SMITHSONIAN CONTRIBUTIONS TO KNOWLEDGE. -------------------------- 647 -------------------------- RESEARCHES UPON THE VENOMS OF POISONOUS SERPENTS. BY S. WEIR MITCHELL, M. D., MEMBER OF THE NATIONAL ACADEMY OF SCIENCES, C. S. A. 5 PRESIDENT OF THE COLLEGE OF PHYSICIANS OF PHILADELPHIA. AND EDWARD T. REICHERT, M. D., PROFESSOR OF PHYSIOLOGY IN THE UNIVERSITY OF PENNSYLVANIA. [ACCEPTED FOR PUBLICATION, MAY, 1885.] PUBLISHED BY WASHINGTON: THE SMITHSONIAN 1886. INSTITUTION. COMMISSION TO WHICH THIS MEMOIR HAS BEEN REFERRED. John S Bii.linos, M. P., IIenky G. Beyek, M. I). Spenceu F. Baird, Secretary S. I. COLLINS PRINT I NO BOUSE, PUILADELl'UIA. PREFACE. The authors desire to express their multiple obligations to the Smithsonian Institution. They have to thank the Army Medical Library for the valuable Bibliography appended to this essay. With that to be found in Dr. Weir Mitchell's former essay, it completes the list of such knoAvledge up to January, 1885. They desire also to thank Her Britannic Majesty's Indian Government for help in secur- ing Indian serpent poisons. Among individuals they owe to no one so deep a debt as to Vincent Richards, Esq., of Goalundo, British India. WTithout his untiring aid the authors feel that it Avould have been impossible to have extended their inquiries beyond our native snakes. The excellent plates were drawn for the most part by Dr. J. Madison Taylor, and thanks are due to Dr. Geo. A. Piersol's skill for the interesting micro- photographs of blood-corpuscles attacked by venom. The authors are also indebted to Dr. Guy Hinsdale for having made the tabulated reductions of kymographion tracings. S. WEIR MITCHELL, EDWARD T. REICHERT. Physiological Laboratory of the University of Pennsylvania. (iii) TABLE OF CONTENTS. Preface List of Illustrations Introduction CHAPTER I. Physical Characteristics of Venom ....... 5 CHAPTER II. The Chemistry of Venoms ....... 9 CHAPTER III. The Effects of Various Agents on Venom ...... 21 CHAPTER IV. The Effects of Venom when applied to Mucous or Serous Surfaces . . .44 CHAPTER V. The Effects of Venom on the Nervous System . . . . .48 CHAPTER VI. The Globulins and Peptones compared as Regards Local Poisonous Activity . 51 CHAPTER VII. The Action of Venoms and their Isolated Globulins and Peptones upon the Pulse- Rate ^. ........ . 56 Section I.—The action of pure venom upon the pulse-rate . . . .56 The action of pure venom upon the pulse-rate of normal animals . . 57 The action of pure venom upon the pulse-rate in animals with cut pneumo- gastric nerves . . . . . . . .63 The action of pure venom upon the pulse-rate of animals in which sections of the pneumogastric nerves and of the upper cervical portion of the spinal cord had been made . . . . . 66 (v) PAGE iii ix 1 T A I! I, K OF CO XTE NTS Section II.—The action of venom globulins upon the pulse-rate Tin" action of venom globulins upon the pulse-rate of normal animals The action of venom globulins upon the pulse-rate of animals with cut pneu mogastric nerves ....... The action of venom globulins upon the pulse-rate of animals with the pneu mogastric nerves and cervical spinal cord cut Section III —The action of venom peptones upon the pulse-rate The action of venom peptones upon the pnlse-rate of normal animals The action of venom peptones upon the pulse-rate of animals with cut pneu mogastric nerves ....... The action of venom peptones upon the pulse-rate of animals with the pneu mogastric nerves and cervical spinal cord cut C'.l i'.'.i 74 79 82 83 CHAPTER VIII. The Action of Vf.noms and their Isolated Globulins and Peptones upon the Arte- rial Pressure ......... 85 Section I.—The action of pure venom upon the arterial pressure . . . K5 The action of pure venom upon the arterial pressure of normal animals 85 The action of pure venom upon the arterial pressure of animals with the pneumogastric nerves cut ....... 92' The action of pure venom upon the arterial pressure of animals with the pneumogastric nerves and cervical spinal cord cut . . . 95 The action of pure venom upon the arterial pressure of animals with the pneumogastric, depressor, and sympathetic nerves and spinal cord cut 98 Section II.—The action of venom globulins upon the arterial pressure . 102 The action of venom globulin.s upon the arterial pressure of normal animals 102 The action of venom globulins upon the arterial pressure of animals with pneumogastric nerves cut . . . . .107 The action of venom globulins upon the arterial pressure of animals with pneumogastric, depressor, and sympathetic nerves and spinal cord cut . 109 Section III.—The action of venom peptones upon the arterial pressure .112 The action of venom peptones upon the arterial pressure of normal animals 1 12 The action of venom peptones upon the arterial pressure of animals with the pneumogastric and depressor nerves cut . . .114 The action of venom peptones upon the arterial pressure of animals with the pneumogastric, depressor, and sympathetic nerves and cervical spinal cord cut ........ H6 CHAPTER IX. The Action of Venoms and their Isolated Globulins and Peptones upon Respiration 119 Section I—The action of pure venom upon the respiration The action of pure venom upon the respiration of normal animals The action of pure venom upon the respiration of animals with the pneumo gastric nerves cut .... Section II.—The action of venom globulins upon the respiration . The action of venom globulins upon the respiration of normal animals The action of venom globulins upon the respiration of animals with the pneu mogastric nerves cut 11!) 119 122 125 125 129 TABLE OF CONTENTS vn PAGE Section III.—The action of venom peptones upon the respiration . 130 The action of venom peptones upon the respiration of normal animals . 130 The action of venom peptones upon the respiration of animals with the pneumogastric nerves cut ... ... 131 CHAPTER X. Pathology .......... 133 CHAPTER XI. General Considerations ....... 153 Bibliography ...... 159 Description of Plates .... \%\ lNDEX ........ . 183 LIST OF WOOD-CUTS. PAGE Figure 1. Snake loop . . . . . . 3 Figure 2. Venom dried ..... . .5 Figure 3. Muscle tissue altered by venom . . 14»j Figure 4. Muscle tissue altered by venom ... _ 147 B (ix) INTRODUCTION. A few words of explanatory character in regard to the following essay may not be out of place. From the time of Fontana, 1767, until the able essay of Lucien Bonaparte, in 1843, on the chemistry of venom, there was no paper of moment on serpent poisons. In January, 1861, one of us, S. Weir Mitchell, published a long study of the venom of the Crotalus durissus, and in 1868 sup- plemented it by a shorter contribution, in which he related some recent discoveries of his own, and corrected certain errors of his former paper. These two essays may be considered as constituting with Lucien Bonaparte's the foundation of the later work in this direction, and perhaps as having left the study of venoms in as definite a position as could be gained with the laboratory facilities of 1843 to 1868. In 1872, the government of India enabled Sir Joseph Fayrer to publish a volume of beautiful plates of the venomous snakes of India, to which was appended also a series of investigations into the toxicology of their poisons. In 1872 the same author and Dr. Lauder Brunton contributed an admirable physiological study of the effects of venoms.1 In 1874, Vincent Richards, as chairman of a government commission, published an excellent report on antidotes. Dr. Wall's2 thoughtful and suggestive book appeared in 1883. It is a compara- tive study of the poisons of the colubrine and viperine serpents of India. These, with a too brief study of the poison of our copperhead by Dr. Isaac Ott, of Easton, Pennsylvania, sum up all of value which has been added to the physiological literature of this most interesting subject. Why it has won so few investigators is not far to seek. Even in India, where the appalling loss of life from snake-bites has of late invigorated research, the power and means of government were needed to overcome the obstacles which surround such scientific effort from inception to close. But, if in a land where snakes abound and professional snake-catchers can be had, it is yet not easy to follow this pursuit with success, elsewhere it is a task set about with inconceivable obstacles. The fear of serpents, the rarity of some species, the distances to which they have to be carried, the mortality of caged specimens, and the great cost of 1 Proc. Roy. Soc. 1872, 1873, and 1875. 2 Indian Snake Poisons; their Nature and Effects. A. J. Wall, M.D., F.R.Coll.S., 1883. 1 April, 1886. (11 I XT II i> DUCT ION purchase and transportation, need only to be mentioned as indicating our own difficulties. What had been done in India, sustained by a government, had to be with us attempted by private individuals, aided by the Smithsonian Institu- tion, without which it would have been impossible to succeed. Our work began in the autumn of lSv.\ by extended efforts on our part, and that of the Smith- sonian, to buy or otherwise get numerous living specimens of the American genera of Thanatnphidea?. This quest was kept up by every means our ingenuity could devise, and neither time nor money was spared. We succeeded in obtaining a sufficient number of rattlesnakes, including Crotaliis adanianfeus and C. dunssus. We have had also enough of the Moccasin (Ana'slrodon _/>/.scvcorns). Our wants as regards Ground Rattlesnakes, Copperheads, and Coral-snakes have been less com- petently supplied, chiefly because these snakes are all jffilll, so that to get enough of their poison for study it was essential, to have a great many snakes. We have had in all about two hundred living serpents, and among them some supeib specimens, which yielded poison in large quantities. Thus one—('. adamanieus— was eight and a half feet long and weighed nearly nineteen pounds. It furnished on one occasion about one and a half drachms of venom. It was thought desirable by Prof. Baird and ourselves to examine the poisons of Indian serpents. To secure these the Secretary of State appealed to Her Majesty's Indian government in our behalf. A courteous response was returned, and orders given which resulted in our receiving a certain amount of Cobra venom. A more constant and larger supply was due to the generous and untiring kindness of Vincent Richards, Esq., M.R.C.S., of Goalundo, B. I. The poison of the Dahoia HussclHi, the Indian viper, we sought in vain to secure. Government aid and private enterprise alike failed to secure a sufficient quantity of the venom of this dreaded reptile. The other Thanatophidea?, of Australia, and South America, still await more careful study, and our preliminary report has already been the means of renewing interest in the chemical aspects of this study in India. Such of our serpents as were not cared for by the hospitality of the Philadelphia Zoological Garden, were kept in large boxes, about four and a half feet high, covered on top with removable wire network, and well-ventilated through wired openings below. They were of course furnished with water, and if they declined to cat, were fed at intervals, by artificial means, with raw beef chopped fine, and passed down into the belly of the snake through a large glass-tube. Under this treatment the deaths were fewer, and the supply of venom far better. Probably tliis method could be usefully employed in zoological gardens, where many snakes are lost owing to their indisposition to feed during the early months of captivity. On all occasions, for forced feeding, or for the purpose of extracting venom, the snakes were caught and held in the snake loop, Fig. 1. This is merely a staff, having a leather strap so arranged that it can be drawn out into a loop in which the serpent's neck is noosed, and so held. With this simple means all risk is avoided, and with it serpents of any size and strength to be met with among our Thanatophideae can be safely held and easily manipulated. For whatever reasons the study of snake venoms had not greatly advanced since INTRODUCTION. 3 the last research of Fayrer and Lauder Brunton until the authors of this paper resumed the work in 1882. One of them (Dr. Mitchell) had long felt that it would be well to revise the toxicology of our American serpents which he had begun in 1858, and as the later English observers had in some points differed from him, to learn if they or he were correct, or whether the divergence as to results was due to variations in the qualities of the venoms employed. Then too he had become conscious of certain errors in his former researches, and wished to aid in correcting them, and in filling up some of the gaps left in this branch of toxi- cology by himself and others. The authors started with a theory long held by Dr. Mitchell that snake venoms are not simple in composition, but composed of two or more poisonous substances, and that in the qualities and quantities of these agents would be found an expla- nation of the differences between serpent venoms as to power to kill and mode of causing death. How fertile has been the germinal idea of this research must be judged of by this present essay; which will, we trust, by leading thought and experiment in new directions hasten the day when we shall be able to treat with success the wretched thousands who now perish annually by snake-bite in India and elsewhere. Some of our earlier results were so soon talked of and even noted in public prints, that it seemed wise for this, and all other reasons, to state what we then knew. This was done in a "Preliminary Report to the United States National Academy of Sciences, in April, 1883." In this brief essay we announced our proofs of the complex nature of snake poisons. The report was incomplete, and in the light of our present more elaborate essay may be seen to contain several erroneous statements. It is not in the nature of things, that a research along such varied lines as our present volume follows, though extending over several years, should be per- fect in detail, or complete for all genera of Thanatophidians. It is our earnest 4 INTRODUCTION hope that it will be complemented and supplemented by some of the able staff of the Uritish Army Medical Service in the East Indies. There, only, is it possible t«i find enough serpents, and all the various species which it will be desirable to re\iew toxicologically from the new stand-point which we think we have estab- lished. We have forborne to overload this paper with comments on the later researches of others, and have made the discussion of our own work as brief as was eousi.steiit with clearness. In writing of the various substances contained in venoms, we have given them names which arc fairly descriptive, but which, as in the case of the peculiar peptone of Cobra, may perhaps excite criticism. Yet, however unsatisfactory our method of nomenclature may be, any other plan of naming the curious bodies in question would certainly have been even more misleading. CHAPTER I. PHYSICAL CHARACTERISTICS OF YEXOM. Physical Characteristics of Venom.—All serpent venoms are more or less alike in appearance when fresh. They are fluids varying in color from the palest amber tint to a deep yellow. Dr. Wall describes the Cobra venom as being occasionally colorless. This peculiarity we have never seen in the fresh poison of any of our serpents, except once in the coral snake; nor can the venom of one kind of snake be distinguished with certainty by any physical peculiarity from that of any other, however remote they may be in the scale of being. When a fluid venom is allowed to dry slowly it presents no specific distinctive appearances. If desiccated too rapidly, it may look a little more gray and opaque than is common, but usually it dries into a beautifully cracked mass, deceptively like an aggregation of crystals, and which is well represented in Fig. 2. In this state it is in solid yellow particles, very fragile, bright yellow, trans- parent or translucent, and seemingly indestructible by time, since the dried venom of the rattlesnake, for twenty-two years in Dr. Mitchell's possession, proved as poisonous as that removed yesterday. It is equally unaltered by solution in glycerin, which keeps it permanently in unchanged toxic force, as we shall here- ( & ) i; t H r. v k n o M s o i c i: i: t a i x t ii a x a to p ii i d i: .i: after point out.1 Neither docs it appear to be injured when dry by mingling ii with pure alcohol. In fact any of these three means, desiccation, glycerin, or alcohol, preserves it well. When fresh venom of any serpent is examined with the microscope it often presents a variety of floating bodies which seem to be much alike in all eases, and are verv well shown in the plates of Dr. Mitchell's former paper and in Vincent Kichards's reports. In healthy serpents, but lately caged, there are fewest of these solid ingredients, as has been noticed by Richards, by Wall, and by S. x\ eir Mitchell. The question of the toxicity of these suspended solids has again drawn our attention to them, and we have had yet more careful and repeated microscopic examinations made by Prof. Eormad. He found, like other observers, that the venom of the more vigorous snakes has the least visible solid matter; but, as in the use of the fang, the mucus and floating solids of the mouth must be considered, and, as in collecting venom from the snake, more or less of the mouth fluids mingle with the venom, it was thought well to reconsider the nature of the floating solids from the point of view of toxic activity. 1 or the better study of the solids found in venoms wo examined numerous specimens, and placed many of these in the hands of Prof. Formad, from whose notes we select the following observations:— A drop of fresh venom, taken directly from the ('rotalus 1: .t: masses of granular matter with epithelial cells and salhary corpuscles, and a few flat erjs'als resembling cholestcrin. The precipitate gives no proteid reactions with the usual proteid color tests, is insoluble in neutral saline solutions, and in weak or strong acids or alkalies. Boil- ing seems to render the mixture clearer. When injected into pigeons this precipitate docs not appear to possess any toxic properties. Tin Globulins.—If, after the separation of the above insoluble precipitate, the venom be mixed with water and placed in a dialyser over running water it will be found that within a few hours a whitish precipitate will occur within the dialyser, and should dialysis be continued sufficiently long the precipitate will have become deposited in abundance. If-the precipitate thus formed be collected on a filter it will be found that all of the coagulable proteids have been thrown down, since the filtrate now yields no coagulum by brief boiling, although it gives a proteid reaction. The jirrcipi/itfr is now washed from the filter and subjected to repeated wash- ings and decantations with distilled water, until the wash-water gives no proteid reaction. This purified precipitate is found to give reactions peculiar to the globulins ; it is insoluble in distilled water, soluble in dilute neutral saline solu- tions, soluble in dilute acids and alkalies, becomes turbid at about G0° C, and is fully coagulated at a point a little above "70 C. The filtrate still contains some proteid in solution, since we find, by the usual color and chemical tests, a proteid reaction, although it is observed that no coagu- lation occurs by momentary boiling. The filtrate is not precipitated by strong or weak mineral acids, by solutions of ferric chloride or cupric sulphate, it is precipitated but not coagulated by absolute' alcohol, and if placed in a dialyser it will be found to be nadily dialysable. These reactions it will be observed place the proteid which remains in solution in the filtrate among the jwjifon.rs. But we shall revert to this hereafter. It will thus be clear that we have separated in venom representatives of two distinct classes of proteids, one of which is insoluble in distilled water and coagu- lated in solution by boiling, and another which is soluble in distilled water and non-coagulable by brief boiling; the former belonging to the globulins and the other to the peptones. The substance, however, which we find belonging to the globulins is a complex body in its composition, since, by appropriate processes, it can be resolved into three distinct principles, each of which is a globulin, but each having some properties different from its fellows. In order to distinguish these principles we have named them icater-venom-gtobuliu., copper-i( uom-glofndin, and dialysis-rrnoiu-globulin,, the names indicating the principal feature of the processes by which they are isolated from each other. As there are some differences in the reactions of similar prin- ciples in different species of venoms, we shall at first speak only of the venom of the Crotalus adauianti us. Wafcr-n noiwglobutiii.—We have already stated that when a solution of the fresh or dried venom in distilled water is allowed to stand for some time, especially if the quantity of water be comparatively large, a whitish precipitate occurs which THE CHEMISTRY OF VENOMS. 11 settles to the bottom of the glass, leaving in the course of a few hours a per- fectly clear supernatant liquid. If sufficient water has been added at first, the addition of more distilled water to the supernatant liquid will not cause any further precipitate. The precipitate is now collected and repeatedly washed with distilled water and decanted until the wash-water yields no proteid reaction. The following gives the results of some of the many reactions upon the addition of the various reagents used • —1 Decided reactions with the usual proteid tests. Boiling—causes coagulation. Sodic chloride (0 15 per cent.)—slightly soluble. '10 " )—soluble, forming a turbid solution ; the solution is not precipi- tated by carbonic acid2 nor by the addition of ether. —boiling the solution causes coagulation. —the solution is precipitated by saturation with sodic chloride. Carbonic acid1—soluble. Sodic carbonate—very soluble; solution not precipitated by carbonic acid. Hydrochloric acid (0 4 per cent.)—very soluble. Me.taphosphoric acid—insoluble. Orlhophosphoric acid—dissolves. Sodic metaphosphate—insoluble. Sodic orthophosphate—very soluble. Potassic sulphate—very soluble. Calcic chloride—very soluble. Acetic acid (5 per cent.)—very soluble. Acetic acid {glacial)—very soluble. Coagulation occurs at about 64-13° C. Since this body is precipitated by saturation with sodic chloride, and dissolves with difficulty in a 0.75 per cent, solution of sodic chloride, it seems more akin to myosin than other of the globulins. The Copper-venom-globulin.—After the separation of the water-venom-globulin the filtrate gives well-marked proteid reactions and decided coagulation by boiling. If now a few drops of cupric sulphate (10 per cent.) be cautiously added a second precipitate will occur, and which can be separated as in the previous instance. In adding the cupric sulphate great caution must be exercised lest too much be added with the result of a complete or partial re-solution of the precipitate. The precipitate is sometimes comparatively slight at first, increasing upon stand- ing, and complete within about twenty-four hours. The clear filtrate should give no precipitate after the addition of a small amount of the copper solution and after standing twenty-four hours longer. ' In all of these reactions with the globulins, unless otherwise apparent, about 1 c. c. of the suspended globulin in distilled water was placed in a small test-tube, and from one to two drops of standard laboratory solutions of reagents were allowed to run down the inside of the tube. We have made a large number of tests with various reagents, and from this number have selected only such as will serve us some purpose in distinguishing these different bodies. 