous spasmodic effects by which the
`action of stryclinia is characterised appear to have suggested the em-
`ployment, as physiological counteragents. of various substances whose
`eneral action includes the production of paralysis; and accordingly
`t ie list of proposed antagonists to this alkaloid embraces opium, curara,
`aconitia, nicotia, bromide of potassium,
`chloroform, chloral, and
`nitrite of amyl. Opium and quinia have been proposed as antidotes to
`each other, on the supposition that
`the former exalts several of the
`organic functions, while the latter depresses them; and the physiolo-
`gical actions of iodine and bromine are said to neutralise each other,
`because the former substance produces sedation, and the latter excita-
`tion, of certain general functions.
`Among these examples, there are several worthy of further examina-
`tion ; and it is not impossible that their existence may thereby be esta-
`blished. Meanwhile, the criticism of the Professor of Therapeutics at
`Paris, in reference to the majority of recorded examples of antagonism,
`appears to be a just one—that “la precision fait souvent defaut dans
`Panalyse des faits, les inductions manquent de rigueur, et la pratique
`attend de nouvelles lumiéres de la part de la physiologic expérimentale
`et de la thérapeutique rationnelle."
`CJ'i:}y'Fm’!a:i‘¢-r fr: bi: }’~.'r'.r'ii'.'.ur.-: .-'t;;r.2iui':‘::‘.;i I/rc Ea-irfciirr ry'A;i!a_grn;:i’.~.vr.
`—This absence of precision may, I believe, with peculiar justice, be
`said to characterise the evidence by which the existence of such general
`antagonism as enables one substance to prevent
`the lethal action of
`another has been supported.
`In nearly every instance, too much weight
`has been placed on a mere modification, or it may be amelioration, of
`the symptoms, while the establishment of the fundamental fact of these
`symptoms being the result of a lethal dose has not been sufficiently
`attended to.
`
`ivlielher, from clinical observation alone, a sufficient
`It is doubtful
`degree of precisimi can ever be obtained. Not only are there ciifficulties
`in the way of discovering what dose of poison has been introduced into
`the system, but even when this dose is ascertained, it is generally im-
`possible to feel assured that
`it
`is a sufficient one to produce death.
`And, further, the effects of the substance administered as a. physiological
`antidote can rarely be accurately observed. The exigencies of treat-
`ment demand that every likely method of alleviating the symptoms
`should be applied ; and, among the various remedial measures that are
`almost always applied,
`it
`is difiicult,
`if not
`impossible,
`to discover
`accurately the effects of any single antidote.
`fl’.-iw tit’-.-rr firrfarfrr .-my far as-oi'rfcif.—The only method whereby the
`existence can satisfactorily be proved of an antagonism, so perfect as
`that which enables one substance to prevent the fatal effect of another,
`is by experiment on the lower animals.
`It is not necessary for me to
`attempt to show that the fallacies asserted to exist in such experiments
`have been greatly exaggerated, or that the supposed dilferences between
`the results obtained in man and in the lower animals do not possess the
`importance that has been claimed for them, as, fortunately, nothing re-
`mains to he done in this direction since the convincing arguments of
`Claude Bernard have been advanced and generally accepted.
`23)’ lestlng the existence of antagonism by experiments on the lower
`animals, the most
`important of the causes of fallacy to which I have
`all uded may readily be avoided.
`In any given species of animal, it
`is
`a simple matter to determine be minimum dose of an active substance
`that can produce death, and the
`to test the antidotal influence of its
`
`supposed. antagoiiist after the administration of a.I1_u11_doI.tl.)tedly lethal
`dose of the poison.
`In this manner, the most convincing proof may be
`obtained of an aiilidotal
`influence; and, inspired with the confidence
`that
`is
`thus gained, the practitioner may with propriety employ the
`antidote in cases of poisoning in man.