2 "Where carbonic acid is used in these tests we have reference to the super-saturated carbonic acid water (soda water) of commerce. l o tii i: v e x o m s o v r i: rtai n t ii a x a t o p ii i d i: .k. The precipitate thus obtained is washed as in the preparation of the watei- venoin-globuliu, and when thus purified it does not give any color reaction with the ammonia or the ferrocyanide and acetic-acid tests for copper, and therefore cannot be regarded as a salt of this metal. The coji/h r-n u.oiu-globnlin gives the following reactions: — Derided reactions with the usual proteid tests. >"die mcla)iho.sph.atc Potassic sulphate < 'nlcic chloride Acetic acid (5 per cent.) Acetic acid (glacial) Water-venom-globulin. Soluble Soluble ( Very soluble; not < precipitated by CO, Very soluble Insoluble Soluble Insoluble Very soluble Very soluble Very soluble Very soluble Verv soluble Copper-venom-globulln. Dialysis-vinoin-icUiliul in Insoluble Insoluble Very soluble ; pr< cipitated by CO, Very soluble Insoluble Very soluble Insoluble Less soluble Insoluble Less soluble Soluble Soluble -) Slightly soluble. Soluble. Very soluble. Very soluble. (Insoluble; rendered (of a yellowish tint. Very soluble. Very soluble. Still less soluble. Insoluble. Less soluble. Very soluble. Very soluble. The venom of the Moccasin (Awixfrodon, piseirorus) was subjected to an analysis similar to that of the Crotalus, the isolated proteids giving the following reactions:— Wat< r-renom-globtditi. Decided reactions with the usual proteid color tests. Boiling—clears the mixture without the apparent formation of any coagula. Sodic chloride (0.15 per cent.)—insoluble. (10 " )—somewhat soluble, solution not absolutely clear; boiling clears absolutely without the formation of coagula (crystals)—somewhat soluble; solution not precipitated by carbonic acid. Carbonic acid—insoluble. Sodic carbonate—soluble, forming slightly turbid solution; boiling clears the solution without giving coagnla; the addition of crystals of sodic chloride to the hot boiled solution causes a precipitate, this precipitate being coagulated by boiling. Hydrochloric acid (0.4 per cent.)—somewhat soluble. (5 " )—soluble. Mt'taphosphoric acid—insoluble. Orlhophosphoric acid—soluble. Sodic metaphosphate—slightly soluble; solution rendered clearer by boiling. Sodic orthophusphale—soluble; solution rendered absolutely clear by boiling. THE CHEMISTRY OF VENOMS. 15 Potassic sulphate—soluble ; solution rendered absolutely clear by boiling. Calcic chloride—soluble; solution rendered clearer by boiling. Acetic acid (5 per cent.)—insoluble. Acetic acid (glacial)—insoluble ? Copper-venom-globidin. Boiling—clears somewhat; no coagula. Sodic chloride (0.15 per cent.)—insoluble. (10 " )—insoluble. (crystals)—insoluble; boiling partially clears without the formation of any coagula. Carbonic acid—somewhat soluble; boiling clears absolutely. Sodic carbonate—very soluble ; boiling no effect. Hydrochloric acid (0.4 per cent.)—very soluble. Metaphosphoric acid—insoluble; boiling appears to clear slightly. Orthophosphoric acid—very soluble. Sodic metaphosphate—insoluble; boiling clears somewhat. Sodic orthophosphate—somewhat soluble; boiling clears beautifully. Potassic sulphate—insoluble ; boiling clears slightly. Calcic chloride—slowly dissolved; not so soluble as water-globulin; boiling gives a slight cloudiness. Acetic acid (5 per cent.)—soluble. Acetic acid (glacial)—soluble. Dialysis-venom-globulin. Boiling—clears almost absolutely without the apparent formation of coagula; boiled solution precipitated by saturation with crystals of sodic chloride. Sodic chloride (0.15 per cent.)—insoluble. (10 " )—somewhat soluble; dissolves slowly, forming a slightly turbid solution; boiling seems to clear some without the formation of coagula. Carbonic acid—very soluble; slight turbidity by boiling. Sodic carbonate—very soluble ; boiling no effect. Hydrochloric acid (0.4 per cent.)—very soluble. Metaphosphoric acid—slightly soluble ; yellowish tint; boiling clears slightly with the formation of coagula. Orthophosphoric acid—very soluble ; boiling no effect. Sodic metaphosphate—insoluble. Sodic orthophosphate—soluble ; boiling no effect. Potassic sulphate—somewhat soluble. Calcic chloride—very soluble, form a beautiful clear solution; boiling causes slight turbidity. Acetic acid (5 per cent.)—soluble Acetic acid (glacial)—soluble Moccasin Peptone. 1. Readily dialysable. 2. Not immediately coagulated at a temperature of 100° C, but gradually coagulated by pro- longed boiling (see Cobra peptone, p. 11). 3. Reaction with the xantho-proteic test (nitric acid and ammonia) 4. Reaction with Millon's reagent (mercuric nitrate) 5. No precipitate with weak or strong nitric acid. 6. No precipitate with C02. 1. No precipitate with ferric chloride. 8. No precipitate with cupric sulphate. l(i THE VENOMS OF CERTAIN T11A N A TOl'H IIIKJ! 9. Precipitated by mercuric chloride la. Precipitated by absolute alcohol. II. (fives a faint reddish tinge with a strong solution of potassium hydrate, and a trace of cupric sulphate 1J. Not precipitated by strong acetic acid (glacial). 13. Precipitated by very dilute acetic acid; precipitate being redissolved by further addition of acid. 14 Full reaction with Adamkiewicz's test for proteids. 15. Precipitated by adding a large quantity of sodium chloride, the precipitate being redissolved on the addition of a large quantity of glacial acetic acid. lfi. Precipitated by mercuric nitrate. 17 Precipitated by absolute alcohol; precipitate being apparently redissolved on the addition of water. is. Precipitated by saturation with potassium hydrate; precipitate being redissolved by the addi- tion of nitric acid, with the formation of a decidedly yellow solution (xantho-proteic) which becomes decolorized by addition of acid. 10. Precipitated by potassium fcrrocyanidc in the presence of weak acetic acid. Venom-peptone by dialysis gives identical reactions. for convenience of comparison we append here in parallel columns the principal reactions of the Moccasin globulins, remembering in this connection the difference in the properties manifest in their methods of preparation. Hcugcnt. Water-venom-globulin. Copper- venom-globulin. Dialysis-vcnom-globulin. ( Clears almost abso- Clears some Clears some. Boiling ( lately Sodic chloride (10 per cent.) Somewhat soluble Insoluble Somewhat soluble. Carbonic acid Insoluble Somewhat soluble Very soluble. Sodic carbonate Soluble Very soluble Very soluble. Hydrochloric acid (0.4 p. c.) Somewhat soluble Very soluble Very soluble. Met a phosphoric acid Insoluble Insoluble Slightly soluble. Orlhophosphori.c a< id Soluble Very soluble Very soluble. Soilic metaphosphate Somewhat soluble Insoluble Insoluble. Sodic orthophosphate Soluble Less soluble Soluble. Potassic sulphate Soluble Insoluble Slightly soluble Calcic chloride Soluble Insoluble A"cry soluble. Acetic acid (5 per cent.) Insoluble Soluble Soluble. Acetic acid (strong) Insoluble Soluble Soluble. For reactions of the peptones of the various venoms see p. 19. Cobra Vinom.—We have been able to isolate in Cobra venom only two proteids, and these correspond in their characters to the two types of proteids found in the venoms of the Crotalus and Ancistrodon. In other words, we have isolated a globulin, and a pcpton.'-lil-e principle. The globulin we are able to precipitate completely by the addition of a proper amount of distilled water, after which the solution gives no coagulum by boiling. There is then left in solution a proteid, which evidently belongs to the peptones, although giving some extraordinary reactions. The venom-globulin thus isolated and purified, as in the preparation of the globulins previously mentioned, possesses the peculiar properties of the globulin family, and, in accordance with our nomenclature, since it is entirely precipitated by the addition of distilled water, is a u:atcr-ceihom-globulin.. THE CHEMISTRY OF VENOMS. 17 The following are some of the reactions given by this substance (the water-venom- globidin suspended in distilled water):— Boiling—coagulates. Sodic chloride (0.15 per cent.)—insoluble. (10 " )—soluble; boiling gives slight turbidity. —sodic chloride solution apparently unaffected by carbonic acid. Carbonic acid—insoluble. Sodic carbonate—soluble, slightly turbid solution; boiling makes perfectly clear. Hydrochloric acid (0.4 per cent.)—soluble. Metaphosphoric acid—insoluble; boiling no appreciable effect. Orthophosphoric acid—very soluble; boiling makes solution absolutely clear. Sodic metaphosphate—insoluble; boiling no appreciable effect. Sodic orthophosphate—somewhat soluble; boiling renders perfectly clear. » Potassic sulphate—somewhat soluble. Calcic chloride—soluble ; opalescence of solution increased by boiling. Acetic acid (5 per cent.)—soluble. Acetic acid (glacial)—soluble. Cobra-venom-peptone.—The venom-peptone from Cobra may be prepared by boiling, thus coagulating the globulin, or" by dialysis. Great difficulty is expe- rienced in the former process, since the coagula are so fine that it is impossible, save in rare instances, to obtain a clear filtrate, and as to these we have no explana- tion to offer for the exception. The peptone prepared by boiling or by dialysis gives identical reactions. Before detailing the reactions of this body it may be well to notice a peculiar property exhibited by all venom-peptones which gives them a very distinguishing feature. After boiling the venom for a few minutes and then filtering, the filtrate will again give further coagula by continued boiling, and so the process of boiling and filtering, and reboiling the filtrate may go on repeatedly, yet the clear filtrate will in every instance give fresh coagula. Indeed the boiling process may be con- tinued for an hour or more, and yet at the end of that time the filtrate will still yield coagula. However, after the venom solution has once been boiled, coagula- tion does not recommence in the filtrate until it has been boiled for a few moments. These most interesting facts suggest that the coagula formed after the first boiling are due to a gradual decomposition of what is in some sense a non-coagulable pro- teid, since coagulable proteids all coagulate at once and completely when a definite temperature is reached; the coagula which follow repeated or prolonged boiling appear to be due to such a decomposition of proteids as violent chemical or physi- cal action could alone account for. It seems to us perfectly clear that the body which is thus gradually broken up by prolonged boiling is a peptone. Our principal reasons for this belief are that the body so coagulated is very readily dialysable, is not precipitated by ferric chloride, or cupric sulphate, and in the case of the Cobra is not precipitated by abso- lute alcohol, or mercuric chloride, is not coagulated below the boiling point, and in fact not until boiling has gone on for a few moments. The following reactions seem to be sufficiently characteristic. These results we obtained from a solution of the Cobra-venom-peptone obtained 3 April, 1886. l s i 111: v 1: no m s o v c e w t a i x t ii a n a t o p ii i d e .1: bv diahsinir venom tor forty-eight hours. The dialysate was perfectly clear and neutral in reaction : — Jlmling—no result until after a few moments, when it becomes cloudy, the cloudiness increasing as boiling continues ; strong nitric acid dissolves the precipitate. Color reactions 0>r proteids—the xantho-proteic, Millou and Diurct reactions are all obtained. Ferric chloride—no effect. Cupric sulphate—no effect. M< roiric chloride—no effect. Mercuric nitrate—decided precipitate. Absolute alcohol—no precipitate. Potassic ferroeyanide -4- u-ea/c acetic acid—precipitate. Nitric acid (strong)—no precipitate. Hydrochloric acid (strong)—no precipitate. Acetic aiiil (strong)—no precipitate. Soda- chloride (saturation)—precipitate; acetic acid, large quantity, dissolves. potassic hydrate to saturation—precipitate. Tannic acid—decided precipitate. Basic acetate of lead—decided precipitate. Several very remarkable facts are the coagulation by prolonged boiling and the non-precipitation by mercuric chloride and absolute alcohol. Since this peptone is precipitated by weak acetic acid in the presence of potassic ferroeyanide it has a slight resemblance to Meissner's A peptone, although materially differing, as some of the above reactions show, from any other described body of this class. As a matter of some interest, it is desirable to know if similar globulins in different venoms are- identical in their ehemieal nature, or whether they give any reactions which may distinguish them. We have- accordingly, as in previous cases, placed the reactions of the corresponding globulins side by side. 1. "Wa.tcr-cciioin-globulin,. Reagent. Cn talus horridus. A ncii-t roilon piseivoris. Cobra. Boiling Coagulates Apparently dissolves ('oagulates. Sodic chloride (10 per cent ) Soluble Somewhat soluble Soluble. 1 'nrlionic acid Soluble Insoluble Insoluble. Sodic carbonate Soluble Soluble Soluble. Hydrochloric acid (0.4 p. c ) Soluble Somewhat soluble Soluble. Mi la phosphoric acid Insoluble Insoluble Insoluble. Orthophosjihuric acid Soluble Soluble Soluble. Sodic metaphosphate Insoluble Somewhat soluble Insoluble. Sodic ortliojihos/diale V cry soluble Soluble Somewhat soluble. J'otassic sulphate A cry soluble Soluble Somewhat soluble. Calcic chloride A cry soluble Soluble Soluble. Acetic acid (5 per cent ) Soluble Insoluble Soluble. Acetic acid (strong) Soluble Insoluble Soluble. THE CHEMISTRY OF VENOMS. 19 II. Copper-venom-glolndin. Reagent. Crotalus horridus. Ancistrodon piscivorus. Boiling Coagulates Apparently dissolves. Sodic chloride (10 per cent.) Insoluble Insoluble. Carbonic acid Insoluble Somewhat soluble. Sodic carbonate Very soluble Arery soluble. Hydrochloric acid (0.4 p. c.) Very soluble Very soluble. Metaphosphoric acid Insoluble Insoluble. Orthophosphoric acid Very soluble Very soluble. Sodic metaphosphate Insoluble Insoluble. Sodic orthophosphate Soluble Soluble. Potassic sulphate Insoluble Insoluble. Calcic chloride Soluble Insoluble. Acetic acid (5 per cent.) Soluble Soluble. Acetic acid (glacial) Soluble Soluble. III. Dicdysis-venom-globulin. Reagent. Crotalus adamanteus. Ancistrodon piscivorus. Boiling Coagulation No coagulation ? Sodic chloride (10 per cent.) Somewhat soluble Somewhat soluble. Carbonic acid Soluble Very soluble. Sodic carbonate Very soluble Very soluble. Hydrochloric acid (0.4 p. c.) Very soluble Very soluble. Metaphosphoric acid Insoluble Slightly soluble. Orthophosphoric acid Very soluble Very soluble. Sodic metaphosphate Very soluble Insoluble. Sodic orthophosphate Soluble Soluble. Potassic sulphate Insoluble Slightly soluble. Calcic chloride Soluble Very soluble. Acetic acid (5 per cent.) Soluble Soluble. Acetic acid (glacial) Soluble Soluble. It will be noticed by a careful comparison that the corresponding principles in different venoms differ quite as much from each other as the globulins in any one variety of venom. Venom Peptones.—We have not been able to detect any chemical differences in the venom peptones of the Crotalus and Ancistrodon. Cobra venom peptone is distinguished from that of the Crotalus and Ancistrodon by its non-precipita- bility by mercuric chloride and absolute alcohol. Daboia Venom.—We have had a small quantity (a few grains) of Daboia venom at our disposal, but too little to attempt any detailed chemical investigations. In two examinations, however, with very small quantities, we separated two bodies corresponding to those in Cobra, that is a tvater-venom-globidin and a peptone. The former exists in exceedingly small quantity while the latter dialyses with appa- rently much more difficulty than that of the Cobra. The Proportions of Proteid, Constituents in Different Venoms.—An examination of good specimens of the dried venoms of the Crotalus adamanteus, Ancistrodon piscivorus, and Cobra gives us the following proportions of the globulins and peptones:— 20 T II E V I. N (IMS O F C E II T Aiy Til A N A T O P 11 I D E J: Crotalll* adamanti us— H.5 gram dried venom = water-venom-globulin 0.0105 copper-venom-globulin 0.d!T5 dialysis-venom-globulin 0.Ootid 0.1230 = globulins. 0.HT10 = peptone' (estimated.) Ancistioilon piscicorns— U.Uoi'et gram dried venom — water-venom-globulin (t.(io:;i copper-venom-globulin 0.01*2 dialysis-venom-globulin 0.0041 0.02i;:{ = globulins. 0.3101 = peptone' (estimated). According to this estimate there would be in 0.5 gram 0.0301 globulins. O.4G00 peptone.' f obra— 0.2 gram dried venom = water-venom-globulin 0.0035 peptone1 0.10(35 (estimated). According to this estimate there would be in 0.5 gram 0.00*1 globulin. 0 4!) 12 peptone.1 From these analyses it will be observed that the dried venom of the Crotalus ndtnnanteus contains 24.6 per cent, of globulins, the Ancistrodon 7.S per cent., and the Cobra 1.75 per cent. The globulins in the Crotalus venom appear to be in almost equal proportions, while in the Ancistrodon the copper-venom-globulin is about five times greater than the water-venom-globulin and about four times more than the dialysis-venom-globulin—the two latter being nearly in the same propor- tion—therefore constituting more than half of tin- entire weight of globulins. These differences in the proportions of the various globulins in any specimen of venom and the differences in the proportions of globulins and peptones in different venoms are of immense importance in affording an explanation of the physiological peculiarities exhibited in poisoning by different species of snakes. It will be observed that the proportion of globulins in Crotalus is over three times the quantity in the Ancistrodon, and nearly fifteen times that in the Cobra. 1 Including the salts, which are in very small cmantity. EFFECTS OF VARIOUS AGENTS ON VENOM. 21 CHAPTER III. EFFECTS OF VARIOUS AGENTS ON VENOM.. Effects of Various Agents on Venom.—The influence of acids, alkalies, and salts on venoms has been studied by several observers, with results which vary remark- ably; so that for this and for other reasons there is still room for research of this nature. The questions thus brought up have a twofold interest, the one chemical and the other toxic. Numerous bodies precipitate or dissolve venoms; but among those which most plainly alter these poisons, only a few so change them as to lessen or destroy their poisonous efficiency. Unfortunately, that which alters the poison as such, is always equally destructive to the tissues of the body, and no agent as yet employed can be shown to have the power to enter the blood, and there affect the venom without doing harm to other albuminous substances. So far, we have learned only that amidst the agents which precipitate venom, there are some which weaken or annihilate its toxic force. They can be thrown into the fang tracks, and where they are made to mingle with the venom will destroy it as impartially as they do the innocent tissues in which it lies. It may not be out of place to remark that we have made no direct study of agents as antidotes. Too much yet remains to be known of these poisons before we can hope to find a means of antagonizing them physiologically. Our local or chemical antidotes are sufficiently effective. Effect of Desiccation of Venom.—Allowed to dry at ordinary temperatures, the venoms retain their poisonous activity almost unaltered. When again water is added they act as usual, except that, owing perhaps to imperfections in redissolu- tion, they do not produce as much local effect within as short a time as do the fresh fluid venoms. Neither, it may be added, is the general toxic influence quite as rapid when venom has been once desiccated. The Effects of Various Agents on the Toxicity of Venoms. Age.—Some fresh venom of the Crotalus horridus was dissolved in an equal quantity of pure glycerine and the vial corked and sealed in 1863. In November, 1882, the contents of the vial were examined. The solution was perfectly clear, and had at the bottom a small mass of what appeared to be a fungous growth. Some of the venom was now injected into various animals to test its toxicity. The following experiment attests its power:— Experiment.—Pigeon. Injected, at 5:12 P. M., into the muscles of the thigh about six drops of the above glycerin solution. 5:14. Animal decidedly weakened. 5:25. There is considerable blackening of the tissues about the point of injection, the parts '2-t Til i: V E N O M S O E V E 15 T A I N 1" II A N A T O P II I D E .E l>cing much swollen, the leg stiff, the muscles at the point of injection are paralyzed, and scn.-ibililv of the leg dotroyed. The pigeon lies on its side unable to stand, is exceedingly prostrated, and breathes laboriously. Observation now ceased until 8 A. M. following morn- ing, when the animal was found dead and in general rigor mortis, excepting the muscles at point of injection. Autopsy.—The tissues were dark, congested, and suffused with serum for an area of one and a half inches from point of injection. The viscera of the thoracic and abdominal cavities appeared slightly congested; the heart was arrested in systole and contained dark clots; the blood everywhere was dark and clotted. Microscopically the muscular fibres did not appear to be greatly disorganized, although in some of the fibres no transverse stria; or nuclei could be discovered. The Effects of Dry Heat. Experiment.—0.03 gram of dried (Crotalus adani- an./cus) venom was subjected in a dry oven to a gradually rising temperature to M..Y (\, and maintained at this point for half an hour. The venom, after cooling, was dissolved in 1 e. c. of distilled water. 2:51. Injected the above into the thigh of a pigeon. 4:49. Violent convulsions and death. Eocal effects decidedly marked. Expi r*im u.t.—llopeated the above, but subjecting the venom to a temperature of 100 C. for ten minutes. 3:4 2. Injected into the thigh of a pigeon. (i:00. No decided symptoms. On the following morning the animal was dead. The local effects were marked. Experiment.—llepeatcd the above, but subjecting the venom to a temperature of 110 C. for thirty minutes. 4:4(i. Injected into the thigh of a pigeon. 5:25. Convulsions. 5:45. Died. The local effects were marked. From these results it seems clear that heating the dry venom to a degree above boiling point does not apparently alter its poisonous activity. The delay in tin' occurrence of death in the second experiment suggests that the venom was altered, but in the third experiment in which the temperature was even higher, and this degree of heat maintained for a much longer time, death occurred even sooner than in the first experiment, showing that the differences must have been dependent upon conditions in the animals. The Eff/cfs of Moist Hint. Experiment.— 0.03 gram dried venom (Crotalus adamanteus) was dissolved in 1 c. c. distilled water, and gradually heated until a flocculcnt precipitate occurred. This was injected into the thigh of a pigeon in the evening. The next morning the animal was found dead. Exjicriment.—0.03 gram dried venom (Crotalus adamanteus) was dissolved in 1 c. c. distilled water and subjected to a gradually rising temperature to o(T C. 3:49. Injected the above into the breast muscles of a pigeon. 3:51. Very weak, pupils apparently contracted, trembling; breathing laborious. 4:00. Dead. At the point of injection the tissues were decidedly congested and purplish and suffused with blood. The blood generally was fluid, but some soft clots were found in the abdominal vessels. EFFECTS OF VARIOUS AGENTS ON VENOM. 23 Experiment.—Subjected a similar amount of venom in solution to a rising temperature to 65° C. 4:01. Injected into the breast muscles of a pigeon. 4:05. Head depressed. 4:10. Very weak, falls on the side. 5:02. Dead. The local effect is not so marked as in the previous experiment. The injec- tion was merely subcutaneous. The viscera did not appear congested or abnormal; the heart was arrested in systole; blood everywhere fluid and dark; no ecchymoses in the peritoneum; muscles appear darker than normal. Experiment.—Repeated the above, but increasing temperature to 74° C. 4:13. Injected into the breast muscles of a pigeon. 4:19. Weak, falls on side. 5:05. Dead. Blood clotted; local effect the same as in previous experiment. Experiment.—Eesults the same as in the last experiment, excepting that the local effects were more marked. This animal lived a half hour longer than the last, which will probably account for the difference. Experiment.—The same, but subjecting the solution to 76.5° C. 4:04. Injected into the breast muscles of a pigeon. 4:21. Unable to stand. G:00. Nearly dead. Following morning. Extremely feeble, too weak to stand; there is a muco-sanguinolent discharge from the bowels. Second day. Very feeble. Third day. Recovering. Experiment.—The same, but subjecting the solution to 79.5° C. 4:00. Injected into the breast muscles of a pigeon. 5:50. No symptoms. Following morning animal well. Experiment.—The same, but subjecting the solution to 81° C. 4:31. Injected into the breast muscles of a pigeon. 4:45. Apparently a little stupid. 5:50. No further effect. Following morning. Animal well. Second morning. Animal well. Experiment.—Boiled a similar amount of solution for two minutes. 3:26. Injected into the breast muscles of a pigeon. 4:30. No effect. Following morning. No effect. The above very interesting series of experiments clearly shows that the effect of heat on a solution of venom is very positive, that the toxicity of venom is decidedly affected, and that the greater the increase of temperature between certain limits the greater is the destruction of the poisonous power of the venom. It will be observed in the second experiment, which is the first in which any positive temperature was observed, that the animal died in about ten minutes after injection; in the third experiment in about one hour; in the fourth and fifth experiments in about three-fourths of an hour, and an hour and three-quarters respectively; in the sixth experiment in about two hours; the animal was nearly •J \ T II E V E N O M S O F C E li T A I N T II A N A To P II I D E -E dead, but finallv recovered in the seventh experiment and in the subsequent ones there were no poisonous symptoms. It will thus be observed that there is a gradual impairment of the toxieitx of the venom increasing with the increase1 of tempera- ture, and tint when we reach 76.5 ('. we have almost reached the temperature at which toxicity seems to be completely destroyed. We say seems completely destroyed, because we have found that the1 solution is still toxic even when boiled, although there is not sufficient active poisonous matter left after boiling in the small amount of venom we used in this group of observations to cause decidedly poisonous effects in pigeons. The results of boiling solutions of Moccasin and Cobra venoms are quite different from the above, as the following experiments clearly show:— Ex peri min,t.—Dissolved 0.015 gram dried Moccasin in 1 c. c. distilled water, and gradually heated to '><' C. 3:40. Injected into the breast of a pigeon. 3:50. Rocking. 4:45. Nearly gone; some local effect. following morning the animal was dead. The local effect (darkening) was marked, but not comparable to that caused by the unboiled venom. Ex peri mend.—Boiled 0.015 gram dried Moccasin (piscicoris) dissolved in 1 c. c. distilled water for one minute. 3:2S. Injected the above into the breast muscles of a pigeon. 3:35. Too weak to stand. 4:15. Dead. There are no local effects. Expcrimc/d.—Dissolved about 1 f, minims of fresh Moccasin venom in about 1 c. e. distilled water, then boiled in a test-tube, filtered and injected one-half into the breast muscles of a pigeon at 4:30. 4:55. Very slight local effect; darkening and swelling; the animal is weak and has respi- ratory disturbance. Injected the other half. 5:00. Rocking; irregular breathing; somewhat stupefied. 5:20. Eves closed; stupefied; breathing irregular. Following morning. There was a large, light-colored, cedematous swelling (sec Plate No. 1) within, which was a cavity about an inch in diameter, full of broken-down tissue, having a grayish muddy, gangrenous appearance, and a putrefactive odor, while the surrounding muscular tissues were normal in appearance. It will be observed in this series of experiments with the Moccasin venom that there is also a very decided alteration in the poisonous properties of the venom. But here we find that although the amount of venom used was only one-half the quantity employed in the Crotalus series, boiling does not destroy its ability to kill. It will also be noticed here, as in the case of the Crotalus, that a sufficient degree of heat has an obvious effect on the power of the venom to produce the peculiar lesions at the point of injection. The effect of heat upon solutions of Cobra venom is not so marked. Exp< rintenf.—0.03 gram dried Cobra venom was dissolved in 1 c. c. distilled water and subjected to a temperature gradually rising to 74 C. 4:10. Injected into the breast muscles of a pigeon. 4:16. Unable to staud. 4:20. Dead. EFFECTS OF VARIOUS AGENTS ON VENOM. 25 Experiment.—The same, excepting that the temperature was raised to 79.5° C. 4:12. Injected as above. 4:21. Unable to stand. 4:25. Dead. Experiment.—The same, solution being brought to boiling point in a test-tube. 4:45. Injected into the breast muscles of a pigeon. 5:00. Unable to stand. 5:03. Convulsions followed by death. Experiment.—0.015 gram dried venom dissolved in 1 c. c. distilled water and boiled in a test-tube for about two minutes. 3:51. Injected into the breast muscles of a pigeon. 4:15. Unable to stand. 4:22. Dead. No local effects. From these experiments it appears that the toxicity of venom is not impaired by brief heating as high as 79.5° C, the time of death being in these experiments about the same as with the unheated solution. In the last two experiments in which the solution was boiled, the time of death is delayed, especially so in the last experiment, but here it must be observed that but one-half the dose was used.1 In one experiment made on the venom of the Copperhead (Ancistrodon contor- trix) the effect seemed to be in degree between that of the Crot us and Ancistrodon piscivorus. Experiment.—0.03 gram dried venom was dissolved in 1 c. c. distilled water and boiled in a test:tube for two minutes. 5:00. Injected into the breast muscles of a pigeon. 5:10. Unable to stand. 5:20. Incoordination. 6:00. Very weak. Following morning. Dead. There were very slight local effects; the blood was clotted in soft black clots; heart arrested in systole, auricles full of clots. The interior of the thoracic cavity had a mucky brownish appearance ; the viscera did not appear congested, and there were no ecchymoses. A similar dose of the unheated copperhead venom kills promptly with decided local effects. It will thus be apparent that boiling decidedly alters its toxic power. The effect of boiling on the venom of the Crotalophorus is as decided as on that of the Crotalus. Experiment.—Two drops of the fresh venom of the Crotalophorus was dissolved in 1 c. c. distilled water and boiled for a moment. 4:58. Injected into the breast muscles of a pigeon. 6:15. In good condition; no symptoms up to this time, excepting a little tendency to droop. Following evening. Animal normal. The venom of the Coral snake (Elaps fidvius) is affected to a less degree. 1 Very prolonged boiling, as has been shown by Fayrer and by Ward, lessens greatly, and at last destroys toxicity in cobra venom. The efficient cobra peptone is, as we have seen, converted into a coagulable albuminoid, which is then incapable of destroying life. 4 April, 1886. >2i\ T II E V i: N O M S O 1 (' E It T A I N T II A N A T O P II I D E JZ. Exj» eitnent.—Boiled 0.015 gram dried Coral venom dissolved in 1 e. c. distilled water. Time of injection ? 5:45. Very weak. 6:00. Nearly dead. 6:10. Dead. No local effects. P>lood coagulates perfectly. A smaller amount of venom unboiled kills in from 10-15 minutes with decided local effects From the experiments with the venom of the Crotalus adamanteus detailed above it appears as though the toxicity of the venom was completely destroyed by boiling, but Weir Mitchell found some years ago that boiling did not destroy the poison- ousness of the venom of the Crotalus durissus, and further work of our own led us to believe that the want of toxicity of our boiled solutions was only apparent, and that there was accordingly a poisonous principle still present, but not in deadly quantities. We therefore made some further observations, using larger amounts of venom. Experiment.—Dissolved three drops of fresh Crotalus adamanteus venom in 1.5 c. c. distilled water and boiled. 4:40. Injected into the breast muscles of a pigeon. 6:10. No positive effects. Following morning. Dead, no characteristic local effects. Experiment.—Dissolved 0.12 gram venom (('rota!us adamanteus) in 2 c. c. dis- tilled water and boiled for two or three minutes. 4:40. Injected the above into two pigeons, giving each half. Death within fourteen hours in both pigeons. There was some slight local effect, but nothing comparable to what is observed in the unheated venom. There were no extravasa- tions, and the blood was clotted. The stench from putrefaction at the points of injection was very great, and the muscles around them presented a pale-grayish color as though they had been boiled. A like result was obtained in the case of another pigeon experimented on in the same way. from the above series of experiments it is perfectly clear that heating the dis- solved venom beyond a definite point, varying no doubt in different venoms, lessens its toxic power. Boiling for some minutes does not destroy the poisonous capacity of the venoms, but simply impairs this quality to a varying degree, depending upon peculiarities in the toxic constituents, as we shall hereafter have reason to observe. Fayrer and Wall, as already noted, found that prolonged boiling of solutions of Cobra venom completely destroyed the poisonous activity of that secretion. We accordingly made some similar experiments with solutions of the venom of the Crotalus adamanteus with analogous results. Experiment.—0.03 gram of the dried venom of the Crotalus adamanteus was dissolved in a little distilled water and boiled for ten minutes in a water bath After being allowed to cool it was injected into the breast of a pigeon. 1:56. Injection practised. 1:57. Weak. 2:00. Convulsions. 2:37. Since last observation has been lying on its side, very weak. 2:43. Dead. EFFECTS OF VARIOUS AGENTS ON VENOM. 27 In a subsequent experiment the solution of venom was boiled for forty minutes. Three minutes after the injection the pigeon vomited; no other toxic symptoms were observed. In another experiment, in which the venom was boiled for one hour, no symptoms occurred but vomiting. Both of these pigeons were watched for three days, but in neither of them did any poisonous symptoms ensue. The Effects of Alcohol.—When alcohol is added to fresh venom or to an aqueous solution of venom a copious white precipitate occurs. The following experiments were made to determine if the active principles were entirely precipitated by the alcohol, and if the precipitate was poisonous. Experiment.—Four drops of the venom of the Crotalus adamanteus were placed in 1 c. c. absolute alcohol. The precipitate was filtered and washed with an addi- tional amount of alcohol, the filtrate then being evaporated spontaneously to 1 c. c. The precipitate was placed in 1 c. c. distilled water and injected into the breast muscles of a pigeon at 5:11. 5:11. Too weak to stand. 5:21. Dead. There was very little local effect. The filtrate was injected into another pigeon, as above, at 5:22. 5:26. Vomits; no further effects. From this experiment it is obvious that the presence of alcohol does not destroy toxicity. Further observations were made to learn the effect of a more prolonged action, and if the precipitate was soluble in water. Experiment.—0.06 gram of dried Crotalus adamanteus was dissolved in 3 minims of distilled water and this was added to 3 c. c. absolute alcohol (Squbb's) causing a dense precipitate. The mixture was allowed to stand for three days. It was then filtered, the precipitate being several times washed with the filtrate and finally with fresh absolute alcohol. The precipitate was finally washed from the filter by distilled water, allowed to dry, then digested in distilled water for twenty-four hours, and, after being filtered, was washed with distilled water. The filtrate was cloudy, and on being allowed to stand for one and a half hours cleared somewhat, there being an upper layer of clear fluid and some sediment. One-fourth of the filtrate was now injected into the breast muscles of a pigeon at 4.43. 4-:54. Unable to stand. 5:10. Dead. There is exceedingly little local effect. The tissues at point of injection are suffused with blood. 5:45. Blood still fluid. To one-fourth of the filtrate one milium of acetic acid was added, which caused the mixture to become clear. 4:41. Injected into a pigeon as above. 4:52. Rocking. 4:54. Down. 5:58. Dead. There is' absolutely no local effect and there is no suffusion of blood in the tissues as in the previous experiment. •JS T H I" V E X O M S O F V I! It T A I N T II A X A T 0 P II I D E M. T<> one-fourth of the filtrate a few crystals of sodic chloride were added, which rendered the solution clear. 4:49. Injected as before. 4:55. Rocking. 4:5v Down. 5:57. Dead. The local effect ?'. gram potassic hydrate in 1 c. c. distilled water. -The animal became very sick soon after the injection, which was given in the evening, and remained in this condition at the end of an hour, when the observation ceased. The following morning it was found dead, with post-mortem appearances of the effects of venom. Also, in another animal, which was given intravenously 0.015 gram of venom with a similar amount of potassic hydrate, death occurred as promptly as with pure venom; in fact rather earlier. In another set of experiments on pigeons, we carefully neutralized the potassic hydrate before injecting. We used in all of this series sulphuric acid as the neutralizing principle, so that a harmless potassic sulphate was formed. The results of this group of experiments also go to show that the potassic hydrate prevents the absorption of the venom. Expi rimeut.—Dissolved 0.015 gram dried venom of the Crotalus adamanteus in 1 c. c. distilled water and added 0.015 gram potassic hydrate, then carefully neutralized with acetic acid. This was injected into the breast of a pigeon, causing death in sixteen minutes. Experiment.—Dissolved 0.03 gram dried Crotalus adamanteus venom in 1 c. c. distilled water and added 0.015 gram potassic hydrate, and then neutralized as above. 4:1'.». Injected as above. 4:55. Weak; breathing rapid. 6:2o. Much weaker. Following morning. Dead. Decided local effect; blood fluid and dark. EFFECTS OF VARIOUS AGENTS ON VENOM. 31 Experiment.—The same, only using 0.0075 potassic hydrate. 4:53. Injected as before. 5:00. Weak; breathing deep. 5:10. Dying. 5:18. Dead. Slight local effect; blood fluid and dark. The records of the above experiments, which are in accord with Wall's, show that the results after the addition of the potassic hydrate are not the same as in the series where the alkali was not neutralized, thus proving that the effect of the action of the added alkali does not remain after the latter is neutralized. In previous observations we found that solutions of venom were more or less impaired by boiling, and that this was particularly marked with the venom of the Crotalus adamanteus, 0.015 gram being rendered completely innocuous to pigeons. It was afterwards found that no coagula were formed by heating solu- tions of venom to which had been added some potassic hydrate, as in the above experiments. This led us to study the results of heating solutions of venom to which the potassic hydrate was added to learn if heat was capable of destroying or impairing toxicity without the occurrence of coagulation as a necessary event. Experiment.—Dissolved 0.015 gram of the venom of the Crotalus adamanteus in 1 c. c. distilled water and added 0.015 grain potassic hydrate, and subjected the solution, as in previous experiments, to a gradually increasing temperature up to 74° C. It was then injected into a pigeon. At the end of twenty-four hours there was no effect. In this experiment the temperature to which the solution of venom was sub- mitted was below the point at which serious impairment of the poisonous power of the venom occurs, yet the amount of potassic hydrate was sufficient to destroy its action. Other experiments were made in which the quantity of potassic hydrate was not sufficient to effect this end. We found in previous experiments that 0.0037 gram potassic hydrate was not sufficient to destroy the toxicity of 0.03 gram of Crotalus adamanteus venom, although the time of the occurrence of death was considerably delayed. We used similar amounts of venom and alkali in the three following experi- ments, using 0.5 c. c. distilled water for the solutions. Experiment.—Dissolved 0.09 gram of Crotalus adamanteus venom in 1.5 c. c. distilled water and added 0.011 gram of potassic hydrate. This solution was divided into three parts. One of which was heated to 76.5° C, one to 79.5° C, and the other to 83.5° C. Each of which was injected into the breast of a pigeon« and without any evil consequence following within twelve hours. These results indicate that heat impairs the poisonous activity of venom under the above conditions, even though coagulation does not occur. In previous expe- riments recorded it was found that at a temperature of 79.5° 0.03 gram of Crotalus adamanteus venom was rendered non-toxic. The explanation of the further impairment of the action of the poison by heating its solutions having potassic hydrate dissolved in them lies probably in the fact that the potassic hydrate is placed by heat under condition of greater activity. The non-coagulability of solutions of venom to which potassic hydrate was added is no doubt due to the alteration ;}v> T 11 E V E X O M S O F C E K T A I X T II A X A T O P II I D E .E of the ooagulable proteids into alkali-albumins, and as a moderate degree of heat incirases the rapidity of this change, it is possible that the smaller amount of alkali is as effective under these1 conditions as the larger amounts under ordinary conditions. It is not at all improbable that the prolonged action of potassium hydrate on solutions of venom may convert all of the globulins into alkali-albumins and thus destroy their poisonous activity. Sodic Hydrate.—The effect of sodic hydrate on solutions of the venoms of the Crotalus (ti/amanteus and horridus appears to be the same as that of the potassic salt. In one experiment with the Crotalus adamanteus, using equal quantities (0.03 gram) of the dried venom and alkali, no poisonous effects followed its injec- tion ; and in another experiment in which 0.015 gram of venom and 0.007 gram sodic hydrate were used the animal was rendered somewhat sick, but fully recovered. In one experiment with the venom of the Crotalus horridus, using equal quan- tities (0.015 gram) of the venom and sodic hydrate, no poisonous symptoms followed. The effect on solutions of dry Cobra venom, as in the case of the potassic salt, is not so marked. Experiment.—Dissolved 0.015 gram dry Cobra venom in 0.5 c. c. distilled water and added 0.015 gram sodic hydrate. 4:0S. Injected into the breast of a pigeon. 4:15. Unable to stand. 4:27. Dead. In two other experiments, using double the quantity of sodic hydrate, one animal died in one hour, and the other in a little less than three hours. Double amounts therefore decidedly impair toxicity. In another experiment, in which four times the1 quantity of sodic hydrate was used (0.015 gram dried venom -(- 0.06 gram NallO). no poisonous symptoms followed.1 The Effafs of Ammonia.—The dry venom of the Crotalus adamanteus, which was the only one used, forms with aqua ammonia a turbid solution, such as is formed with water. The effect on the toxicity of the venom exerted by the ammonia is not so marked as with the potassic or sodic hydrates. Experiment.—Dissolved 0.03 gram dried venom in fu:o minims aqua ammonia (20 ) with 1 c. c. distilled water. 5:20. Injected into the breast muscles of a pigeon. 5:37. Unable to walk. 5:46. Convulsions; death. The local lesions are decidedly lessened by the alkali. Experiment.—The same, using six minims aqua ammonia. 4:14. Injected as above. ., 6:00. No marked symptoms up to this time, excepting droopiness. The local effect is slightly more marked than in No. 1. Following morning the animal was dead. Iii three other experiments in which eight minims of aqua ammonia were used two of the animals were found dead the following morning and one recovered. In 1 See Shortt. Wall, op. cit., p. 133. On the effects of alkalies and of permanganates, see Vincent Richards, F.R.C S. Ed., etc., op. cit. EFFECTS OF VARIOUS AGENTS ON VENOM. 33 another experiment in which the alkali was neutralized by sulphuric acid, death did not occur for four hours. In the first experiment, in which a very small amount of ammonia was used, death occurred in less than twenty minutes; in the next, in which three times the quantity of ammonia was used, death did not ensue for some hours, while in the next three a more positive effect was no doubt apparent in the fact that one of the pigeons recovered. In the last experiment death did not occur for over four hours, even after neutralization of the alkali, indicating, as in the case of the potassic hydrate, that some permanent effect had been exerted on the venom by the ammonia. Potassium Carbonate.—Two experiments made with the venom of the Crotalus adamanteus render it probable that the potassic carbonate does not exert any decided effect. Experiment.—Dissolved 0.015 gram venom in 1 c. c. distilled water and added 0.015 gram potassic carbonate. 4:16. Injected into the breast of a pigeon. 4:22. Down. 4:25. Dead. No appreciable local effect. Experiment.—Dissolved 0.03 gram venom in 1 c. c. distilled water and added 0.12 gram potassic carbonate. 5:25. Injected into the breast muscles of a pigeon. 5:45. Down; observation now ceased. Following morning found dead; slight local effect. Nitric Acid.—The powerful destructive action exerted by this acid on albumi- noids suggests at once that it would in all likelihood completely destroy the poison- ous properties of venom, yet it has been asserted that such is not the case. In the latter instance the result was no doubt due to the insufficiency of acid used, as we have clearly determined in our experiments. Experiment.—Dissolved 0.03 gram Crotalus adamanteus venom in 0.5 c. c. dis- tilled water and added 2| minims C. P. nitric acid, which caused a considerable precipitate. 3:32. Injected the above into the breast of a pigeon. 3:33. Convulsions, followed by death. From this result it seemed probable that not enough acid had been added to throw down all of the precipitable proteids. In another experiment the acid was added to a solution of venom and the mixture filtered. The filtrate was now tested with nitric acid and a further precipitate occurred. This process was repeated until no further precipitate followed. The filtrate was set aside, and the precipitate on the filter washed with dilute nitric acid and then with water. Experiment.—5:05 injected into the breast of a pigeon the above filtrate, which measured 3 c. c. and contained 1 c. c. nitric acid. 6:05. No symptoms except slight droopiness. Following morning no effects from venom. 5 April, 1886. 31 T II E V E X () M S 0 F C E II T A I X T II A X A T O P II I D E .V. Exj" rimenf.—5:55 injected the pncipitate in 1 c. c. dilute nitric acid with which it had been in contact for two hours. li:05. No symptoms. Following morning animal in good condition. It will thus be observed that the acid has completely destroyed the toxicity of venom. We made still another experiment in which the venom was rubbed up in a mortar and the acid added to it, and then diluted with water. Experiment.