`Tflv .-fmfrrl-;r=:r.".rm ifirfrumrz Afroprir mm’ P/l_t'.rn.r{{;rmrr.—A plan of this
`kind was followed in a research which I lately undertook on the anta-
`gonism between atropia and physostigma. The experiments were chiefly
`performed on dogs and rabbits, to whom the substances were administered
`by subcutaneous injection; and their rnain purpose was to determine
`whether the fatal effect of physostigma can be prevented by atropia.
`Home of the results seem of sufficient interest to justify me in bringing
`them before you at this time.
`In order to iihistrate the elTects that are produced by physostigma
`alone, let me, in the first place, describe the symptoms that occur when
`a lethal dose of the extract of this substance is given to a rabbit.
`Soon
`after such a dose is administered, unfrequent and slight twitchings take
`place over the surface of the animal, and then movements of the
`mouth and lips occur, as if an accumulation of saliva were being re-
`moved.
`In the course of a very few minutes, there is evident difficulty
`in going about ; gradually, still" extension shows itself in the anterior,
`and then in the posterior, extremities ; and thereafter the animal stumbles
`about, or stands shaking with the body elevated on the extended
`limbs.
`In a short time, the extended state of the limbs is succeeded by
`their partial paralysis; great weakness, accompanied with constant
`tremblings, is present ; fluid escapes from the mouth, and soft and pul-
`taceous faeces are passed at frequent intervals. The respirations be-
`come infrequent and laboured, and the heart‘s contractions diminished
`in their frequency and force; while the pupils contract below their
`normal size.
`Soon afterwards, the respiratory rnovenients assume the
`character of more laboured gasps, the pupils still further diminish in
`size. and general weak tremors succeed each other; while the flow of
`saliva, the discharge of semi-liquid fceces. and the incessant fibrillary
`twitches of the surface continue. By and by, it is a matter of difficulty
`to distinguish any respiratory movement or cardiac impulse, and they
`soon altogether cease on the occurrence of death.
`Such a train of symptoms is usually produced by a dose of physo-
`stigma representing the smallest quantity that can kill a rabbit, and
`this event occurs in from twenty to thirty minutes. Let us now see
`how the effects of a considerably larger dose may be modified by
`atropia.
`A rabbit received, by subcutaneous injection, a dose of extract of
`physostigma considerably greater than the minimiirn-lethal; and one
`minute and a half afterwards it received, also by subcutaneous injec-
`tion, half a grain of sulphate of atropia.
`In three minutes after the in-
`jection of atropia,
`the pupils measured {-5 x 3;-,t,ths of an inch, the
`measurement immediately before the experiment having been {,3
`it
`—,"_—,ths.
`In seven minutes, the pupils measured 1,3 X -}_,":tlis, the rate of
`the heart's contractions was considerably accelerated, fibrillary twitches
`were occurring, and 9. little restlessness was present. Soon afterwards,
`the pupils became still more dilated, and the animal had some (lifti-
`culty in moving about.
`In twenty-five minutes, this difticulty had be-
`come greater—even to such an extent, that often the anterior extremi-
`ties yielded, and the rabbit fell on the thorax.
`In fifty-two minutes,
`the pupils measured gg x J5,i,ths of an inch, but no obvious change had
`occurred in the general condition of the animal.
`In one hour and ten
`minutes, however, evidences of recovery were manifested; the rabbit
`went about with but little difficulty, and frequently a perfectly normal
`sitting posture was assumed.
`Indeed, the only symptom of an abnormal
`character that was now apparent consisted of frequently occurring and
`well marked fibrillary twitches. From this time the condition of the
`animal steadily improved, until perfect recovery occurred.
`Prelimiiiary experiments had satisfied me that the dose of pliyso-
`stigma extract given in this experiment was at least twice as large as
`the minimum-lethal. Yet the fatal effect of this large dose was pre-
`vented in a remarkable manner by the dose of atropia that was given
`in conjunction with it. To add to the proof that was thereby obtained
`of an antagonism between these two substances, I administered to this
`rabbit, nine days afterwards, a dose of extract of physostigrna only one
`half as large as that from which it had thus recovered.