—0.03 gram dried Crotalus venom was rubbed in a mortar until powdered, and 4 gtt. C. P. nitric acid added. This formed a pasty mass of an orange-yellow color. With 1 c. c. distilled water it formed a cloudy, orange- yellow solution. The above was injected into the flank of a half-grown rabbit, without any symp- toms of venom poisoning following within twelve hours. A similar experiment was made with a pigeon with a like result. The acid, however, having been neutralized with sodic carbonate before injection. Muriatic Add.—This acid does not seem to exert so strong an effect. Only one experiment was made. Experimeid.—0.015 gram dried Crotalus venom was rubbed in a mortar, and to it was added 4 gtt. C. P. muriatic acid forming a clear solution. With 1 c. c. distilled water it made a turbid solution. 3:44. Injected the above into the breast muscles of a pigeon. 5:00. Very sick. 5:50. Nearly dead. Following morning dead; no local lesions from venom. Here the amount of venom used was only one-half of that employed in the nitric acid experiment. The quantity of acid was the same, but in this experiment a pigeon was used. As in the scries with nitric acid, an experiment was also made in which the dried venom was powdered in a mortar and a few drops of the pure acid used. About 1 c. c. of distilled water was added, and the mixture neutralized with sodic carbonate. It was then injected into the breast of a pigeon with the result of death in twenty-six minutes. Sulphuric Acid.—Repeated the above, using instead of the muriatic acid 5 gtt. sulphuric acid. The venom and acid formed a clear syrupy solution which became milky by the addition of the water. 3:53. Injected as above. 5:50. Sickish. Following morning dead; no local symptoms of venom poisoning.' Dr. Mitchell had observed that if the acid was afterwards neutralized the action of the venom was not affected The delay of death in this experiment seems to be due to the action of the non-neutralized acid. We, however, made an experiment by powdering the dried venom (0.015 gram) in a mortar, adding a few drops of the pure acid, diluting then with about 1 c. c. distilled water, and neutral- izing with sodic carbonate. This was injected into the breast of a pigeon. EFFECTS OF VARIOUS AGENTS ON VENOM. 35 For some time after the injection the bird was weak, and continued in a feeble condition until eighteen hours after the injection, when death ensued. It seems quite remarkable that such a powerful acid as sulphuric does not com- pletely destroy the poisonous properties of the venom, and it is even more curious that pure muriatic acid seems to be without effect. Acetic Acid. Experiment.—Dissolved 0.02 dried venom (Crotalus adamanteus) in 0.1 c. c. distilled water and added 3 minims of glacial acetic acid. 4:30. Injected into the breast of a pigeon. 4:37. Incoordination. 4:41. Dead. Death occurred in this experiment in such a short time that it was thought that the acid itself might have contributed to this end. We therefore made another experiment in which the acid was neutralized. Experiment.—Prepared the venom as before, only neutralizing the solution with sodic carbonate. 4:35. Injected into the breast of a pigeon. 5:10. Pigeon unable to stand. 5:15. Dead. The result of this experiment indicates that the presence of the free acid aids the toxic action of venom. Hydrobromic Acid. Experiment.—Powdered 0.015 gram dried Crotalus ada- manteus venom in a mortar and added 5 gtt. hydrobromic acid (sp. gr. 1.274), after five minutes added 0.5 c. c. distilled water. The venom and acid formed a slightly reddish-colored solution, which became milky when diluted with water. 4:25. Injected into the breast muscles of a pigeon. 4-45. Sickish. 4:55. Unable to stand. (Final result not noted, but death most certainly followed.) We repeated the above experiment, using 10 gtt. of acid mixed with an equal part of water, before dissolving the venom in it. 2:49. Injected as above. 3:07. Rocking. 3:30. Dead; local effects of the venom apparent. Notwithstanding we used double the amount of acid in this experiment, it does not appear as though the activity of the venom was made to differ much from that noted in the previous experiment. Since the previous dilution of the acid before mixing with the venom might have affected its action a third experiment was made in which the same quantity of acid was added, without dilution, to the powdered venom. Experiment.—Powdered 0.015 gram dried venom and added 10 gtt. hydro- bromic acid, then 1 c. c. distilled water. • 4:20. Injected the above into the breast muscles of a pigeon. 5:00. No apparent effect. 5:10. Sickish. 6:00. Sickish. Following evening. Well. 3(i T II E V K N O M S 0 F C E II T A I X T II A N A T O P II I D E .E . This la>t experiment was repeated with the modification of leaving the acid in contart with the venom for one-half hour before the addition of the water. It was then injected as above without any obvious effects following. The destructive action of the acid on the venom of the Crotalus horridus seems to be the same if we can judge from the single experiment which follows. Experiment.—Powdered 0.015 gram dried venom and added 10 gtt. hydro- bromic acid, which formed a muddy solution with a reddish color. 5:18. Injected into the breast of a pigeon without any obvious effects within twenty-four hours. The effect on the activity of Cobra venom, using similar quantities of venom and acid is very different. Experiment.—Repeated the above, only substituting Cobra venom. 4:4s. Injected into the breast muscles of a pigeon. 5:18. Sick; breathing difficult. 5:30. Breathing more difficult; convulsive movements; incoordination. 5:35. Dead. Tannic Add.—The action of tannic acid upon albuminoids is so decided that we might confidently expect, since we find the poisonous elements in venoms to be proteids, that the activity of venom would be greatly diminished or entirely destroyed by it. In one experiment made with the venom of the Crotalus ada- manteus we found comparatively little effect. Experiment.—Dissolved 0.03 gram dried venom in a little distilled water and added 1.5 c. c. saturated solution of tannic acid. 3:35. Injected into the breast muscles of a pigeon. 4:00. Droopy. 4:45. The same. Following morning dead. It will be observed that there is a great delay in the action of the venom, possi- bly due to the powerful local constrictive action of the tannic acid on the tissues, and possibly, also, to a direct action of the acid on the venom itself. As death may have resulted from the tannic acid we made a control experiment in which 1.5 c. c. saturated solution was injected into the breast of a pigeon. The animal did not exhibit any signs of active poisoning, but it died at the end of the fourth day. Alum.—We made but two experiments with alum, one with the venom of the Crotalus horridus and one with Cobra. Experiment.—Dissolved 0.015 gram dried venom in 0.5 c. c. distilled water and added 3 gtt. saturated solution of alum (18° C), but no precipitate occurred; we then gradually added powdered alum nearly to saturation, which caused precipita- tion. The precipitate was filtered off, and the clear filtrate tested by the further addition of alum to see if any more precipitation would occur, with a negative result. The precipitate and filtrate were now mixed together and injected into the breast of a pigeon without any poisonous result occurring within forty-eight hours. In another experiment in which 0.06 gram of dried Crotalus venom was used, the animal died in forty-five minutes. EFFECTS OF VARIOUS AGENTS ON VENOM. 37 Alum added to saturation does not precipitate the peptone, although it precipi- tates all of the coagulable proteids. The following is the experiment with Cobra venom:— Experiment.—Dissolved 0.015 gram dried venom in 0.5 c. c. distilled water and added alum to saturation (16° C). 4:32. Injected into the breast muscles of a pigeon. 4:50. Down. 4:52. Dead. This last experiment is of interest in proving that even so powerful an astringent as alum is not sufficiently strong to prevent the prompt absorption of the poison. Death followed in twenty minutes. Chlorine Water.—This reagent does not seem to exert any influence. Experiment.—Dissolved 0.015 gram Crotalus adamanteus venom in 0.5 c. c. dis- tilled water and added 0.5 c. c. fresh chlorine water. 4:28. Injected into the breast muscles of a pigeon. 4:52. Down. 5:10. Dead. Bromine.—The action of bromine in bromohydric acid solution is very marked. Experiment.—Powdered 0.015 gram dried Crotalus adamanteus venom in a mortar and added 2 gtt. of bromine in 4 or 5 gtt. bromohydric acid, then added 0.5 c. c. alcohol. 5:05. Injected into the breast of a pigeon. 5:30. No effect. Twenty-four hours. No effect. This experiment was repeated once with Crotalus venom and once with Cobra, using water as the diluent instead of alcohol. In both experiments we found a similar result, thus proving that the activity of the venom is completely destroyed by this reagent. Iodine. Experiment.—Dissolved 0.015 gram dried venom of Crotalus ada- manteus in 0.33 c. c. distilled water, then added 0.5 c. c. tr. iodine which formed a dense brown precipitate. 5:07. Injected into the breast of a pigeon. No poisonous effects within twenty-four hours. If, however, the amount of iodine be much smaller the venom is still potent, as is shown by the following experiment. Experiment.—Dissolved the venom as above, then added 1 drop tr. iodine and afterwards 1 c. c. distilled water. 4:56. Injected into the breast of a pigeon. 5:05. Weak. 5:15. Dying. Iodine -f- Potassic Iodide. Experiment.—Dissolved 0.015 gram dried venom of Crotalus adamanteus in 0.5 c. c. distilled water, then added a saturated solution of equal parts of tr. iodine and potassic iodide. 4:41. Injected the above into the flank of a small rabbit (half grown). The auimal died in about eighteen hours. ;;s T HE V I! N O M S 0 F C E R T A I N T II A N A TOPHI D E .E The delay in the occurrence of death in this experiment was considerable, and that this was due to the action of the iodine on the venom is rendered probable bv tin- results of the preceding experiments with iodine and by the following i xperiment with the potassic iodide. J'n/assic Iodide.—This salt does not seem to exert any influence upon the activity of venom. Experiment.—Dissolved 0.015 gram dried venom of the Crotalus ada ma ideas in 1 c. c. saturated solution of potassic iodine. 4:31. Injected into the breast of a pigeon. 4:40. Down. 4:45. Dead. Potassic Bichromate. Experiment.—Dissolved 0.03 gram dried Crotalus ada- manteus venom in 1 c. c. distilled water and added 0.01 gram potassic bichromate. 4:14. Injected into the breast of a pigeon. 4:20. Down. 4:25. Convulsions followed by death. Experiment.—Dissolved 0.004 gram dried venom in 0.5 c. c. distilled water and added 0.03 gram potassic bichromate dissolved in 0.33 distilled water, which pro- duced a dense coagulum. 3:38. Injected into the breast muscles of a pigeon. 4:05. Dead. Potassic Permanganate. Experiment.—Dissolved 0.03 gram dried Crotalus adamanteus venom in 0.5 c. c. distilled water and added 0.0G gram permanganate in 0.5 c. c. distilled water. This formed a very cloudy solution. 5:27. Injected into the breast of a pigeon. Death occurred within forty-eight hours. Experiment.—The same, using 0.015 gram of the permanganate. At the end of the second day no poisonous effects from the venom. The parts where the injec- tion was made look as though they would slough. Experiment.—The same, using 0.005 gram of the permanganate. The solution formed is a dark wine color. 4:37. Injected into the breast of a pigeon without effect. Experiment.—The same, using 0.0038 gram of permanganate. 4:26. Injected as above. 4:42. Down. 4:45. Dead. Experiment.—The same, using 0.0025 gram of permanganate. 3:57. Injected as above. 4:06. Down. 4:10. Dead. In another experiment, the mixture was injected into the femoral vein of a rabbit, using 0.005 gram permanganate. The animal lived, and at the end of the second day was apparently unaffected. In one observation made with the venom of the Crotalus horridus 0.015 gram of venom was dissolved in 0.5 c. c. distilled water, to which was afterwards added O.OOS gram of the permanganate. After standing for twenty-four hours the EFFECTS OF VARIOUS AGENTS ON VENOM. 39 mixture was very thick and tarry, and would not flow from the inverted test-tube. It seems from this that the full extent of the action of the permanganate on the venom is not exerted for some hours. The permanganate is efficient in destroying the activity of Cobra venom. Experiment.—Dissolved 0.015 gram dried Cobra venom in 0.5 c. c. distilled water and added 0.015 gram permanganate. 4:35. Injected into the breast muscles of a pigeon. No symptoms of venom poisoning within twenty-four hours. Peroxide of Hydrogen.—Notwithstanding the powerful nature of the peroxide of hydrogen as an oxidizer, it does not seem to affect to any great extent the poisonous activity of venom. Only one experiment was made. Experiment.—Added 3 drops of fresh venom of the Crotedus adamanteus to 3 c. c. fresh solution of peroxide of hydrogen, specially prepared by Prof. Leeds, of Hoboken. 5:05. Injected into the breast muscles of a pigeon. 5:15. Unable to stand ; decided local effects appearing. 6:05. Dead, with all the usual phenomena of venom poisoning. The quantity of peroxide of hydrogen used in this experiment was so large that the test was a satisfactory one. Argentic Nitrate.—Notwithstanding the powerful action of nitrate of silver on albuminoids it does not seem to possess great power to disturb the toxicity of venom. Experiment.—Dissolved 0.015 gram of dried venom of Crotalus adamanteus in 3 c. c. distilled water, to which was afterwards added 0.015 gram nitrate of silver, forming a decidedly milky solution. 4:40. Injected into the breast of a pigeon. 4:50. Down; deep breathing, gasping. 4:53. Dead. As there was a possibility of the quantity of salt being insufficient for the amount of venom, another experiment was made in which double the weight of nitrate was used. The mixture was injected into the breast of a pigeon. At the end of three days no symptoms of venom poisoning had occurred. Mercuric Chloride.—When mercuric chloride is added to a solution of Crotalus or Moccasin venom a dense precipitate occurs, consisting of all the proteids in solution. In order to learn if the precipitated proteids still retained any toxic power we dissolved 0.03 gram of dried venom of the Crotalus adamanteus in 1 c. c. distilled water and then added 0.03 gram mercuric chloride. The precipitate was collected on a filter and repeatedly washed with distilled water. During this washing the precipitate seemed to diminish a little in quantity, and was no doubt partially dissolved. 3:30. The precipitate in 1 c. c. distilled water was injected into the breast of a pigeon. 6:00. No symptoms up to this time. Twenty-four hours—the animal showed no signs of venom poisoning. Ferrous Sulphate.—Three experiments were made with the sulphate of iron with results materially different; the difference no doubt depending upon the mode 40 T II E VENOMS OF C E U T A I X T II A N A T O P II I D E M. of administration. In all the same quantities of venom and salt were used, but in one the solution was injected simply beneath the skin and in the others directly into the muscles of the breast. In the former the animal did not die until after the lapse of nearly thirty-six hours, while one of the others died remarkably soon —within four minutes after the injection, and the third in twenty-eight minutes. Experiment.—Dissolved 0.03 gram dried venom of the Crotalus adamanteus in 1 e. c. distilled water and then added 0.03 gram ferrous sulphate. The addition of the iron salt renders the solution clear. 3:40. Injected beneath the skin of the thigh of a pigeon. 6:00. Xo apparent effects. Twenty-four hours—no effects. Thirty-six hours—dead. Slight local effects of venom, but the destructive action of the iron salt on the tissues is much more prominent. Experiment.—The same as above. 3:32. Injected into the breast muscles of a pigeon. 3:36. Convulsions ; death. Xo local lesions. In another experiment the bird died in twenty-eight minutes after injection. It must be concluded from this that the ferrous sulphate does not destroy the activity of the venom. Dialyzed Iron.—When dialyzed iron is added to a solution of venom all of the proteid matter is precipitated, and the filtrate is found to give no reaction for proteids with the xanthoproteic or picric-acid tests. The precipitate is brown, and so gelatinous that if the solutions are somewhat concentrated it does not flow. The precipitate does not dissolve in distilled water, yet it must be very soluble in the tissues since the toxic e-ffects of the venom rapidly appear after its injection. We made two experiments, both with Moccasin venom, one with the dried and the other with fresh venom. Experiment.—Dissolved 0.015 gram dried Moccasin venom in 0.5 c. c. distilled water and added 3 gtt. dialyzed iron. This caused a considerable amount of brownish gelatinous precipitate which thickened the mixture appreciably. Now added 1 c. c. distilled water. 3:20. Injected into the breast muscles of a pigeon. 3:25. Down. 3:45. Dead. Experiment.—Took two drops of fresh Moccasin venom and added first 5 gtt. dialyzed iron, and then 1 c. c. distilled water. The iron and venom made a very thick brownish mixture. 5:1s Injected into the breast muscles of a pigeon. 5:30. Dead. One experiment was made in this connection to see if dialyzed iron exerted any poisonous effect, we injected thirty drops into the breast muscles of a pigeon, without toxic result. Ferric Chloride.—We have used the chloride of iron in two forms; the officinal tincture, V. S. P., and the officinal liquor. Both these solutions greatly affect the poisonous activity of venom, the latter, indeed, if used in sufficient quantity, EFFECTS OF VARIOUS AGENTS ON VENOM. 41 wholly prevents the occurrence of any of the symptoms of venom poisoning. The tincture does not appear to be nearly as efficient. Experiment.—Dissolved 0.015 gram dried venom of the Crotalus adamanteus in 0.5 c. c. distilled water and added 10 gtt. tr. chloride of iron. As the iron was added the solution cleared, but in a few moments became milky, and finally thick with whitish precipitate. 4:22. Injected into the breast of a pigeon. 5:00. No symptoms. 5:45. No symptoms. Following morning—dead. No local effect. In two similar experiments, in which double the quantity of the tincture of iron was used, the result was much the same, the time of death being notably delayed. The following experiments were made with the liquor:— Experiment.—Dissolved 0.015 gram dried venom of Crotalus adamanteus in 0.5 c. c. distilled water and added 4 gtt. liquor ferri chloridi. A heavy precipitate fell. 4:45. Injected into the breast of a pigeon. 5:00. Very quiet. 6:00. No symptoms, and none of venom poisoning within two days. A similar experiment was made with identical results. In one experiment with the venom of the Crotalus horridus, in which only two . drops of the liquor were used, the animal showed no evidences of poisoning; and in four experiments made with the dried venom of the Moccasin, in which 0.015 gram of dried venom was used and eight, four, two, and one drop of the liquor were used, three animals gave no symptoms of venom poisoning, and one died on the third day—the animal receiving the injection containing but one drop of the iron. This was the only pigeon of the four which gave any signs of poisoning. In three-fourths of an hour the bird was shaky, and at the end of three hours decidedly feeble, remaining pretty much in this condition until death. About the point of injection the iron produced considerable hardening of the tissues. The effect on Cobra venom is not marked, although in one experiment there was an appreciable delay in the occurrence of death; but in the other, in which the quantity of iron was larger, death occurred with remarkable rapidity. Experiment.—Dissolved 0.015 gram dried Cobra venom in 0.5 c. c. distilled water and added 2 drops liquor ferri chlor. A slight precipitate occurred in the solution after a few moments. 3:47. Injected into the breast muscles of a pigeon. 4:15. Convulsions. 4:27. Dead. Experiment.—Dissolved 0.015 gram dried Cobra venom in 1 c. c. distilled water and added 5 gtt. sol. perchloride of iron. This was injected into the breast of a pigeon, with the result of death in twenty seconds. The reason why ferric chloride is inefficient in destroying the toxicity of Cobra venom no doubt lies in the fact of its main poisonous substance being a peptone, 6 April, 1886. 12 T II E V E N O M S O F C E 11 T A I N T II A NATO P II I D E .E and, like that clement in all the venoms, unaffected bv the iron, while the principal t<>v.e effects of the Crotalus and Ancistrodon venoms is due to the globulins which are precipitated and chemically altered by the iron salt. Filtration tltrou.Ji Various Subs/aneis.—Filtration through alumina or /rood charcoal docs not affect the poisonous activity of the venom, but by filtration through animal charcoal all of the poisonous material in venom is left behind and the filtrate is accordingly innocuous. Ex p> rinuut.—Dissolved 0.03 gram dried Moccasin venom in 2 c. c. distilled water and filtered four times through animal charcoal. The fib rate gives no proa-id reaction. 4:20. Injected 1.5 c. c. of the filtrate into the breast of a pigeon. At the end of twenty- four hours no symptoms of venom poisoning had occurred, but there was some cedema at the point of injection. Repeated the above experiment, using 0.045 gram of Moccasin venom, and with similar results. Suahi' Bile.— Among the curious substances which have been extolled as anti- dotes for venom poisoning is snake bile. We made but one experiment, which speaks volumes. J'x/icrinuid.—Mixed 1^ minims of fresh venom from a dead Crotalus adam- anteus with 1 c. c. of bile from the same animal. 4:4 7 Injected into the breast of a pigeon. 4:47V- Incoordination. 4:50. Gasping respiration. 4:55. Convulsive movements. 4:56. Dead. ])i,jest'um..— 15y digestion in strong artificial gastric juice made from the pig's stomach the toxic power of venom (Crotalus) is completely destroyed. Experiment.—Three drops of the glycerine solution of venom (Crotalus horridus) (lN>2) were digested for sixteen hours in about 1 c. c. fresh artificial gastric juice from the pig s stomach. S:30 a. m. Injected into the breast muscles of a pigeon. Up to the end of forty-eight hours no poisonous symptoms ensued. This experiment was repeated with an identical result. We also made two experiments in which the digestive process was not carried on for such a length of time, in both only four hours, and with similar results. In one we used six drops of the glycerine solution of venom as above—just double the dose—and in the other 0.015 gram of the dried Crotalus a.da/mauteus venom. The results of digestion in artificial pancreatic juice are similar. AVe made but one experiment, and that with the venom of the Crotalus adamanteus. Experinuut.—Digested 0.03 gram dried venom in 1 c. c. fleshly prepared pan- creatic juice from the pig for twenty-four hours. 3:44. Injected into the breast muscles of a pigeon. 5:45. Slightly droopy. Following morning, no effects apparent. EFFECTS OF VARIOUS AGENTS OX VENOM. 43 Resume.—The above experiments, with others too numerous for detail, have enabled us to confirm Lacerda's and Vincent Richard's views as to the power of permanganate of potassium to destroy venoms. As a local antidote it is for all snake poisons the best. It is also clear from what we have seen that ferric chloride is a very efficient local destroyer of the venom of our own snakes, which owe their vigor to venom- globulin, but has little value as a local antidote to the peptone which gives power to the poison of the Cobra. The chloride needs to be locally used in full doses, whence it is that the strong liquor ferri chloridi (U. S. P.) is more efficient than the tincture. That bromine may prove valuable as a local means of relief seems to be plain from our experiments, and is in fact one of their most interesting results. It was used, as we have seen, either as hydrobromic or bromohydric acid. Probably any solution of bromine would answer, and—as was shown by its free local use to control gangrene during our civil war—there need be no fear in using it with freedom. It has long been known in India that the strong alkalies destroy venom, and this we are able to confirm. Brainerd long ago taught that iodine has destructive value as regards Crotalus venom, and this also seems to us to be true. In fact many agents more or less alter venoms if allowed to remain long in con- tact with them, and usually act with increased vigor as the temperature is raised above that of the air; but it is chemically singular that brief exposure of venoms to strong acids should so little affect the toxicity of the poisons in question. Except where otherwise1 distinctly stated, the chemicals used by us have been added to the poison immediately before injecting it. Enough has been here proved to make it now worth while to study still more carefully the value of bromine and ferric chloride as local poison destroyers. One agent may be at hand or available when others are not, and the more numerous are the means we possess as local antidotes the better is the chance of escape or relief for persons bitten. | 1 1 II I. V E X CMS O F C E li T A 1 N 1 II A X A T O P II 1 D I. .1. CHAPTER IV. THE EFFECTS OF VENOM WHEN APPLIED TO MUCOUS OR SEROUS SURFACES. The Elf crop, the solution of venom was then poured through the tube by means of a funnel, and afterwards washed down with a little water. Expi rimtnt.—Dissolved 0.025 gram dried Cobra (Xuja trip.) in about 1 e. c. distilled water, and placed it in the crop of a pigeon by means of an (esophageal tube. Up to four days the animal showed no signs of poisoning. Five other experiments, like the above, gave identical results. In one experi- ment the animal died within twelve hours. Experiment.—Dissolved 0.013 gram dried Cobra (Xaja trip.) in about 1 c. c. distilled water and gave to a pigeon, as above, at 4:00 i\ m. A little while after the dose the pigeon appeared sickish and remained in much the same condition for about two hours, when observation temporarily ceased. At 8:30 the following morning the bird was dead. The heart was found in systole and contained dark clots. fhe blood was everywhere coagulated. No apparent lesions were present in any part of the body, and a most careful examination of the mouth, gullet, and crop revealed no abrasions or other raw surface. The crop contained a little cracked corn and a small amount of yellowish fluid. In another pigeon, etherized, an opening was made through the skin into the craw, and its contents washed out. The pigeon was kept on its back and the edges of the wound were held up by retractors. A solution of venom was placed in the cul-de-sac on the left side and the animal watched. In a half hour the bird had convulsive seizures, and at the end of forty minutes was dead. At that time there seemed to be about the same quantity of venom solution in the crop as before. It was, however, somewhat glutinous and darker in color. The mucous THE EFFECTS OF VENOM. 45 membrane preserved its natural tint. On the side in which was the poison the mucous membrane was wrinkled and raised in points like the surface of a mul- berry. By stretching the mucous membrane this roughness disappeared. After death it increased somewhat. There was no oedema. Experiment.—0.01 gram of dried Cobra dissolved in a little water was given to a frog by an oesophageal tube as in the case of the pigeons. The frog presented no toxic symptoms for two hours. After twelve hours it was dead. Autopsy.—All the tissues had a cyanotic appearance and the animal was perfectly flaccid. The heart was still irritable as well as the intestines. The stomach con- tained a viscid mass of mucus, which was not bloody, and which was expelled from the stomach by the normal contractility when the organ was cut. A most careful examination of the mouth, gullet, and mucous membrane of the stomach did not reveal any abrasions or other raw surface. The liver seemed pale and decidedly friable. In Dr. Mitchell's former experiments made in the opened crop, fatal results did not occur with use of fresh or dry venom of Crotali; but a single needle pricked through the mucous surface covered by the poison, sufficed to let in death. It seems possible that minute ulcers or abrasions, quite invisible to the eye, might, in like manner, enable the venom in some cases to pass the barrier of the intestinal mucous lining. The deaths from ingested Cobra venom related by Fayrer took place in mammals, and we ourselves found in like experiments with rabbits, that, although death was rare after swallowing Cobra venom, it was less so than in pigeons; but our Cobra experiments are not strictly comparable with those done in India with fresh poison. Certainly Cobra venom is much more apt to kill when swallowed than is Cro- talus poison. In the rattlesnake it is the globulins which are in largest amount, and which are not dialysable, but in Cobra the fatal peptone is the material which, both as to vigor and amount, represents the poisoning capacity, and is as we know dialysable. It is only astonishing, therefore, that it does not kill in every case in which it is swallowed; but, as we have seen, the gastric juices in so far as they have time to act are destructive of venoms, and hence their protective agency has also to be considered. The Activity of Venom when appAieel to Serous Surfaces.—One of the most remarkable and interesting of the physiological effects produced by the venom of the Crotalus is the occurrence of ecchymoses, especially in the serous tissues. The character of these ecchymoses is fully treated in another part of the work, so that we need here only detail some of our observations in connection with the direct effect of the application of venom to the serous tissues. A rabbit was etherized and kept in this condition during the whole of the experiment. The abdominal cavity was opened and a knuckle of intestine exposed. On the peritoneum were placed a few small particles of the dried venom of the Crotalus adamanteus. In two or three minutes some extravasations appeared immediately about the point of the application of the venom; a few moments later these extravasations were diffused over a considerable area and had run into each other to such an extent as to form a patch of bleeding surface. So II, T II E V E N (IMS O I ( E IJ TAIN T II A N A T O P II I D E .E rapidly do these hemorrhages spread that they can literally be seen to grow under the* eve. Another portion oi' the intestine was exposed, and upon the peritoneum was placed a very small portion of the glycerine solution of venom (prepared in 1^02), which has already been referred to. Ten minutes after the application small points of extravasation appeared, and in three minutes more1 had increased so much in number and spread so rapidly as to form a continuous area of bleeding surface. Four drops of the glycerine solution of venom in a little water were boiled and carefully evaporated to a thick paste and then applied to a fresh surface of the peritoneum. After one hour no ecchymoses appeared. In another experiment 0.03 gram of the dried Moccasin venom was boiled and injected into the peritoneal cavity of a pigeon. The animal died in forty-two minutes, when we found large ecchymoses scattered over all the abdominal viscera, In later experiments we have fully determined that the venom peptone may cause1 ecchymoses, but that this power exists in an insignificant degree as compared with that of the globulins. In another experiment, not irrelevant here, we injected one drop of the fresh venom from the Crotalus adamanteus into one of the mesenteric arteries of an etherized rabbit. In a few seconds ecchymotic patches appeared on the large intestine followed by a few on the small intestine, and in another moment the animal was dead. In an experiment on an alligator, elsewhere quoted, the activity with which venom may be absorbed by serous membranes is well illustrated. In a frog death occurred within two hours after the injection of two drops of the fresh venom of the Crotalus ailamuidius into the peritoneal cavity. In one experiment made upon an etherized rabbit in which 1 drop of fresh Moc- casin venom was dissolved in 1.5 c. c. of distilled water and injected into the peritoneal cavity the1 animal died in one and a quarter hours. In an autopsy one hour after death, it was found that there was no rigor mortis; the whole of the inside of the1 peritoneal cavity was stained, and in places was literally dripping with blood ; the mesentery contained a large amount of blood resembling a free clot. On the surface1 of the intestines the effusion of blood was of a brilliant red color as though from the arterioles; the whole interior of the abdominal cavity was stained; the heart was arrested in systole. In still another experiment in which the solution of venom was boiled the results were strikingly different. We dissolved 0.03 gram of dried Moccasin venom (repre- senting a much greater dose than was given in the previous experiment) and after boiling it for a moment filtered it. The filtrate was injected into the peritoneal cavity of a rabbit. The animal was killed after the lapse of one hour and the peritoneal cavity examined. There were absolutely no alterations to be seen in the viscera, excepting one minute spot where there appeared a little reddening. The length of time during which the venom used was boiled was not distinctly stated in the notes of some of our observations. The omission was of moment. At the time these experiments were made, we did not fully know that while in all venoms—brief boiling throws down the globulins at once—much longer boiling by degrees precipitates, and at last makes innocent the peptones. Apparentlv it THE EFFECTS OF VENOM. . 47 is the globulins which most rapidly alter blood and vessels, and by a mechanism hereinafter to be described cause ecchymoses. Yet are the peptones not without this toxic capacity, as is seen in some of the above observations. Clearly, however, boiling impairs the activity of Crotaline peptones, as it does that of like constitu- ents of Cobra poison. It will have been seen that none of these direct experiments on serous tissues were made with pure or boiled Cobra venom. It is desirable that this should be done, and especially with fresh venom. In another portion of this paper there are some relative studies of the power of dried Cobra and Rattlesnake venoms to cause local hemorrhages from the peritoneum. In the former work of Dr. Mitchell, and in that of Fayrer and Brunton, are sufficient studies of the ab- sorbing power of rectal and pulmonary surfaces and of the eye. IS THE VENOMS OF CERTAIN 1 II A N A T O P H I D E .E. CHAPTER V. THE EFFECTS OF VENOM ON THE NERVOUS SYSTEM. Excepting as regards the marked action on the respiratory centres we cannot ((insider venom as essentially or solely a nerve poison. In animals which do not immediately die from the effects of this poison, the first signs of nerve poisoning are drowsiness, incoordination, followed by loss of voluntary motion, by convul- sions, or failure of reflex activity and by death. H'j/'X Action.—In six experiments on frogs with the Crotalus. made in connec- tion with a direct study of the effect on reflex action, in none of them was there found a slow, gradual diminution of reflex activity, but invariably a sudden loss of this function. The time of the occurrence of the loss of reflex activity varies very greatly. In four experiments on pithed frogs, each of the fiogs was given 0.015 gram of the dried Crotalus ailauiunteus venom in 10 minims of distilled water, by means of injection into the post trior lymph sac. In one experiment no alteration in reflex activity occurred after one and three-quarter hours, although it seems probable that the venom was not by any means completely absorbed since the lymph sue seemed bulged with fluid which had accumulated. In another experiment no alteration occurred in one and a half hours. In a third reflex action was suddenly abolished in one hour, and in a fourth in forty-five minutes, without there being in. any case gradual diminution of reflex activity preceding the com plete loss. Two experiments were made on pithed frogs to determine if the loss of reflex activity was due to an action of the venom upon the nerves or upon the spinal cord, and for this purpose we- ligated all of the bloodvessels in the right hind leg of each animal, and thus prevented the access of the venom to these parts. To each of these frogs was given 0.015 gram of the dried venom of the Crotalus adamanteus dissolved in 5 minims of distilled water, and injected into the posterior lymph sac. Keflex activity suddenly ceased in both of the frogs in one and a half hours. No reflex action was elicited by irritation of the nerves of either leg, although the motor fibres of the nerves were very excitable. We also found that direct excitation of the spinal cord in the dorsal region produced movements in the posterior extremities, but none in the anterior extremities, thus showing that impulses could travel down the cord through the motor apparatus but not upwards through the sensory portions. These observations make it clear that the loss of reflex activity is. no doubt, dependent to a great extent at least upon an action of the venom upon the sensory portions of the cord, although it is not clear that the sensory nerve fibres may not also be seriously affected. EFFECTS OF VENOM ON THE NERVOUS SYSTEM. 49 Sensory and Motor Nerves.—In order to more directly test the action of venom upon the motor and sensory fibres we exposed the sciatic nerve along the whole extent of the thigh of pithed frogs, and placed in the middle of the exposed trunk a little (Crotalus) venom (concentrated by spontaneous evaporation). Comparative observations were now made from time to time by exciting the mixed nerve trunk above and below the point of application of the venom by means of electrodes connected with a Du Bois-Reymond induction coil, using minimum strengths of current. After about fifteen minutes, irritation of the foot of the leg with the poisoned nerve did not give as good reflexes as irritation of the other leg. After five hours, irritation of the trunk of the nerve below the poisoned part did not give reflexes, but above the part did give reflexes, showing that the sensory fibres were functionally destroyed by the local application of the poison. When the trunk was irritated above the poisoned part marked contraction of the muscles of the limb occurred, showing that the motor fibres and muscles were still intact. After the lapse of six hours the motor nerves would no longer respond to stimulus, although the muscles were still irritable. From these observations it seems obvious that both the sensory and motor nerves are affected by the poison, and that the sensory nerves are far more susceptible than the motor nerves, and that the depression of the sensory nerves may be con- nected with the depression of reflex activity; but it seems more than likely that the loss of reflex activity is essentially of spinal origin, since there is not a slow, gradual diminution of reflex activity but a sudden paralysis—a characteristic which may be considered almost exclusively spinal. The Spinal Cord.—AVe have already stated that the motor columns of the cord remain irritable after complete paralysis of the sensory columns. We have supplemented these observations by some experiments showing the direct action of venom upon the exposed spinal cord, which prove that the motor columns them- selves ultimately succumb to the poison. In two experiments made upon large frogs, in which was laid bare the spinal cord in the dorsal region and in which the animals were left to fully recover from the shock, a concentrated solution of the dried venom of the Crotalus adamanteus was placed on a small portion of the cord. Before the application of the venom the cord responded actively to slight mechanical irritation; after the application of the venom there occurred a gradual impairment in irritability for the first fifteen minutes; this impairment increased, so that at the end of two hours the cord would not respond to moderate electrical stimulus. The diminution of function continued until at the end of seven hours the strongest current induced no response, although the motor nerve trunks responded actively. Voluntary Motion.—Usually the earliest signs of nerve poisoning with venom are a disturbance of coordination and loss of voluntary motion. In frogs we found that as long as voluntary motion lasted the reflexes were active, but that with a loss of volition reflexes were at once decidedly diminished and suddenly disappeared. In frogs in which the abdominal aorta was ligated so as to prevent the poison from affecting the nerves of the posterior extremities, the results were1 similar. In a number of observations made upon mammals the above conclusions were 7 April, 1886. OO T II E V E N O MS O F 0 E K T A I N T HAN A T () P II I |> E M. borne oat. We have also found that the1 orbital reflexes are completely gone before death, and that before their loss voluntary motion disappears. Moreover, if tin1 spinal cord is irritated immediately after the cessation of the orbital reflexes it will be found that irritation will give vise1 to movements in the posterior extremities only, and that after the cord will no longer respond to irritation the motor nerves are still excitable. After the motor nerves cease1 to respond the muscles remain irritable. These results all go to establish the conclusion that the respiratory centre is the most vulnerable point of the nervous system, that the coordinating and volitiomil centres are then prominently affected, that the sensory part of the spinal cord and the sensory nerves are next attacked, and that the motor parts of the cord, and the motor nerves are the last to succumb. GLOBULINS AND PEPTONES AS LOCAL POISONS. 51 CHAPTER VI. THE GLOBULINS AND PEPTONES COMPARED AS REGARDS LOCAL POISONOUS ACTIVITY. It seems needful at this place to consider the relative local toxic capacity of globulins and peptones, the two substances found in varying quantities in all venoms as yet examined. In order to do this effectively it will be needful at the risk of anticipating a part of what belongs strictly speaking to the pathological section, to speak briefly of the macroscopical lesions brought about at the seat of injection by these potent substances. What takes place intensely where the injection needle enters, but represents in a violent and coarser manner lesions to be found soon or late throughout the body, and this especially applies to entire venom and to the globulins. .These studies of local changes are not without definite explanatory value. It has long since been shown that the cobra and the rattlesnake are distinctive poisoners, and now our latest work seems to explain just why this is so, and enables us to see already that what might efficiently aid one bitten by the Indian serpent, would be by no means sure to succor the victim of our own less fatal snake. Venom Peptones. local Action.—The albuminous elements of venoms are, as already shown, two in number, and belong by virtue of their reactions respectively to the classes, peptone and globulin. Hence, as we now see with clearness, it is easy to separate them by boiling, which if brief, destroys the globulin as a poison and leaves the peptone unaltered. When after boiling we inject the fluid and coagula, we still poison, if the dose be large, for the venom peptone is toxically unchanged. The wound shows, however, hardly any of the singular appearances which characterize lesions due to fresh or unboiled venom. Boiling leaves the poison less active locally. If continued it also affects more or less the general toxicity, but this influence is most marked in the Crotaline venoms, because in them the peptone is least in amount and is also the least deadly of the two constituent poisons. Venom Peptone.—When venom peptone in full dose is injected into the breast of a pigeon, if the animal dies within an hour or two, there is scarcely any appreci- able local effect, as will be clearly seen by examining the results of experiments recorded in the chapter on the influence of various agents on the poisonous activity of venom. If the dose be smaller, so that life is prolonged, the first local effect observed is a considerable cedematous swelling without any dark discoloration. After the lapse of about eighteen hours there is apt to be some discoloration, and generally a discharge of muddy putrescent serum. If the animal be killed after a 52 T II F V E N O M S OF C E l\ T A I N T II A X A T O P II I D E .E day it will be found that the muscles on the injected side about the region of the oedema are pale and bloodless, having the appearance of half-cooked chicken moat. In animals which lived longer there was sometimes found considerable congestion, marked by greenish streaks, and giving off horrible putrefactive1 odors. In others beneath the cedematous swelling lay a cavity about an inch in diameter, which was full of broken-down tissue1, having a muddy, gangrenous appearance1, and decidedly putrescent, while the surrounding muscular tissues were not apparently altered in appearance. In none of these experiments were ecchymoses found in the intestines, and in all of them the blood was coagulable. In the following experiment Crotalus peptone obtained by dialysis was at 2:37 injected into the breast of a pigeon; 3:15 weak; 3:50 rocking slightly, no local discoloration, some slight cedematous swelling; 4:00 more unstoadv on its feet; 5: 15 there was considerable watery effusion in the subcutaneous cellular tissue1 on the side of the injection. The following afternoon there was a large swelling over the site of the wound. It was an inch or more above the healthy skin, and was apparently purely cedematous in character, there- being no dark discolora- tion nor appearances of congestion. The superficial local effect was in every way unlike that produced by the globulins. The following afternoon (after 4S hours) the pigeon died. The swelling was unaltered as to size, and but very little discolored. The- tissues around it were slightly darkened, the coloration fading away gradually at about one-half inch from the border, and there was a well-defined pale streak of tissue between the swelling and the surrounding tissue like a lint1 of demarcation. Upon cutting into the tumor serum dropped from tin1 incision, and the1 subcutaneous cellular tissue was found greatly infiltrated. The swelling seemed to be almost entirely (edematous and the serum had a putrefactive odor. The mus- cular tissues were greatly congested and somewhat'blackened, and in places as green as though infiltrated with bile. This green appearance could be seen distinctly through the skin on the surface of the superficial muscles, extending over the entire side of the breast. The odor emanating from the cut muscles was also putre- factive. In the intermuscular tissues there was some greenish gelatinous matter. Beneath the swelling was a streak of muscular tissue about one-fourth of an inch thick, which was very pale, like half-stewed meat, contrasting strongly with the other parts of the muscles. All of these observations on slow poisoning were made with peptone derived from the venoms of the Crotalus adamautetts or the Moccasin. Judging from the fact that the venom peptone does not give rise to any darken- ing of the muscular tissues within a short time after injection, and indeed, as it seems probable, not until putrefaction has set in, it is likely that the darkening and congestion which ultimately occur are to be regarded as mere secondary effects, and due to putrefactive changes induced by the poison. The peptones, whether obtained by boiling or dialysis, seem to cause locally an enormous oedema, gradual breaking down of the tissues, and rapid production of horrible putrefactive processes, with finally a more or less extensive slough. They possess little power to produce large hemorrhages, because they do not so well as venom globulin destroy the coagulability of the blood. Hence in peptone GLOBULIXS AND PEPTONES AS LOCAL POISONS. 