`Symptoms of
`poisoning very quickly appeared, and death occurred in about four-
`teen minutes.
`
`In another experiment on a. rabbit, which I shall briefly describe, a
`lethal dose of sulphate of physostigmia was allowed to exert its action
`for a longer period than in the last. experiment, before a dose of sul-
`phate of atr_opia was administered.
`Previously to the administration of
`the pliysostigmia, it was found that the average rate of the cardiac con-
`tractions was 38, and that of the respiratory movements 22,
`in ten
`seconds; and that the pupils measured —;--3,-ths by -'3-fltlis of an inch. Fif-
`
`2 of 3
`
`Alkermes, Ex. 1041
`
`

`
`Oct. 26, 1872.]
`
`THE BRITISH MEDICAL _‘?0URNAL.
`
`459
`
`teen minutes after the lethal dose of sulphate of physostigmia. had been
`given, the rabbit was lying on the side, and saliva was flowing copiously
`from the mouth ; unfrequent,
`laboured, and noisy respirations were
`occurring; the cardiac :5:-ntractiotts were extremely feeble, and at
`the
`rate of only nine in ten seconds; and the pupils had contracted to
`.,‘,,ths of an inch.
`In fact,
`the animal was at the point of
`
`A marvellous change, however, was quickly produced by the ad-
`ministration of sulphate of atropia. Two minutes after seven-tenths of
`a grain of this substance had been injected under the skin, the 1'espir:t-
`tions were occurring at the rate of 18 in ten seconds, while their cha-
`racter was nearly normal; and the cardiac contractions were strong,
`and at the high rate of 50 in ten seconds, the rate before the antidote was
`given having been only nine in ten seconds.
`Soon afterwards, the pupils
`dilated and the flow of saliva ceased ; and, by and by, the attimztl again
`turned from the side, raised the body on the limbs, and then assumerl
`a perlectly normal posture.
`It was shown that the dose of sulphate of
`physostigmia from which this animal had recovered was a lethal one,
`by administering to it, several days afterwards, a dose of equal size,
`without any atropia. The usual symptoms of physostigma-poisoning
`were thereby prutluced, and death occurred in sixteen minutes.
`I have said that the antagonism between atropia and physostigma
`was tested in dogs as well as in rabbits, and in order to illustrate the
`nature of this antagonism in the former animal, it may be proper to
`give a few details of one of my experiments. An active young Scotch
`terrier dog, weighing ten pounds and three ounces, received, by subcuta-
`neous injection, tliree-Iifths of agrain ofsulphate ofphysostigmia, dissolved
`in a few drops of distilled water. Before the injection, the rate per ten
`seconds of the cardiac impulses was 32, and that of the respirations 4,
`and the size of the pupils, in a full light, was If, x -1_-:‘-,ths of an inch.
`In four minutes after the commencement of the administration, slight
`tremors occurred, and fibrillary twitches were present.
`In five minutes,
`a. solution containing three-tenths of a grain of sulphate of atropia was
`injected under the skin.
`In two minutes thereafter, the tremors already
`noted had become more prominent and strong, the limbs were unable
`properly to support the body, saliva escaped from the mouth, and the
`eyeballs were unnztlurally moist.
`In five minutes,
`the pupils were
`greatly dilated, but now the secretions of the salivary and lacrynral
`glands were (liminisltetl.
`In seven minutes, the dog lay quietly on the
`abdomen and thorax ; and in thirteen minutes it fell over on the side.
`An endeavour was made to count the cardiac impulses, but, when the
`hand was placed. over the heart, the tremors 1'eferred to became so
`greatly increased that it was impossible to distinguish the heart's im-
`pulse.