53 wounds there are only such local bleedings as are due to the leakage caused by gangrenous processes. The ragged, sodden grayish look of the muscles is very remarkable, and once seen is too unfamiliar not to be remembered as a most striking pathological appearance. For effects of peptone, see Plate I. Venom Globulins. Local Influence.—When we inject unboiled venom, we are using globulin as well as peptone, in amounts which differ with every serpent. If we use the isolated globulins the contrast in the local phenomena as compared with those caused by peptones is immense. The different globulins already described were all examined in this connection. As the globulins are insoluble in water free from salines, dialysis kept up long enough, as from forty-eight to seventy-two hours, in a temperature so low as to insure absence of putrefaction, will throw down the mass of the globulins in a form which enables us to collect and re-dissolve them. Three drops of Moccasin venom were mixed with 6 c. c. distilled water and dialysed by a current of pure water for fifty-six hours. As the salts passed out a precipitate increased within the dialyser. After having been washed with distilled water, it was thrown into the breast of a pigeon. Death took place in twenty-four hours. This delay in a fatal result was owing to the dose being small, and perhaps also to the fact that it did not represent all the globulin of three drops of venom; after death there was a tense black swelling at the site of the wound, and the tissues, for two inches in every direction, were soaked with black absolutely fluid blood. It is difficult to subject venom constituents to any processes like solution or dry- ing without more or less altering their toxicity. Desiccation certainly affects whole venom, and in a measure lessens the severity of its local symptoms. The same is true of venom globulins. An equal dose of globulin dried and redissolved takes longer to kill, than if not previously dried; also if the dried venom be given in unusual dose, the local effects are slighter than those seen with pure venom or fresh globulin in smaller dose, but killing within the same time. A long survival of course enables the local phenomena to develop and might mislead as to the fact of drying having an enfeebling influence. Desiccation greatly lessens the solubility of venom, and of its albuminous constituents, and in consequence they fail to permeate the tissues and to enter the blood at the rate which characterizes fresh venom. In the experiment which follows, death was long delayed, and owing to this the local results were strongly marked. A quantity of globulin obtained by dialysis, representing two grains of the venom of the Crotalus adamanteus, was allowed to dry. It was then placed in a little distilled water, and after a few minutes a small amount of common salt was added, which caused the venom and water to form a milky solution. This was injected into the breast muscles of a pigeon at 3:25; 3:40 some darken- ing and swelling of the side of injection; 4:25 unable to stand; 6:00 convulsions, followed by death. Autopsy.—The local effect of the venom was remarkable ; beneath the skin in the areolar tissue, over the wounded side and over half the breast of the opposite side, was a mass of bloody gelatinous effusion, and the muscles beneath on the injected ;■> I T II i: V E N () M S () 1 C E R T A I N T II A N A T O P H I D E .!■: side wore swollen and darkened and enormously infiltrated with blood. See Plate II.. Fig. 1. fin se experiments, which have been supplemented by many others, give a some- what definite idea of the marked difference in the local effects of the globulins as a group in comparison with those produced by the boiled solution of venom, or in other words by the venom peptone. Experimeu-f.—The trater-n uom-globu/in from 0.03 gram of dried venom of the Crotalus ailamunti us, dissolved in a little water by means of a few crystals of salt, w.is injected into the breast muscles of a pigeon at 3:55. At 5:50 the animal was dead. The region of injection was terribly swollen, blackened, and suffused with liquid blood. (The amount of globulin injected was about 0.003 gram.) In a rabbit to which had been given some of the ictder-renom-gtobu/iu intra- venously, enormous extravasations were found when the abdominal cavity was opened. In another experiment with the irater-venom-glolrulin obtained from the venom of the Moccasin, the animal lived for some time, and very characteristic effects of slow poisoning from venom globulin were observed. Expi rimeid.—One c. c. of distilled water containing 0.001 gram of water- reu.om-globulin, from the Moccasin was thrown into the breast muscles of a pigeon at 5:20. At 0:00 the local darkening and swelling of the lissues at the region of injection were noticeable. After twenty-four hours the animal was in a generally fair condition ; tin- side was considerably darkened, and on the breast was a large1 swelling, which appeared to be due to a bloody effusion into the subcutaneous tissue. After forty-eight hours there was a discharge of red serum with a putre- factive1 odor. The whole of the side was darkened and greenish, and had the appearance of commencing gangrene. Copper-venom-globulin. — Sonic1 of the lopper-reuom-globulin, from the venom of the Crotidus ad a muidi us was injected with a little water into the breast muscles of a pigeon at 4:35. At 5:00 it was weak, but no local effects were apparent. On the following morning it was dead. The local effects were intense; there1 was considerable swelling, blackening, and diffusion of fluid blood. The heart was arrested midway between systole and diastole, and contained fluid blood of a dark color. ])ialysis-renom-globulin.—Some of the dialysis-renom-globulin, from the venom of the Crotalus adamanteus was injected into the breast muscles of a pigeon at 5:03. At 5:IS was sickish; 5:1!) unsteady, side somewhat swollen and darkened; 5:30 local effect increased. Following morning—dead. Eocal effects intense—great swelling, blackening, and diffusion of blood, which is incoagulable. In another experiment, in which a larger quantity was used, the bird died in twenty-five minutes, after the occurrence of stupor, incoordination, deep laborious breathing, and convulsions. There was no time for very decided local effects, but the blood was tarry and incoagulable. These experiments, which have been frequently repeated, render it clear that tin1 remarkable local effects produced by the venoms of the Crotalus and Moccasin, and which are not observed after the venom is boiled, are due to the venom GLOBULINS AND PEPTONES AS LOCAL POISONS. 55 globulins, all of which bring about essentially the same local alterations. To fully satisfy ourselves that these interesting local effects were dependent upon the physiological activities of the globulins and not upon a possible contamination by peptone, observations were made with the boiled globulins. In none were there the least evidences of the presence of any poisonous element. Whevever globulins alone are used, we have these local bleedings, fluid blood, and capillaries giving way soon after the poison reaches them. The system at large soon or late repeats the coarser phenomena of the wound; and yielding vessel walls, fluid blood, and countless hemorrhagic outflows exhibit the power of the globulins. Peptone, or, which is much the same, briefly-boiled venom, causes putrefactive changes swiftly, and shows but slight capacity to make fluid the blood, or to corrode the capillaries. The wound is foul and cedematous, but not filled with blood, whilst in its general effects the venom peptone fails again to exhibit the capacity of the globulins to multiply hemorrhages, and to destroy the natural ability of the blood by clotting to. check its own wasteful expenditure. In proportion as the peptones predominate will we have then a lessening of rapidly formed local lesions, and this is of course why Cobra venom does not give us the same terrible local consequences which ensue in Daboia, Moccasin, and Crotalus bites, where we have the potent combination of enough peptones and an excess of globulins. For a comparison of the local effects of Cobra and Crotalus poisoning, see Plate II., Figs. 2 and 3. 1 II E V E X O M S O I C E R T A 1 N T 11 A N A TOPHI D E -E CHAPTER VII. THE ACTION OF VENOMS AND THEIR ISOLATED (JLOI5ULINS AND PEPTONES UPON THE PI LSE-RATE Sfiction I.—Pure Venom. The experiments made in connection with the pulse-rate were performed upon rabbits, and in every cast1, unless otherwise noted, the poison was dissolved in 1 e. e. of distilled water and injected intravenously, usually into the1 external jugular vein. In researches made with the isolated poisons doses were usually employed which represented the amount of the individual poison contained in the commonly employed doses of the pure dried venom, thus giving a fair idea of the part played bv the individual principles in the results produced. In some experiments, how- ever, much larger doses were used to learn more fully the1 poisonous character of these substances. In all of our observations we find that the- results produced in animals, under apparently the same conditions and by using the same doses, vary very greatly; sometimes the pulse is quickened from the first and remains beyond the normal until death ensues, sometimes there is a primary diminution followed by an increase1, at others there is a diminution which continues until death. The.1 pulse is generally found to vary much in frequency. These facts all suggest that the action of the pure venom is of a complex nature; there being several factors con- cerned in the various alterations, and render it not improbable that in some instances ecchymoses in the various organs may account for exceptional variations. Twentv experiments were made with pure venoms upon normal animals; six of these were made with the venom of the Crotalus adamaideus; in three the pulse- rate was diminished and remained below normal, in two there was a primary increase1 followed by a diminution, and in one of these the pulse-rate afterwards went above the normal, while in another there was a primary diminution followed by an increase. Of two experiments made with the Crotalus horridus, in one there was an increase which continued until death, and in the other an increase followed by a diminution below7 the normal, this diminution in turn being followed by a rise above the normal, which continued until approaching death. In two experiments with the Auxis/rodon pisdrorus, in one there was an increase and in the other a decrease1. One experiment with the An.cistrodon. coidortrix gave an increase. In one experiment with the Crotalophorus miliaris there was a decrease followed by an increase. In one with the Daboia Russellii, which was not a perfectly satis- THE ACTION OF VENOMS UP OX THE PULSE-RATE. 57 factory experiment, there was a decrease, and in six experiments with the Cobra there was an increase in all, the increase being followed in three by a permanent decrease; in one the increase was followed by a diminution, and this in turn by an increase; in two experiments there was a permanent increase, excepting near death when a decrease ensued. It will thus be clear that even under apparently the same conditions we cannot foretell what the alterations in the pulse-rate will be in any given experiment; although the results of the six experiments with Cobra venom are so uniform in regard to the primary increase as to indicate that with it at least we should always expect to find more or less acceleration which may or may not continue above normal, even up to the time of death. We may also add here, that we cannot trace any relations in the alterations in the pulse, arterial pressure, and respiration to each other, so that it seems as if the changes must depend essentially upon actions peculiar to each apparatus. This holds good with the study of the pure venoms or their isolated poisons. Action of the Pure Venoms upon the Pulse-rate in Normal Animals. 1. REMARKS. Experiment No. Time: Normal 1 1 1 2 5 7 8 9 10 II 1-2 13 20 21 23 20 40 00 20 40 00 00 00 00 00 00 00 00 00 00 30 00 Pulsations per minute. 285 285 285 285 285 285 285 285 285 270 270 240 255 270 270 270 270 Injected 1 drop of fresh venom from the Crotalus adamanteus into the thigh of a large rabbit. Clot in canula. At 1:00 the blood-pressure began falling and reached a minimum at 10:00, when it was one-third less than the normal. Experiment No. 2. Normal Time: Pulsations min. sec. per minute. 240 20 240 40 240 1 00 195 1 20 Lpril, 1886. REMARKS. Injected 3 drops of the fresh venom of the Crotalus adaman- teus into the thigh of a large rabbit. Animal broke loose and tore the canula from the artery. ,)S THE VENOMS OF CERTAIN T II A N A T O P II I D E .E. Experiment A". »i. mlu. tir. per iimiuu-. Normal o.v, Injected intravenously 0.00:5 gram dried ve-ne.in of the ( to- tal us adamanteus in 1 u. c. distilled water. 1 imi': I'lilMitiong ill), tir. per iniiiuU'. 255 10 240 20 225 30 225 40 210 50 195 1 .00 195 1 20 210 1 la 210 2 00 225 2 20 270 2 40 270 KKMAIIKS. Ex pi rimeut Xo. 4. Normal Time: Pulsations mln. =ec. per minute. 300 5 310 10 330 2(1 330 30 300 40 50 270 270 1 1)0 270 1 20 2S0 1 40 270 0 10 270 4 00 2S0 i 00 3(10 s 00 ill) 8 10 130 8 20 170 s 30 2tn s 40 292 s 50 320 10 30 320 13 00 2S0 13 30 13 50 300 14 00 300 If, 00 280 1G 05 16 30 280 17 00 REMARKS. Injected intravenously 0.003 gram dried venom of the Cro- talus adamanteus dissolved in 1 c. c. distilled water. Struggles accompanied by remarkably slow heart beats a-ncl considerable increase of arterial pressure. Injected 0.003 gram dried venom dissolved in 1 c. c. distilled water. Repeated the injection. Dead Heart in complete diastole; blood incoagulable, ecchy- uioses in pericardium and peritoneum. THE ACTION OF VENOMS UPON THE PULSE-RATE. 59 Experiment Xo. 5. Normal Time: 10 20 30 40 00 20 40 00 00 00 Pulsations per minute. 225 270 120 180 285 285 285 285 285 ? REMARKS. Injected intravenously 0.015 gram dried venom of the Cro- talus adamanteus dissolved in 1 c. c. distilled water. I Struggles. Too feeble to count. Dead. Experiment No. 6. Time: Normal 1 1 3 5 7 8 13 17 5 20 30 40 00 30 30 30 30 00 00 30 Pulsations per minute. 323 315 214 225 255 255 255 240 240 225 195 195 REMARKS. Injected intravenously 0.015 gram dried venom of the Cro- talus adamanteus dissolved in 1 c. c. distilled water. Dead. Experiment No. 7. Time: Pulsations min. sec. per minute. Normal ... 260 5 260 20 98 30 84 40 120 1 00 REMARKS. Injected intravenously 0.02 gram dried venom of the Crotalus adamanteus dissolved in 1 c. c. distilled water. Blood pressure increased, probably due to asphyxia. Dead. Experiment No. 8. Normal Time: 10 30 44 55 60 80 1 40 Pulsations min. sec. per minute. 300 195 60 70 130 220 260 REMARKS. Injected into the right carotid artery 0.015 gram dried venom of the Crotalus adamanteus dissolved in 1 c, c. distilled water. Dead. CO T II E V E N O M S O I (' E R T A I N T II A X A TO P II I D E A\. J.Xpi rimrnt Xo. {). Normal Time : Pulsations min. sec. per minuU1. 225 Injected hit Ill 235 talus horj 20 210 30 2 40 50 240 1 00 210 1 10 240 1 20 240 1 30 240 1 Ml 210 3 41) 2i;o 5 4 Time: Pulsations min. sec. per minute. 205 1 00 205 3 00 203 8 00 205 10 00 126 15 00 105 17 00 105 19 00 REMARKS Injeeted intravenouslv 0.003 gram dried Cobra venom dis- solved in 1 c. c. distilled water. REMARKS. Injeeted intravenously 0.003 gram dried Cobra venom dis- solved in 1 c. c. distilled water with a few crystals of sodic chloride. Dead. Experiment Xo. 17. Normal Time: Pulsations min. sec. per minute. 260 Injected intrai 20 270 solved in 1 c 30 250 chloride. 40 250 1 00 250 1 20 250 1 40 230 4 40 240 7 40 250 s 40 190 !l 10 Clot in canula. 15 00 Dead. REMARKS. Injected intravenously 0.005 gram dried Cobra venom dis- solved in 1 c. c. distilled water with a few crystals of sodic THE ACTION OF VENOMS UPON THE PULSE-RATE. 63 Experiment No. 18. Normal Time: min. sec. 10 20 30 40 00 30 00 10 20 50 30 20 Experiment No. 19. Normal Time: min. sec. 10 15 20 30 40 2 00 Pulsations per minute. 310 310 320 310 260 310 330 340 340 150 150 165 Pulsations per minute. 290 290 280 280 280 REMARKS. Injected intravenously 0.015 gram dried Cobra venom dis- solved in 1 c. c. distilled water. Dead. REMARKS. Injected intravenously 0.005 gram dried venom of the Daboia Bussellii dissolved in 0.5 c. c. distilled water. Tetanic convulsions. Dead. Experiment No. 20. Normai Time: 0 13 20 40 00 30 00 00 9 00 12 00 14 00 20 Pulsations. min. sec. per minute. 216 252 252 264 288 260 264 231 108 48 126 REMARKS. Injected intravenously 0.003 gram dried venom of the Cobra dissolved in 1 c. c. distilled water. Respiration ceased; artificial respiration used. Actions of Pure Venoms on the Puh'e-rate in Animals ivith Cut Pneumogastric Nerves.—After section of the pneumogastric nerves we invariably found an increase which was, as a rule, very slight. Seven experiments in all were made on animals thus operated upon: one with the venom of the Crotalus adamanteus; one with the Crotalus horridus; one with the Ancistrodon piscivorus; one with the Ancis- trodon contortrix, and three with the Cobra. (;4 TH E V i: N (» M S O 1 ( E 11 T A I N T II A N A TOPHI 1) E -E R1-: MARKS. Pneumogastric nerves cut. Injected intravenously 0.003 gram dried venom of the Crotalus adumaiUeus dissolved in 1 c. c. distilled water. l.xjH'iuim nt Xo. 21. Time: Pulsations min. sec. per minute. Normal 295 10 300 30 300 1 00 300 1 30 295 •) 0(1 300 ■) 30 305 5 30 290 7 00 2s> •> 9 30 30 Exjn rnneut A 'o. 22. Time : Pulsations min. sec. per minute. Normal 315 Injected a similar dose. Dead. REMARKS. Pneumogastric nerves cut. Injected intravenouslv 0.015 gram dried venom of the Crotalus horridus dissolved in 1 c c. distilled water. 20 ... Violent struggles. 1 00 320 1 20 335 1 to 330 2 00 320 2 20 340 4 20 310 5 50 350 Dead. Experiment Ae>. 23. Time: Filiations REMARKS. min. 6ec. per minute. Normal . . . 210 Pneumogastric nerves cut. Injected intravenously 0.003 20 300 gram dried venom of the Ancistrodon piscivorus dissolved in I c. c. distilled water. 30 300 Struggles. 40 300 50 300 1 00 240 1 20 225 3 5() 210 Struggles. 5 50 270 6 00 300 Convulsions. s 00 2^5 10 00 270 12 00 270 14 00 2s5 19 00 240 Injected a similar dose. 19 10 255 19 20 255 19 30 255 19 40 240 19 50 240 2o 00 24U THE ACTION OF VENOMS UPON THE PULSE-RATE. 65 Time: Pulsations min. sec. per minute. 20 20 240 21 20 255 23 20 300 25 20 270 28 20 255 33 20 255 38 20 255 44 20 255 44 40 225 REMARKS. 45 10 Injected a similar dose. Dead. Experiment No. 24. Time: Pulsations min. sec. per minute. Normal . . 300 10 300 20 310 30 310 40 310 1 00 310 1 50 310 4 20 310 7 00 310 7 05 7 10 320 7 20 300 7 40 300 8 00 310 9 00 315 11 30 300 11 40 295 12 00 290 12 30 290 13 00 290 13 30 290 19 00 285 19 20 270 19 40 270 20 20 285 21 50 285 22 50 285 Experiment No. 25. Time: Pulsations min. sec. per minute. Normal 330 10 330 30 330 1 00 330 3 30 340 6 30 330 10 30 320 14 30 295 16 30 275 0 May, 1886. REMARKS. Pneumogastric nerves cut. Injected intravenously 0.003 gram dried venom of the Ancistrodon contortrix dissolved in 1 c. c. distilled water. Injected a similar dose. 'Struggles. Injected a similar dose. REMARKS. Pneumogastric nerves cut. Injected intravenously 0.003 gram dried Cobra venom dissolved in 1 c. c. distilled water with a few crystals of sodic chloride and filtered. Clot formed in canula. tili T 11 E V E X O M S O 1 C E R I A1 N 1 11 A N A T O P 11 1 D E .E. Experinu id Xo. 2(>. Time: Pulsations REMARKS. min. sec. per minute. Normal 320 Pneume>gastric nerves cut. Injeeted intravenouslv 0.006 gram dried Cobra venom prepared us in the foregoing experiment. 1(1 315 30 330 ] 00 330 1 :;o 330 3 30 335 5 30 310 . 27. Pul.-utious REMARKS. per minute. Normal 390 Pneumogastric nerves cut. Injected intravenously 0.003 . . . gram dried Cobra venom dissolved in 1 c. c. distilled water. 396 390 360 354 Clot in canula. Dead of asphyxia, Tin Actions of Cure V< uoms on Animals in 'irhhli Sdions of the Emumogast'ric, X< rres and of tin lpp< r Cervical Portion of the Spiu.al Cord had been made.— After isolation of the heart from the nerve centres by making section of the pneumogastric nerves and spinal cord in the middle or upper cervical region, and maintaining the animal alive by means of artificial respiration, we find that the pulsations of the heart arc almost invariably slightly diminished in frequency upon use1 of venom. Sewn experiments were made: three with the venom of the Crotalus adamanfius; one with the Crotalus horridus; one with the And*trodon piscivorus ; one with the And ^trodon contort rio-,, and one with Cobra,. In one expe- riment with the Crotalus a,la maidens ill which two doses were given, there occurred a diminution after the hist close, while there was a marked increase after the second. In the experiment with the Crotalus horridus there was but little alteration. E. xperimeiU Xo. 2 s. Time: Pul-atioli- min. MV. per minute. Normal 240 10 235 20 2o0 30 225 40 215 1 00 210 1 20 210 1 40 210 solved in 1 c. c. distilled water. Dead. THE ACTION OF VENOMS UPON THE PULSE-RATE 67 Experiment No. 29. Time: Pulsations min. sec. per minute. Normal 185 10 185 20 185 30 180 1 00 180 1 20 180 3 20 180 3 50 180 5 50 160 7 50 Experiment No. 30. Time: Pulsations min. sec. per minute. Normal 240 10 230 20 230 30 230 40 195 1 00 200 1 20 205 1 40 210 2 00 230 2 30 265 3 00 250 6 00 300? 6 05 265 6 15 6 35 270 7 05 260 7 35 260 8 05 260 15 05 Experiment No. 31. Time: Pulsations min. sec. per minute. Normal . . 235 10 230 30 240 40 240 1 00 235 2 00 240 4 00 240 6 00 230 8 00 220 REMARKS. Pneumogastric nerves and cord cut. Injected intravenously 0.003 gram dried venom of the Crotalus adamanteus dis- solved in 1 c. c. distilled water. Dead. REMARKS. Pneumogastric nerves and cord cut. Injected intravenously 0.003 gram dried venom of the Crotalus adamanteus dis- solved in 1 c. c. distilled water. Injeeted a similar dose. Dead. REMARKS. Pneumogastric nerves and cord cut. 0.015 gram dried venom of the solved in 1 c. c. distilled water. Injected intravenously Crotalus horridus dis- 12 00 Dead. lis T II E V E X CMS () E C E II T A I N T II A N A T O P II I D E .E Ex]* ruin id .V». 32. Normal . . . 220 Pneumogastric nerves and cord cut. Injected intravenously 0.OO3 gram dried venom of the Ancistrodon piscievrns dissolved in 1 c. c. distilled water. Struggles. Time: Pulsations min. bCC. per minute. 220 20 210 30 200 40 200 1 00 210 1 30 210 1 50 210 4 20 195 S 20 210 10 2o 210 12 20 210 15 20 210 is 20 210 21 20 REMARKS Dead. Experiment Xo. 33. Time : Pulsations REMARKS. min. sec. per minute. Normal . . . 260 Pneumogastric nerves and cord cut. Injected intravenously 10 255 0.003 gram dried venom of the Ancistrodon con/ortri.r 20 250 dissolved in I e-. c. distilled water. 40 213 1 00 243 1 30 24 5 2 00 240 4 00 240 7 00 240 9 00 240 11 00 240 13 00 240 15 00 240 17 00 240 20 00 240 22 00 240 Injected 0 006 gram. 22 15 ? 22 30 ? Dead. Experiment Xo. 34. Time: Pulsations REMARKS. min. sec. per minute. Normal . . . 220 Pnenmogastric nerves and cord cut. Injected intravenously 10 215 0.003 gram dried Cobra venom dissolved in 1 e-. c. distilled 30 215 water. 1 00 210 3 00 215 5 00 215 s 00 225 11 00 225 14 00 225 19 00 225 Killed by pithing. THE ACTION OF VENOMS UPON THE PULSE-RATE. 69 Summary and Conclusions of the Actions of Venoms on the Pulse-rate.—The results of this series of experiments indicate that the primary tendency of venoms is to cause an increase of the pulse-rate, that this tendency is greater after section of the pneumogastric nerves, and that it rarely occurs after conjoined section of the pneumogastric nerves and the upper or middle cervical region of the spinal cord. From the increased tendency to acceleration of the pulse-rate in poisoning by venom after section of the pneumogastric nerves we infer that there is some direct or indirect effect of the venom upon the pneumogastric centres by which an inhibi- tory influence is exerted, and which tends to neutralize the action bringing about acceleration. Since hasten1' g of the pulse is a rare occurrence after conjoint section of the pneumogas^ ic nerves and the cervical spinal cord, we think that the increase is due for the most part to some effect upon the accelerator centres in the medulla, whereby impulses are sent through (chiefly at least) those of the accelerator fibres which pass by the cord. The increase of the pulse-rate which may occur after division of the nerves distributed to the heart, by section of the pneumogastric nerves and cervical spinal cord, must be dependent upon a direct action of the venom upon the heart muscle or its contained ganglia. The diminution in the heart beats must be due to a direct cardiac action, since it occurs after isolation of the heart, as above, from any central nervous influence. In these as in all other experiments which involve intravenous use of venoms we are liable to disturbing elements which do not trouble our explanations in dealing with other poisons. At any moment, anywhere in nerve-tissue or muscles, we may have abrupt and quite countless hemorrhages. How these may introduce con- flicting symptoms and modify results has already been pointed out by one of us many years ago.1 They make absolute constancy of effects quite improbable. Section II.—The Actions of Globulins on the Pulse-Rate. The Actions of the Venom Glolndins on the Pulse-rate.—The actions of the venom globulins upon the pulse-rate appear to differ somewhat in quality from what is found in poisoning with pure venoms; there is a greater tendency to the primary increase in the pulse than with pure venoms, while the action by which this is brought about seems to differ. Of eleven experiments in which the amounts used represented the proportion of the respective globulins contained in the usual doses of venom given, six were made with the water-venom-globulin, two with the copper-venom-globulin, and three with the dialysis-venom-globulin; all of these poisons, excepting in one experiment with the water-venom-globulin of the Ancistrodon, were derived from the venom of the Crotalus adamanteus. The water-venom-globulin seems to be the most active, and the copper-venom- 1 Researches on the Venom of the Rattlesnake. S. Weir Mitchell, isiil. ■jll THE VENOMS Ol CERTAIN T II A N A T O P II I D E .E . globulin the1 least so. Of the six experiments with the1 feirmer, in four there1 was a primary increase- in the pulse-rate followed by diminution, and in one case by a sti!w( ijui nt increase; in the other two there was a diminution from the1 first, the puke regaining its normal frequency, or, as in one instance1, rising above it. In both the experiments with copper-venom-globulin there1 was a primary increase1 followed by a diminution in one case, and in the other by a return of the rate1 to about the normal. In the three experiments with clialysis-vcnom-globulin, a primary increase occur- red. In two this was followed by a drop below normal, while in the other tin1 rate remained above the normal. F.xp< r'nuent Xo. 3.3. Time : Pulsation? min. tec. per minute. Normal . . 290 10 305 20 310 40 315 1 00 290 1 30 270 3 00 270 5 00 270 7 1)0 270 9 00 2s() 12 00 290 15 00 3O0 Is 00 315 25 00 320 35 00 330 45 00 330 55 00 330 Experiment A' o. 3d Time: Pulsations min. 6ec. per minute. Normal . , 310 10 310 20 275 40 265 1 00 260 1 20 260 1 40 2s0 3 40 290 7 40 310 9 40 310 10 00 315 10 20 300 10 40 300 14 00 300 17 00 300 20 00 300 30 no 300 HEM ARKS. Injected intravenously 0.0012 gram water-venom-globulin (—0.015 gram dried venom) from the venom of the Cm- talus adamanteus. Killed. REMARKS. Injected intravenously the voter-venom-globulin from 0.03 gram dried venom of the Crotalus adamanteus. Clot in canula. Injected tvater-venom-ghbulin from 0.015 gram dried venom. Killed by pithing. THE ACTION OF VENOMS UPON THE PULSE-RATE. 71 Experiment No. 37. Normal Time: Pulsations min. sec. per minute. 320 10 350 20 330 30 305 50 300 1 10 300 4 10 300 4 30 310 4 35 310 4 40 310 4 50 310 REMARKS. 15 Experiment No. 38. Normal Time: min. sec. 10 20 30 50 00 30 30 30 30 30 30 30 30 30 30 30 00 00 00 15 00 00 00 1 1 3 5 7 9 12 14 16 17 19 21 26 28 30 30 35 37 39 Experiment No. 39. Time: Normal 30 50 00 30 50 00 40 10 Pulsations per minute. 270 290 295 295 260 255 260 265 260 265 265 260 260 270 275 275 260 260 260 200 260 260 260 255 Pulsations per minute. 280 270 230 220? 280 260 180 260 280 Injected intravenously 0.0033 gram water-venom-globulin from the dried venom of the Crotalus adamanteus dissolved by the addition of a trace of sodic carbonate. Injected double dose. Injected double dose. Killed by pithing. REMARKS. Injected intravenously the water-venom-globulin from one minim of fresh venom of the Crotalus adamanteus. Clot in canula. Clot in canula. Animal killed by pithing. REMARKS. Injected intravenously the water-venom-globulin from 0.004 gram dried venom of the Ancistrodon piscivorus dissolved in 1 c. c. distilled water by the addition of a few crystals of sodic chloride. Injected a similar dose. T II E \ E N O .M S () E ( E K T A 1 N I II A N A T () P II I D E .E. REMARK.' Experiment S o. 40. Time: Pulsations min. sec. per minute. N"rnjul . , 0 312 10 314 20 30 360 1 3o 316 •2 3o 304 5 30 324 10 30 354 14 30 360 19 30 396 24 30 3S4 29 30 372 34 30 372 42 30 372 47 30 372 52 30 372 57 30 360 67 30 31C 77 30 316 so S5 30 120 Injected intravenously the ivatcr-vcnum-rjlobulin from 0.015 gram dried venom of the Crotalus adamanteus. Hematuria. I.xperiuuid Xo. 41, Normal • • ■ -s,» Injee-ieel intravenously 0.0012 gram coppcr-veuom-globulin from the dried venom of the Crotalus adamanteus. Time : Pulsations miu. sec. per minute 2sil 10 2 s;, 20 290 30 2 s;, 50 2 SO 0 50 270 4 50 270 6 50 2i;o s 50 260 10 50 255 11 50 260 17 20 2s 0 is 20 2so IS 30 300 Is 40 290 Is 50 2v", 19 00 2sn 20 00 2sf, .)o 00 285 o- 00 290 Dead; eee-livmose-s in intestines; blood fluid. REMARKS. Injected a similar THE ACTION OF VENOMS UPON THE PULSE-RATE. 73 Experiment No. 42. Time: Normal 1 3 5 7 8 10 12 26 26 26 26 27 27 10 30 00 00 00 00 00 00 00 22 00 24 00 00 10 20 30 00 00 29 00 31 00 34 00 39 00 41 00 43 00 45 00 52 00 58 00 Pulsations per minute. 290 290 305 310 310 310 310 310 310 312 2S0 280 280 285 290 290 290 290 280 270 250 295 290 285 285 295 295 REMARKS. Injected intravenously 0.00225 gram copper-venom-globulin from the dried venom of the Crotalus adamanteus. Clot in canula. Injected 0.0045 gram. Experiment No. 43. Time: Normal min. sec. 20 40 50 20 20 20 20 23 30 45 05 25 55 25 25 00 1 3 5 18 18 18 18 19 19 19 20 21 22 30 00 10 May, 1886. Pulsations per minute. 290 305 305 305 295 275 275 280 290 280 270 270 270 138 315 REMARKS. Injected intravenously 0.0017 gram dialysis-venom-globulin from the dried venom of the Crotalus adamanteus dissolved in 1 c. c. distilled water with a trace of sodic carbonate. Animal broke loose. Injected 0.0034 gram dialysis-venom-globulin. Struggles. Dead. T II E V i: N () M S O F C i: K T A I N T 11 A N A TOPHI D E .E /'. xp< r inn id .\ppc r-ve u.om-globuli n, one with dialysis-vcu.oni- globulin (all from the Crotalus adamanteus), and one with the water-re uom-glolml in, of the Cobra—there wa* a tendency to a lowered pulse-rate, although in one experiment there was a primary increase, and in another a slight increase above the- healthy number after repeated injections. The effects were generally less than in normal animal. THE ACTION OF VENOMS UPON THE PULSE-RATE to Experiment No. 46. Normal Time : min. sec. 10 20 00 40 40 40 Pulsations per minute. 205 220 230 210 190 170 180 Experiment No. 47. Normal Time : min. sec. 0 15 25 45 15 00 00 00 00 00 00 1 2 4 8 13 18 23 28 Experiment No. 48. Normal Time: min. sec. 20 40 10 10 10 10 10 10 40 15 1 3 5 7 9 23 23 24 Pulsations per minute. 324 ai2 318 264 300 304 276 288 310 319 Pulsations per minute. 305 300 288 285 285 2S5 300 290 310 310 310 Experiment No. 49. Normal Time: Pulsations min. sec. per minute. 300 20 300 40 300 50 300 2 50 300 4 50 300 6 50 300 8 50 300 11 50 300 REMARKS. Pneumogastric nerves cut. Injected intravenously 0.0011 gram ivater-venom-globulin from the dried venom of the Crotalus adamanteus. Clot in canula. REMARKS. Pneumogastric nerves cut. Injected intravenously water- venom-globulin from 0.035 gram dried Cobra venom dis- solved in 1 c. c. distilled water. Animal broke loose from canula. REMARKS. Pneumogastric nerves cut. Injected intravenously 0.0012 gram copper-venom-globulin from the dried venom of the Crotalus adamanteus. Injected 0.0024 gram. Killed. REMARKS. Pneumogastric nerves cut. Injected intravenously 0.0012 gram copper-venom-globulin from the dried venom of the Crotalus adamanteus. T II E V E N (IMS O E ( E K T A 1 N T HAN A TOPHI D E .E. REMARKS. Injected 0.0024 gram. Struggles. Time : Pulsations min. SOC. per minute 13 5(1 300 15 5(1 300 16 10 300 16 20 300 16 30 300 16 45 300 17 45 300 19 45 300 21 45 300 23 45 270 25 45 2-.H 26 45 270 27 00 270 Animal killed by pithing. Expert iiu id Xo. -30. Time: Pulsations REaIARKS. min. sir. per minute. Normal . . . 310 Pneumogastric nerves cut. Injected intravenously 0.0017 10 305 gram dialysis-venom-globulin from the dried venom of the 20 300 Crotalus adamanteus. 30 300 50 310 Struggles. 1 50 300 4 20 310 6 20 300 S 20 295 10 20 295 12 20 300 Struggles. 17 50 300 is -jo 300 Injected 0.0034 gram. 1* 40 310 1!) 00 . . Struggles. » 19 15 320 19 20 330 21 50 320 23 00 310 25 00 310 27 00 310 29 00 310 34 00 305 34 30 300 3* 30 290 41 00 2*u 47 00 217 49 00 Dead. The Actions of Venom Globulins on the Pulse-rate in Animals tvitji the Pneu mo- gastric Xerves and Cervical Spinal Cord Cut.—In four experiments in which the pneumogastric nerves and spinal cord in the middle cervical region wen1 cut—one was made with the water-venom-globulin. one with the eojgter-vcuom-gffjbuliit,, and two with dialysis-vi nom-gloLtdin of the ('retains adamanteus: in one experiment THE ACTION OF VENOMS UPON THE PULSE-RATE. 77 there was a fall followed by a rise to the normal, and succeeded by a slight fall; in a second the pulse-rate always remained below normal, while in the third there was an almost inappreciable rise, this followed by a fall, and by an increase due to a further injection of the poison. The last showed a slight fall, then a return to the normal. Experiment No. 51. Time: Pulsations min. sec. per minute. Normal . . 250 10 250 30 215 1 00 240 1 10 240 2 10 245 3 10 245 5 10 245 7 10 245 9 10 245 11 10 250 15 10 250 17 40 245 19 00 240 21 00 240 23 00 240 25 00 240 27 00 240 Experiment No. 52. Time: Pulsations min. sec. per minute. Normal . . 255 10 255 20 240 40 250 1 00 250 3 30 240 5 30 225 9 30 225 11 30 210 13 30 210 16 30 210 17 00 204 17 30 210 18 00 210 20 00 210 24 00 195 26 00 180 28 00 180 30 00 180 32 00 180 34 00 187 REMARKS. Pneumogastric nerves and cord cut. Injected intravenously 0.0011 gram water-venom-globulin from the dried venom of the Crotalus adamanteus. Killed. REMARKS. Pneumogastric nerves and cord cut. Injected intravenously 0.0048 gram copper-venenn-globulin from the dried venom of the Crotalus adamanteus. Injected 0.0048 gram. Killed. T II E V E N 0 .M S O E C E l\ T A I N T II A N A T O P II I D E .E E. rpertuti u Normal t Xo. Time: nun. sec. 10 30 00 00 00 30 30 30 50 10 30 50 00 00 00 ')•). Ill 12 12 13 13 13 15 16 1* Experinu id Xo. 54. Time min. m Normal 10 20 30 40 50 oo 10 20 n0 Pulsations per minute. 240 240 215 230 220 220 220 230 230 220 225 210 210 200 190 Pulsations per minute. 300 290 290 300 300 300 300 300 300 REMARKS. Pneumogastric nerves and cord cut. Injected intrav 0.0017 gram dialysis-venom-globulin from the driei of the Cvolalus adamanteus. Injected 0.0034 gram. cnouslv I venom Dead. REMARKS. Pneumogastric nerves and cord cut. Injected intravenously O.OOOS gram dialysis-veiimn-globulin from the dried venom of the Crotalus adamanteus. Tremors. Clot formed in canula. Dead. A review of the results of these experiments with the globulins on the pulse-rate in normal animals indicates that water-venom-globulin is the most potent, and the copper-venom-globulin the legist so. With the former there occurred in four of the six experiments a primary increase followed by a fall, while in the other two there was a diminution from the first. In experiments with the copper-venom-globulin and dialysis-venom-globulin there was always a primary increase, and in four out of the five experiments this was followed by a decline. Alter section of the pneumogastric nerves a primary increase (due probably to some accidental cause) occurred in one out of the five experiments, in two of the other four there at first was no appreciable change, and then a diminu- tion, while in the remaining two there was a lessening of the rate from the time of injection. These results suggest that the increase of the pulse-rate, which occurred in animals with intact vagi, was in some degree at least dependent upon an influence1 exerted through the pneumogastric centres and nerves. It will be observed that we here1 have results which are directly opposed to what we have seen with pure venom ; that is a lessened tendency to the primary increase of the THE ACTION OF VENOMS UPON THE PULSE-RATE. 79 pulse after section of the pneumogastric nerves. If the increase in the pulse-rate in normal animals is due for the most part to excitation of the accelerator centres, whereby impulses are generated which pass chiefly through the accelerator fibres running in the spinal cord, it would seem probable that the accelerator impulses induced by the globulins take for the most part the course of the fibres through the pneumogastric nerves, but are much feebler than the impulses which are gene- rated by the pure venoms, and which take their path chiefly through the fibres in the spinal cord. After section of both the pneumogastric nerves and cervical spinal cord, we found in all of our experiments a diminution in the heart-beats; this must be due to a direct action of the globulin upon the heart. It therefore seems probable that the globulins cause a primary increase of the pulse by an excitation of the accelerator centres, whereby impulses are conveyed principally by the accelerator fibres passing through the pneumogastric nerves; and a diminution of the heart beats by a direct action on the heart. Section III.—The Actions of Venom Peptones upon the Pulse-Rate The Action of Venom Peptones on the Pidse-rate.—In seven experiments made with peptone on normal animals—four with the peptone from the venom of the Crotalus adamanteus ; one with that of the Ancistrodon piscivorus; and two with that of the Cobra—we find results which vary and which resemble closely those obtained by the'administration of pure venom. In three experiments there was a primary increase of pulse followed generally by a diminution; in three the pulse remained below normal; while with Ancistrodon peptone there was a primary fall of rate followed by a rise. The differences in the results, as in previous experiments, do not seem to depend at all upon the dose or the variety of venom from which the peptone was obtained. REMARKS Experiment No. 55. Time: Pulsations min. sec. per minute. Normal 280 Injected intravenously 20 102 venom of the Crotalui 30 190 40 190 50 190 1 00 180 3 00 190 6 00 340 Struggles. 11 00 285 Struggles. Broke loose, 49 00 Dead. T II I. V E N O M S O 1 C E 11 T A I N T 11 A N A TO P II I 1> E .E. Exjh rinuut A ■>. i)(\ Time : Pulsations min. bCC. pei ' minute, Normal 225 10 260 30 260 1 00 2*5 2 00 270 5 00 260 9 00 25(1 REMARKS. Injected intravenously the peptone from 0.03 gram dried venom of the Crotalus adamanteus. Killed by pithing. Expcrimi nt Xo. 57. Time : Pulsations min. sec. per minute. 2*0 30 2s0 1 00 270 1 30 285 4 30 270 10 30 270 10 50 270 11 10 270 11 30 270 REMARKS. Normal 2*0 Injected intravenously the peptone from 0.015 gram dried venom of the Crotalus adamanteus. Injected double the amount. Experiment Xo. 5s. Normal 270 Injected intravenously the peptone from 0.015 gram dried venom of the Crotalus adamanteus. till ie : Pulsations in. see. per minute. 270 10 270 20 270 30 270 1 00 280 1 30 290 2 00 290 2 30 290 3 00 260 5 00 2C0 5 20 260 5 40 260 (i 00 260 6 30 255 7 00 250 7 30 240 s 00 260 REMARKS. Injected a similar quantity. Injected double the quantity. Experiment Xo. 59. Normal 300 Injected intravenously the peptone from 0.05 gram dried venom of the Ancistrodon piscivorus. Time: Pulsations min. sec. per minute. 300 10 175 30 110 1 00 2*5 1 20 290 1 40 300 2 00 310 REMARKS. THE ACTION OF VENOMS UPON THE PULSE-RATE 81 Time : min. sec. 20 40 40 50 00 20 6 30 13 30 Pulsations per minute. 340 315 340 348 340 340 340 REMARKS. Experiment No. 60. Normal Time : min. sec. 10 20 30 40 00 20 20 20 20 20 50 50 20 50 00 10 30 50 10 30 1 1 3 fi- ll 16 16 17 18 18 19 19 19 19 20 20 Experiment No. 61. Normal Time : min. sec. 10 15 30 50 20 20 20 3 8 10 10 40 10 50 11 11 20 40 11 12 00 12 20 12 40 May, 1886. Injected peptone from 0.01 gram venom. Killed. Pulsations per minute. 225 220 220 220 230 230 220 204 165 280 260 200 150 100 130 190 110 38 35 35 Pulsations per minute. 290 300 310 240 245 225 97 72 300 300 105 85 120 90 REMARKS. Injected intravenously the peptone from 0.005 gram dried Cobra venom. Struggles. Convulsive twitchings. Blood is asphyxiated ; no respiration. Killed. REMARKS. Injeeted intravenously the peptone from 0.06 gram dried Cobra venom. Tonic convulsions. Convulsive twitchings; asphyxiated blood; respiration ceased. Dead. SJ T II E V E N O M S 0 E C E K T A I N T II A N A T O P II I D E .E . The Actions of V> nom Pep1oti.es on. Animals in uh'uh the Pneumogastric Xirnx had b,en Cut.—Four experiments were made with the peptone on animals the pneumogastric nerve's e>t' which had been previously cut. In three of the four there was a primary increase in the pulse, while in the fourth there was a temporary diminution followed by a rise above normal. These1 experiments are1 in accord with those made with pure venom, and indicate a greater tendency to primary pulse frequency after section of the pneumogastric nerves. One of the above experiments was made with the peptone from the Crotalus ndu.iuun.icus; one with the Ancistrodon piscivorus ; and two with the Cobra. REMARKS. Pneumogastric nerves cut. Injected intravenously the peptone from 0.015 gram dried venom of the Crotalus adamanteus. Experiment X u. i\->. Time: Pulsations min. sec. pei ■ minute. Normal 2*5 10 2 so 30 2*5 40 300 50 300 1 00 300 1 20 300 1 30 300 3 30 315 s 30 330 15 30 345 20 30 325 25 30 315 30 30 315 35 00 315 40 00 315 45 00 270 50 00 255 62 00 2S5 Struirjrles. Killed. Experiment Xo. (V-\. Normal . . . 295 Pneumogastric nerves cut. Injected intravenously the peptone from 0.015 gram dried venom of the Ancistrodon pisci- vorus. Time: Pulsations min. sec. per minute. -)95 30 315 40 315 50 310 1 00 310 1 20 315 1 40 320 2 00 330 2 30 310 2 40 lo2 2 50 150 3 00 240 REMARKS. 4 20 ... Dead. THE ACTION OF VENOMS UPON THE PULSE-RATE. 83 Experiment No. 64. Time: Normal 1 1 3 5 7 9 10 21 25 26 10 20 40 00 30 30 30 30 30 00 30 30 30 Pulsations per minute. 230 235 240 230 230 230 230 230 230 220 220 225 230 235 REMARKS. Pneumogastric nerves cut. Injected intravenously the peptone from 0.005 gram dried Cobra venom. Twitchings. Killed. Experiment No. 65. Time: min. sec. Normal 1 3 5 16 34 10 20 40 00 00 00 00 00 Pulsations per minute. 265 265 255 260 260 270 270 275 REMARKS. Pneumogastric nerves cut. Injected intravenously the peptone from 0.006 gram dried Cobra venom. Dead. The Actions of Venom Peptones upon the Pulse-rale of Animals after Section of the Pneumogastric Nerves and, Cervical Spinal Cord.—Six experiments made on animals in which the heart was cut off from central nervous influence by section of the pneumogastric nerves and section of the spinal cord in the middle cervical region gave uniform results. Three were made with peptone from the venom of the Crotalus adamanteus; tw-o with the peptone from the Ancistrodon piscivorus, and one with that of the Cobra. In all of these experiments there was a diminu- tion of the pulse-rate, and usually this was well marked. These results are also in accord with what was found in experiments with pure venom. Experiment No. 66. Time : Pulsations min. sec. per minute Normal 200 10 185 20 195 40 195 1 00 190 3 00 160 13 00 195 15 00 200 REMARKS. Pneumogastric nerves and cord cut. Injected intravenously the peptone from 0.015 gram dried venom of the Crotalus adamanteus. (s J T II E V E N O M S O E C E K T A 1 N 1 II A N A I (» P H I D E. .E /•:. Time : Pulsations min. sec. per minute. 17 00 190 17 3(1 19 30 1*7 21 30 190 23 30 1S(I 25 3o 170 31 30 165 3 4 30 '•/" ii me id A o. 67. Time : Pulsations min. sec. per minute. -s ormal . . (I 15 20 282 276 30 264 1 00 264 1 30 246 2 00 234 xptrtincut A 'o. (is. Time: Pulsations min. sec. [mt minute Nr ormal 0 324 11 300 40 3is 1 40 276 5 40 272 10 40 276 15 40 3(»6 16 00 16 06 16 15 306 16 25 300 17 00 276 1* mi 270 REMARKS Injected peptone from 0.03 gram dried venom. Dead. REMARKS. Pneumogastric nerve-s and cord cut. Injected intravenously the peptone from 0.015 gram dried venom of the Crotalus adamanteus. REMARK:- Pneumogastric nerves and cord e-ut. Injected intravenously the peptone from 0.015 gram dried Cobra venom. Injected a similar dose. 23 00 ... Dead. In the above series of experiments with venom peptones we find results which agree with those in which the pure venoms were used. We conclude, therefore, that the peptones cause a primary increase and a secondary diminution of the pulse-rate, and that they occasion primary hastening of the heart beat by excita- tion of the accelerator centres in the medulla, and that the impulses are carried through fibres passing chiefly by the spinal cord. This increase is more marked after section of the pneumogastric nerves, thus suggesting that this principle has some direct or indirect effect upon the pneumogastric centres, tending to slow the action of the heart and to neutralize the accelerator influence. Peptones cause the diminution of the heart beat by a direct action on that organ. THE ACTION OF VENOMS UPON ARTERIAL PRESSURE 85 CHAPTER VIII. THE ACTION OF VENOMS AND THEIR ISOLATED GLOBULINS AND PEPTONES UPON THE ARTERIAL PRESSURE. Section I.—Pure Venom. The experiments made on the blood pressure with venoms and their icolated poisons were all made on rabbits. The manometer tube was connected with one of the carotid arteries, and the injections were always made into the external jugular vein unless otherwise noted. Eighteen experiments were performed with the venoms of different species of serpents, and in all of them there was a distinct lowering of the blood-pressure. It fell immediately after the injection, and indeed sometimes before injection was complete, and the fall was generally so marked as to indicate a most profound action of the poison upon some part or parts of the circulatory apparatus. If the dose be not immediately fatal the pressure gradually rises, but finally undergoes a more or less steady decline to death. At other times the pressure sinks without subsequent rise until death ensues. The tendency in Cobra poisoning is to a decided rise of pressure following the primary fall. In five out of six experiments with this venom the primary fall was followed by a rise which went above the normal. Of the eighteen experiments, five were made with the venom of Crotalus ada- manteus, in two of which the poison was given hypodermatically; two with that of the Crotalus horridus; two with the venom e-i Ancistrodon piscivorus; one each with the poisons Ancistrodon contortrix, Crotalophorus miliarius, and Daboia Russellii; and six with the venom of the Cobra. In all cases ether was given freely to the animal poisoned. Action of the Pure Venoms upon the Arterial Pressure in Normal Animals. Experiment No. 1. Normal Time: Pressure min. sec. m. m. 126 20 126 40 126 1 00 124 1 20 122 1 40 120 2 00 118 5 00 114 REMARKS. Injected into the thigh of a large rabbit 1 drop of fresh venom from the Crotalus adamanteus. Clot formed in canula. t ii i: v i; n o m s o 1 <■ 1: u r a i n t ii a n a t o p ii i i> i: a: Time : Pressure min. see. m. m. i 00 84 - 00 *4 !i o;i *4 III 00 *2 1 1 no S2 12 no 7* 13 00 S2 2o 00 52 21 30 56 23 25 00 00 64 56 REMARK? 