`It was not until thirty-eight minutes, that an attempt
`to count
`the heart's contractions was successful, and then it was found that
`the
`impulses occurred at the rate of 45 in ten seconds. At the same time,
`the respimtions had a rate of 7 in ten seconds, and the pupils measured
`X ,1_fit|:.-: of an inch.
`In forty-eight minutes, the condition of the
`dog had so far improved that, after some elforts, it rose on the limbs,
`and then lay down in a normal crouching attitude, with the head
`raised.
`Soon :'tfter\\':tt'd.~:,
`it again got up and walked about the room,
`with only :1 little unstcadiness.
`In one hour and fifty-five minutes, the
`animal
`:i£.‘t.'t1'lCtl
`to be perfectly well. On the following day, the dog
`was active, and in a perfectly normal condition. Nineteen days after
`the performance of this experiment, the same dog received, by sub-
`cutaneous injection, a dose of sulphate of physostigmia, only one-half
`as large as that from which it had recovered when atropia was also
`giyen ; and the result was that death was produced in twenty-two
`mmtJtes.*
`
`Gentlenicn, the details of these three experiments will serve, I trust,
`to convince you that atropia exerts a powerful counteracting influence
`upon the lethal action of physostigma.
`I am glad to be able to state
`that several cxperirnents bearing on this antagonism have been per-
`formed by Dr. llourneville of Paris, which have led to equally satisfac-
`tory results. The experiments which I have brought under your notice by
`no means represent
`the amount of evidence that may be advanced in
`support of this antagonism ; for results similar to those I have described '
`were obtained in a large number of other experiments. These additional
`experiments, however, were not undertaken for the mere purpose of
`increasing the amount of this evidence.
`
`* l"ul1tEet_n':Ix' nftlac:-v,;rmio1l1cr :;iInil.'ir cxpcrilnetits, are coritairied in :1 pnpcr by
`|-l'|9 3‘-llllm‘. In the J’ r'.rrr.i'rr-.‘mu:s qftrlie .’t‘r:)-art’ .S'r)cr'c!y cf .:':'¢I'3'Jn'5.'.-:3,-I-“r, vol.
`.\:.\'\'i, part
`III, I370-]"I,11|,t. 5-.--j.7;_,-.
`[To Err: ra:rm:.=.rm'.]
`TEs'rI_\ro.\|.\I..—_\lr. Clement llamerton of
`Irelf,
`Naval}, F:
`I
`has been pi'cseIitetl with a carriage, :2. purse containing {:45 : IO, and :1
`highly c_ompl1:nent:t1'y address, as a mode of evincing the gratification .
`of his friends at his recovery from a severe and protracted illness.
`
`CRITICISMS OF DR. CHAUVEAU OF LYO.\'S
`ON THE DISCUSSION AT THE PATHO-
`LOGICAL SOCIETY ON PY/EMIA.
`
`BURDON SA'N'DERSOX, hI.D., F.R.S.,
`By
`Professor of l’r:tctical Physiology in University College.
`
`l'i.lEDIC!t.L ]oLrrw.\1.for
`I luv}: to thank the Editor of the BRITISI-I
`having called my attention to a recently published criticism, by my
`friend Dr. Chauvcau of Lyons, of my communication to the Patholo-
`gical Society last April on the subject of pyzemia. The criticiszn in
`question forms an Appendix [entitled “ I-e poison pyohémique 51 la So-
`ciété Pathologique de Londres”) to a course of lectures on the Physi-
`ology of infective Liquids, which has been published during the last
`three months in the 1t’r.'::¢' Saixrrffiyin-.
`In these lectures the author
`has embodied the results of a lengthened and most important experi-
`mental inquiry, which in its general bearing somewhat resembles that
`in which my colleague Dr. Klein and I were engaged last winter. M.
`Cha.uveau's purpose is to demonstrate the close relation which exists be-
`tween the virulent (or, as I prefer to call them, the infective) diseases
`and ordinary inflammation. He founds this 9'.-:',fp;'0r/rrrmwt' mainly on
`the resemblance between the irritant properties of inflammatory pro-
`ducts, and those of the specific morbid poisons ; and asserts that ordi-
`nary pus induces inflammation in any living tissue with which it is
`brought into relation, in the same way that a. virus reproduces the dis-
`case from which it originated under similar conditions. Those of M.
`Chauveau‘s experiments which have to do with recent—r'.c., living—in-
`Iiammatory products are in close relation with ours. But, in addition
`to these, he has made others in that older field of inquiry which con-
`cerns the toxic action of pus in various degrees of pntridity.
`Knowing as I do, by personal intercourse with M. Chauveau, the
`extreme accuracy of his method of working, and regarding myself as
`in some measure his pupil (for there are few men from whom I have
`learnt more pathology}, I felt perfectly certain, as soon as I found that
`we were on the same ground and looking in the same direction, that,
`if there were disagreement between us, it could only arise from the
`imperfect manner in which the facts had been presented on one side or
`the other—in this case on my side.
`At the Patliological Society, I founded what I had to say on an en-
`tirely new experiment, which I then regarded, and still regard, as :1
`fundamental one.
`It is to this experiment, or rather to my interpreta-
`tion of it, that
`.\l. Cllauveau objects.
`I shall have no difficulty in
`showing that his objection arises from a misconception.
`ll e (IE.-iCl'IlJC$
`it
`in terms which (with the important exception of the words I have
`put
`in italics) are correct: “If a pyremic liquid. introduced into the
`peritoneal cavity of aguinea-pig, be left
`there for a couple of days,
`rz’rr.4":'.t.r_:_“ tctafrm-l’ if r."tr.‘.r rm.’ r."t‘!;*1‘m:'m' (my i.u!r‘.r:.r.' .I'y.vr/Jfum.
`.r'.r.r fa-imrrrfrrrrtf,
`the toxic power of that liquid increases to such a degree that, when
`taken from the first animal and transported to a second, it manifests
`the most pernicious activity, and produces symptoms which are very
`rapidly fatal." This, M. Chauveau adds, was demonstrated to the So-
`ciety in a “dog, into the abdominal cavity of which six drops of a
`p)".\:l.‘I1l.C liquid which had resided two days in the peritoneal cavity of a
`guinea.-pig had been injected."
`ltl. Chauveau expresses no doubt as to the strict accuracy ofthc facts,
`but thinks I have misunderstood them, and proceeds to recite an experi-
`ment of his own, which appears to him to furnish the ltey to mine.
`It
`is as follows. An old horse was sent to the veterinary school with a
`seton, the discharge from which was extremely foetid ; the animal, how-
`ever, was in good health ; pulse, 32 ; temperature in rectum, 99.7 deg.
`l.’us was collected from the seton, diluted with twice as much distilled
`water, and strained. Of this liquid, 15 minims were injected subcu-
`taneously on the right side into the neck of the same animal from which
`it had been taken.
`In twenty-four hours, the pulse had increased to
`+5 and the temperature to roI.S deg. On the fourth day the animal
`died. There was an enormous diffuse swelling around. the seat of in-
`jection, due to “ :.:cderna.tous gelatiltiforrn infiltration" of the subcutane-
`ous tissue. The swelling was gangrenous at the centre, and exliibiied
`elsewhere patches of vascular engorgement or extravasation. There
`were no internal
`lesions. Thus, to quote M. Cl1a.1tveat1’s own corn-
`mentary on the facts, “ at few drops of the same pus, which when con-
`tained in a pyogeuic cavity occasions neither local irritation nor any ap-
`preciable general disturbance, when injected into the cellular tissue of
`the same animal destroys it
`in less than four days ; and the inflamma-
`tion thereby produced is of so violent a character that
`the circulation
`stops, hzcmorrhagic 3'2;/frrrrrrr are formed, the tissues die, and the animal
`
`3 of 3
`
`Alkermes, Ex. 1041