26 Struggles followed by death. J'.xperiincnl Xo. 2. Normal Tii ne : Pressure min. sec. m. m. 144 20 144 40 138 1 00 136 1 20 130 1 40 130 2 00 126 REMARKS. Injected into the thigh of a rabbit 3 drops of fresh venom from the Crotalus adamanteus. St mirth's. Animal tore loose from the canula. Experimnd Xo. 3. Normal Ex nt Normal Time : Prc.-surc min. sec. m. m. 70 10 5S 20 54 30 60 40 68 50 68 1 00 68 1 20 68 1 40 62 o 00 5S 2 20 54 2 40 44 tnt A o. 4, Time : Pressure min. sec. m. in. 110 5 76 10 72 20 64 30 62 40 60 1 00 f)S 1 20 58 1 40 56 2 10 51 REMARKS. Injecteil intravenously 0.003 gram dried venom of the Cro- talus adamanteus in 1 c. c. distilled water. Death. REMARKS. Injected intravenously 0.003 gram dried venom of the Cro- talus adamanteus dissolved in 1 c. c. distilled water. THE ACTION OF VENOMS UPON ARTERIAL PRESSURE. 87 Time: Pressure min. sec. m. m. 4 00 45 7 00 40 8 00 110 8 10 94 8 20 74 8 30 78 8 40 76 8 50 60 10 30 56 13 00 64 13 30 13 50 50 14 00 50 16 00 16 05 48 16 30 44 REMARKS. 17 00 Experiment No. 5. Time: Normal 10 20 30 40 00 20 1 40 55 00 00 00 Experiment No. 6. Normal Time: min. sec. 5 10 20 30 40 50 00 10 20 30 40 40 40 40 1 1 1 1 1 3 5 7 9 40 10 10 Pressure m. m. 124 100 60 96 84 70 56 48 44 38 32 Pressure m. m. 104 84 68 74 80 78 70 64 60 56 52 48 40 44 46 42 38 Struggles. Injection as before. Dead. Heart in complete diastole. Ecchymoses in pericar- dium and peritoneum. Blood incoagulable. REMARKS. Injected intravenously 0.015 gram dried venom of the Cro- talus adamanteus dissolved in 1 c. c. distilled water. Struggles. Pulse feeble. Dead. REMARKS. Injected intravenously 0.015 gram dried venom of the Cro- talus horridus dissolved in 1 c. c. distilled water Convulsions. Dead. Some ecchymoses; blood fluid. Svj T II E V i; N O M S 0 E C E R T A 1 N T II A N A T 0 P II 1 D E -E Ex pi rinu nt .V". 1. Normal 110 Injected intravenously 0.015 gram dried venom of the Cro- talus horridus elissolved in 1 c. c. distille-d water. Animal broke loose from mouth-pieee. and was (irmly held and retixed. Tin ie : Pressure ilu. see. 5 in. m. 110 76 10 76 2(1 30 "s 70 0 40 60 3 no 44 5 00 42 i; 30 40 i .'ill 36 - 00 32 - 30 20 !i 00 20 10 11(1 10 REMARK? Dead. Respiration failed before the heart. Experum nt Xo. *. Time: Pres.-ure REMARKS min sec. m. m. Normal 13* Injected intravenously 0.004 gram elrieel venom of the .1/ 2() SO trodon piscivorus dissolved in 1 c. c. distilled water. 30 <>4 Convulsions 40 74 1 DO *4 1 30 76 Injected as above-. 1 50 60 St rubles 2 10 74 2 30 74 3 00 S4 4 00 ... Killed by pithing. Ex peri me id Xo. 9. Normal 134 Injceteel intravenously 0.001 gram elrieel venom of the- Ancis- trodon piscivorus dissolved in 0.5 c. c. distilled water. Time : PresMir lin. see. in. m. 134 10 10* 20 "■j 30 70 1 00 70 1 30 72 0 00 74 2 30 70 3 00 70 5 00 70 5 30 0* 5 35 76 5 45 70 6 05 60 6 15 62 6 25 66 6 45 60 Injection repeated as before. Convulsive movements. THE ACTION OF VENOMS UPON ARTERIAL PRESSURE 89 Time: min. sec. 15 25 35 45 55 05 15 25 Experiment No. 10. Normal Time: min. sec. 10 30 00 30 00 30 30 30 50 1 1 2 2 4 5 5 6 30 6 50 7 50 10 00 Experiment No. 11. Normal Normal 12 Pressure m. m. 54 72 70 66 104 120 100 86 Pressure m. m. 96 70 76 72 72 72 70 48 48 42 50 50 46 REMARKS. Time: Pressure min. sec. ra. m. 170 20 122 30 120 40 136 50 116 1 00 150 1 10 84 2 10 108 2 40 106 2 50 80 3 20 84 ' 5 20 70 7 20 74 9 20 80 nt No. 12. Time: Pressure min. sec. m. m. 130 10 110 20 102 30 96 40 88 June, 1886. Animal died in a few minutes. REMARKS. Injected intravenously 0.003 gram dried venom of the Ancis- trodon contortrix dissolved in 1 c. c. distilled water. Injection repeated. Struggles. Injection repeated. Dead. Heart flabby blood incoagulable ; no ecchymoses. REMARKS. Injected intravenously 0.003 gram dried venom of the Crota- lophorus miliarius dissolved in 1 c. c. distilled water. Injection repeated as before. Killed by pithing. REMARKS. Injected intravenously 0.003 gram dried Cobra venom dis- solved in 1 c. c. distilled water. ij{) THE V END M S O E C E R T A 1 N T II A N A T O P II I D E .E REMARKS. Time : Pressure min. MT. m. m. 5(1 70 1 00 7* 1 10 70 1 20 52 1 30 52 Convulsions. 1 40 50 2 00 38 2 20 34 3 20 Dead. Ilea Dead. Heart in svstole ; blood clotted ; no ecchymoses. Ex pi n no nt Xo. 1 '■!. Time: Pressure min. sec. in. in. 140 10 150 3(1 140 1 Oil 134 1 20 134 3 20 110 5 20 14« REMARKS. Normal . . . 140 Injected intrave-nouslv 0.003 gram dried Cobra venom dis- solved in 1 c. c. distilled water. Death from hemorrhage ; artery torn. REMARKS. Ex per inn.id Xo. 14. Normal . . . 132 Injected intrave-neiuslv 0.003 gram dried Cobra venom dis- solved in 1 c. c.-distilled water with a few crystals of sodic chloride. Time: Pressure min. mt. in. in. 132 1 00 122 3 00 120 * 00 130 10 00 13S 15 00 106 17 00 66 1S 00 4S 19 00 Dead Ex peri mend Xo. 15. Normal 145 Injected intravenously 0.003 gram dried venom of the Cobra dissolved in 1 c. c. distilled water. Time : Pressure min. see. in. in. 145 20 142 40 135 1 00 12s 1 30 130 o 00 140 4 00 150 9 00 143 12 00 13* 14 00 15* 20 00 135 REMARKS. Respiration ceased; artificial respiration used. THE ACTION OFVENOMS UPON ARTERIAL PRESSURE. 91 Experiment No. 16. Normal Normal Normal Time: Pressure min. sec. m. m. 120 20 108 30 96 40 88 1 00 90 1 20 82 1 40 96 4 40 94 7 40 100 8 40 122 9 10 156 15 00 \t No. 17. Time: Pressure min. sec. m. m. 90 10 94 20 66 30 84 40 90 1 00 88 1 30 86 2 00 78 2 10 74 4 10 90 4 40 96 5 10 92 6 10 72 6 20 60 6 50 32 7 30 24 8 20 6 it No. 18. Time: Pressure min. sec. m. m. 110 10 112 11 15 80 20 64 30 46 40 30 50 54 1 00 46 1 15 46 2 00 REMARKS. Injected intravenously 0.005 gram dried Cobra venom dis- solved in 1 c. c. distilled water with a little sodic chloride and filtered. A clot was probahly beginning to form in the canula, and no dependence is to be placed upon the after record. Struggles. Clot in canula. Dead. REMARKS. Injected intravenously 0.015 gram dried Cobra venom dis- solved in 1 c. c. distilled water. Dead. REMARKS. Injected intravenously 0.005 gram dried venom of the Daboia Russellii dissolved in 0.5 c. c. distilled water. Pressure falling. Violent general convulsions. Dead. Heart in diastole; no ecchymoses; after twenty-four hours the blood is still fluid. Artificial respiration was used in this experiment from the beginning. [)•> T II E V I! N 0 M S O I V I! 11 T A I N T II A N A T () P II I D E .E. This single experiment confirms the1 statements of Fayrer and of Wall in regard t<> the convulsivaut power of Daboia. The spasms are- not due to defect ot'oxvgen, h* the) arise- early and occur despite the use of artificial respiration. Ancistrodon \eiiom seems to have the same capacity to produce convulsions. The Action of Pun V u,oms on. the Blood I'nssurt of Animals trith Cut Pu< uuto- gartrif Xervm.—After section of the pneumogastric nerves, including the depressor fihrc-s, we find that the same alterations occur in the blood pressure as in normal animals. Nine experiments were made altogether: two with the venom of the Crotalus adamanteus ; one with the Crotalus horridus; two with the An.dstrot/011 jiist irurus; one with the Ancistrodon, contortrix; and three with the Cobra. Experiment Xo. 19. Normal ... 96 Injected intravenously 0.003 gram dried venom of the Cro- talus adamanteus dissolved in 1 c. c. distilled water. Time : Pressure min. Bee. m. m. 96 10 74 30 68 1 00 68 1 30 76 2 00 64 2 30 60 5 30 44 7 00 44 s 30 4S 8 40 42 9 00 46 9 10 44 9 20 44 9 30 44 Injected the same as above. Dead. Experimcn.t Xo. '20. Normal . . . 130 Injected intravenously 0.015 gram dried venom of the Cro- talus adamanteus dissolved in 1 c. c distilled water. Time: Pressure min. see. m. in. 130 10 100 20 90 30 96 40 76 50 56 1 00 50 1 10 :>s 1 20 32 REMARKS. 1 30 22 Dead. THE ACTION OF VENOMS UPON ARTERIAL PRESSURE. 93 Experiment No. 21. Normal Time: min. sec. 10 20 40 00 20 40 00 20 20 50 00 Experiment No. 22. Time: Normal 10 20 30 40 00 20 1 40 Experiment No. 23. Time: Normal mm. sec. 10 20 30 40 50 00 20 50 50 00 00 00 00 00 00 10 20 30 40 50 1 1 3 5 6 8 10 12 14 19 19 19 19 19 19 Pressure m. m. 144 146 124 124 94 80 70 56 54 54 44 12 Pressure m. in. 90 76 54 44 50 54 44 24 Pressure m. m. 110 84 64 68 78 76 72 66 52 64 86 100 74 70 66 70 70 52 98 68 90 REMARKS. Injected intravenously 0.015 gram dried venom of the Cro- talus horridus dissolved in 1 c. c. distilled water. Struggles. Violent struggles. Dead. REMARKS. Injected intravenously 0.0035 gram dried venom of the Ancis- trodon piscivorus dissolved in 1 c. c. distilled water. Convulsions. Dead. REMARKS. Injected intravenously 0.003 gram dried venom of the Ancis- trodon piscivorus dissolved in 1 c. c. distilled water. Struggles. Struggles. Convulsions. Injection repeated, using the same amount. • II E V E N 0 M S () E C E R I a 1 N T II A N A I O P II I 1> E A-]. Time: 1'nssurc REMARKS. min. see. in. in. 20 oo 90 20 20 7 2 21 20 60 23 20 56 25 20 60 2-1 20 70 33 20 70 3S 20 66 4 4 2o 58 Third injection, same amount 41 30 50 4 4 40 4* 44 50 44 45 00 36 45 10 26 Dead. end Xo. 24. Time: Pressure REMARKS min. sec. m. m. . . . 154 Injected intravenously 0.003 gram dried venom of the Ancis- 10 114 trodon contorlrix dissolved in 1 c. c. distilled water. 20 mi; 30 76 40 *2 1 00 Ml 1 50 so 1 20 9* 7 oo 100 Injection repeated. 7 05 13* Strugirh-s. 7 10 110 7 20 106 7 40 10* 8 00 9* s 30 ss 9 00 SO 11 30 7* Third injection. 11 4o 76 12 00 70 12 30 66 13 00 6S 13 30 6S l'.i 00 72 Fourth injection. 19 20 54 19 40 50 20 20 44 21 50 40 22 50 38 Dead. Heart in diastole; blood remains fluid; muscles all respond to electrical irritation; motor nerves react feebly. THE ACTION OF VENOMS UPON ARTERIAL PRESSURE 95 Experiment No. 25. Normal Normal Time: Pressure min. sec. m. m. 148 10 146 30 136 1 00 140 1 30 140 3 30 150 6 30 150 10 30 146 14 30 152 16 30 156 U No. 26. Time: Pressure min. sec. in. in. 134 10 136 30 126 1 00 118 1 30 118 3 30 132 5 30 136 7 30 136 9 30 136 11 30 136 18 30 188 Experiment No. 27. Normal Time: Pressure min. sec. m. m. 130 0 10 20 130 1 00 118 2 00 118 4 ' 00 115 10 15 REMARKS. Injected intravenously 0.003 gram dried Cobra venom dis- solved in 1 c. c. distilled water with a few crystals of sodic chloride and filtered. Clot formed in canula. Animal killed. REMARKS. Injected intravenously 0.006 gram dried Cobra venom pre- pared as in the foregoing experiment. Convulsive movements; asphyxia; respiration ceased in three minutes. REMARKS. Injected intravenously 0.003 gram dried Cobra venom dis- solved in 1 c. c. distilled water. Clot in canula. Dead from asphyxia The Action of Pure Venoms on the Blood Pressure of Animals in, which the Cervical Spinal Cord had been Divided.—Upon section of the spinal cord in the upper cervical region, by which the influence of the vaso-motor centres in the medulla is practically destroyed, the primary fall of pressure from venom is gener- ally very slight, and after this diminution there is a secondary rise which may go above the normal. In one experiment with Crotalus adamanteus venom there was a rise of pressure for a moment at the time of injection; in one experiment with Crotalus horridus, in which a somewhat larger dose was used than in the others, there was a distinct rise of pressure a few seconds after injection, followed by a fall; and in the experiment with the Cobra the pressure never went below }|(i T 11 1: V i: N (> M s o V c E u T A 1 N T HAN A TO P II I I) E A'). the normal, but in a few moments a rise occurred which continued to increase for half an hour, when the animal was killed. In this se lies we- observed a marked difference from the preceding (unless the dose- had been immediately toxic), since the profound primary fall of pressure- was not observed, excepting in a very slight degree if at all; we found, however, that the ultimate fall of pressure still occurred, save in the case1 of the Cobra. flight e-xpe rinients were made: two with Crotalus atlamuutt its; one with Cro- talus horritlus; three with Aucistration piscivorus ; one with Am is/rodon contortrix, and one with Cobra venom. hxpermit id Xo. 2S. Injected intravenously 0.003 gram dried venom of the Cr< talus adamanteus dissolved in 1 c. c. distilled water. Time : Pressure min. see. m. m. Normal 9 62 70 20 56 30 56 40 58 1 00 5* 1 20 56 1 30 48 1 40 46 2 00 44 2 20 40 2 40 38 5 20 36 6 50 36 7 20 :)(] M 00 Experiment Xo. 29. Time: Pressure min. sec. in. in. REMARKS. Normal . . 66 Injected intravenously 0.006 gram dried venom of the? Cro- 5 60 talus adamanteus dissolved in 1 c. c. distilled water. 10 58 20 58 30 64 40 62 50 5* 1 00 56 1 30 48 2 30 40 3 30 60 4 30 56 5 30 40 * 00 ... Dead. THE ACTION OF VENOMS UPON ARTERIAL PRESSURE. 97 Experiment No. 30. Time: Pressure min. sec. m. m. Normal 20 40 00 20 20 20 20 9 20 10 50 12 50 14 50 16 50 17 05 17 35 18 00 Experiment No. 31. Time: Normal 10 20 30 40 50 00 00 00 00 10 00 Experiment No. 32. Time: min. see. Normal . . . 10 20 30 40 50 Experiment No. 33. Normal Time: min. sec. 10 20 30 40 56 00 00 00 30 30 46 42 38 26 26 26 24 30 30 28 26 26 10 Pressure m. m. 56 50 46 46 40 34 30 22 28 26 18 Pressure m. m. 58 54 40 32 26 16 Pressure m. m. 46 38 40 38 40 48 38 30 28 REMARKS. Injected intravenously 0.015 gram dried venom of the Cro- talus horridus dissolved in 1 c. c. distilled water. Conjunctival reflexes gone. Dead. REMARKS. Injected intravenously 0.007 gram dried venom of the Ancis- trodon piscivorus dissolved in 1 c. c. distilled water. Dead. The cord proved not to have been completely cut—a few fibres of the posterior columns remaining undivided. REMARKS. Injected intravenously 0.003 gram dried venom of the Ancis- trodon piscivorus dissolved in 1 c. c. distilled water. Convulsions. Dead. REMARKS. Injected intravenously 0.003 gram dried venom of the Ancis- trodon piscivorus dissolved in 1 c. c. distilled water. Dead. 13 June, 1886. THE VENOMS OI CERTAIN T ,1 A N A T (> P 11 I D E .E. Pxjmi intent Xo. 3 1. REMARKS Nurmal 52 Injeeted intravenouslv 0.003 gram dried venom of the Ancis- trodon contortnx dissolved in 1 c. c. distilled water. Tina : Prccsurc mil), sec. Ul. III. 52 10 44 20 46 40 50 1 00 54 3 00 46 5 00 30 7 on 34 9 00 34 11 00 30 13 00 30 15 00 30 17 no 3(1 l'.t 00 30 21 00 30 23 00 30 25 00 32 27 on 32 29 00 34 56 00 31 61 00 32 75 00 30 Killed by pithing. Experiment Xo. 35. Nunmil 4 2 Injected intravenously 0.003 gram dried venom of the Cobra dissolved in 1 c. e. distilled water with a few crystals of sodic chloride and filtered. Time: Pressure min. sec. in. III. 4 2 10 46 30 44 1 00 42 3 00 4 0 ti 00 4S 9 00 46 12 00 50 15 30 50 1* 30 52 21 30 54 24 30 56 27 30 54 27 40 56 2* 00 64 2*' 30 68 30 30 78 REMARKS. Injected the same as the foregoing. Clot formed in canula. Killed animal by pithing. The. Action of Pure Venoms on the Blootl Pressure of Animals in, which the Pneuiiuijastrie, lhpressor, and Sympathetic; Xerves autl Spinal Con/ have been Si virtd.—Since we found in the last series of experiments that after section of the cord there did not occur such a decided primary fall of pressure, it seemed obvious that the fall of pressure must be due, in major part at least, to a toxic depression THE ACTION OF VENOMS UPON ARTERIAL PRESSURE 99 of the vaso-motor centres A fall of pressure does, however, ultimately occur, and, excepting in the case of the Cobra, increases until death ensues In seven other experiments, supplementary to the above, in which we made section of the pneumogastric, depressor, and sympathetic nerves in the neck, and section of the spinal cord in the middle or upper cervical region, thus cutting off both the heart and capillaries from centric nervous influence, we obtained results which were practically the same Three of these experiments were made with the venom of the Crotalus adaman- teus , one with that of the Crotalus horridus ; one with the Ancistrodon piscivorus ; one with the Ancistrodon cotdortnx, and one with the Cobra. Experiment No 36 Normal Time Pressure min sec. m m. 62 10 56 20 46 30 56 40 52 1 00 46 1 20 40 1 40 36 2 00 30 2 20 24 Experiment No. 37 Time: Pressure min. sec, m in. Normal 48 10 46 20 48 30 46 1 00 48 1 20 46 3 20 40 3 50 32 5 50 36 7 50 30 Experiment No 38. Time : Pressure min. sec. m. m. Normal 30 5 32 10 28 20 28 30 26 40 28 50 28 REMARKS. Injected intravenously 0 003 gram dried venom of the Cro- talus adamanteus dissolved in lec distilled water. Dead. Heart arrested in diastole ; blood incoagulable ; a few ecchymoses in peritoneum. The section of the cord was not quite complete. REMARKS. Injected intravenously 0.003 gram dried venom of the Cro- talus adamanteus dissolved in 1 c. c. distilled water Dead. Heart arrested in diastole; blood incoagulable; no ecchymoses in serous tissues REMARKS. Injected intravenouslv 0.003 c;ram dried venom of the Cro- talus adamanteus dissolved in 1 c. c. distilled water. 1()0 T H E V E N HM S O I ( E R T A 1 N 1 II A N A T () P II I D E ,E. Time. Pressure min. sec. ni. m. 1 00 27 1 30 27 2 00 27 2 30 22 9 30 REMARKS. Deael. Heart arrested in diastole; blood incoagulable, (•(Thymuses well-marked in peritoneum anil pericardium ; intestines congested ; 50 c. c serum in peritoneal cavity. Section of cord complete, except anterior columns. Exjn riuunt No. 39. Normal ... 44 Injected intravenouslv 0.015 gram dried venom of the ('r< talus horridus dissolved in 1 c. c. distilled water. Time: Pressure min. sec. m. m. 44 10 44 20 56 30 62 40 60 1 00 52 1 20 44 1 40 44 2 00 3* 4 00 30 0 00 2S H 00 26 REMARKS. 12 00 22 Dead. Experiment X o. 40. Time. Pressure min. see. m. m. Normal 4 6 20 40 30 48 40 44 1 00 44 1 30 40 1 50 3* 4 20 2* 6 20 2S * 20 28 10 20 28 12 20 28 15 20 28 is 20 2S 21 20 REMARKS. Injected intravenously 0.003 gram dried venom of the Ancis- trodon jitseivorus dissolved in 1 e. c. distilled water. Muscular movements. Dead. Blood is incoagulable; no ecchymoses in serous membranes. r.xpf rt no nt Ao. 41. Time: Pressure REMARKS. min. see. m. m. Normal • ■ • f>4 Injected intravenously 0.003 gram dried venom of the Ana's- 10 56 trodon contorlrix dissolved in 1 c. c distilled water. 20 54 40 4S THE ACTION O F V E N O M S UPON ARTERIAL PRESSURE. 101 Time: min. 6ee. 00 30 00 00 7 00 9 00 11 00 13 00 15 00 17 00 20 00 22 00 22 15 22 30 Experiment No. 42. Normal Time: min. sec 10 30 00 00 00 00 00 00 00 1 3 5 8 11 14 19 Pressure m. m. 42 40 42 50 56 54 48 48 48 48 48 48 38 32 Pressure m. m. 56 60 56 52 48 48 52 58 60 62 REMARKS. Injected 0.006 gram. Dead. REMARKS. Injected intravenously 0.003 gram dried venom of the Cobra dissolved in 1 c. c. distilled water and a few crystals of sodic chloride and filtered. Animal killed by pithing. To recapitulate the actions of pure venoms upon the arterial pressure—we find that the injection of venom subcutaneously causes a progressive fall of blood pressure; when injected intravenously, there is a sudden and decided fall of pressure, which may be immediately followed by death, or by a gradual rise, to be in turn succeeded by a decline with feeble pulse as death approaches. In the Cobra there is a tendency to a rise of pressure, which may go above the normal as death appears. After section of the pneumogastric nerves and its depressor fibres we find no alterations in the results obtained in normal animals, but when section of the cord is made in the middle or upper cervical region by which the vaso-motor centres in the medulla oblongata are practically destroyed, or when accompanying this section the nerves in the neck and the spinal cord in the middle cervical region are also cut, thus practically isolating the vaso-motor centres in the medulla and cutting off all central nervous connection with the heart, we find that the primary profound diminution of pressure is not so marked. There may even appear to be a slight tendency on the part of the arterial pressures to rise above the normal just before death. Even after section of the spinal cord, as above, we find in Cobra the increase of pressure occurring before death as in normal animals. These results indicate that the primary positive failure of pressure is due chiefly 102 T II E V E N O M S OF (' E R T A I N T II A X A T (> P II I D E .E to a eh prcssant action of the venom upon the vaso-motor centres in the medulla oblongata, and slightly upon 'he heart. The tendency to a rise of pressure1, as well as the ultimate fall, must be due to some action upon the heart itse-lf or the general s\stemic capillaries. It seems probable that the rise of pressure in those experi- ments is of capillary origin since the pulse'-curves do not indicate increased heart power, and we have already had reason to believe that venom exerts a decided action upon the capillaries themselves to bring about the remarkable ecchymoses found se> commonly in cases of poisoning—an instance also of peripheral irritation, applicable1 here, is the effect of venom on the vagi peripheries in causing an in- creased respiration rate. The ultimate1 fall of pressure1 seems to be cardiac in origin, since there is an accompanying diminution in the force of the1 beats. Section II.—The Action of Venom Globulins upon the Blood Pressure. The Adion of Venom Globulins upon the Blood Pressure of Xormal Animals.— Thirteen experiments were made with the globulins upon normal animals. The doses usually given were- those representing the amount of globulin in 0.01 ;j gram of dried venom. The results of all of these- experiments indicate that all the globulins exert an action analogous to that of the pure venom, but that they exhibit a material difference in the relative degree of their toxicity. Of the thirteen experiments, seven were made with the watcr-vcnom-cjlobulin, two with the eopper-vi< uom-g/obuliu, and four with the diulysis-veuom-g/obnlin. Of the first scries, five were1 made with the globulin from the Crotalus adamanteus ; one with that of the A iwisf ration piscivorus, and one with that of the1 Cobra. The second and third serie-s were made with globulins from the1 Crotalus atlamaideus venom. The wa,kr-rt nom-globulin, produces the most profound changes, causing a primary diminution of pressure1 almost equalling that produced by pure venom, while diulysis-vt lunu-ij/obuliu, conies next; the coppcr-vcn,oin-globulin, has but little effect. The actions of all of these globulins is to cause a primary fall of pressure, which is followed by a rise towards the normal and more or less well marked, while if the dose is sufficiently large the rise is followed by a fall to zero at death. In one experiment made with the globulin from 0.03") gram of dried Cobra venom there was no appreciable effect. This was probably due to the very small proportion of globulin in this variety of venom. Experinunt Xo. 43. Normal ... 110 Injected intravenously 0.0012 gram water-venom-globulin (=■- 0.015 gram dried venom) from the dried venom of the Crotalus adamanteus. Time : Pressure min. sec. m. m. 110 10 SI) 20 92 40 90 1 00 *4 1 30 84 3 00 95 5 00 96 7 00 104 REMARKS. T HE AC T ION OF V E N O M S UPON A R T E R I A L PRESSURE. 103 Time: Pressure nin. sec. m. m. 9 00 106 12 00 106 15 00 110 18 00 116 25 00 124 35 00 130 45 00 130 55 00 130 REMARKS. Experiment No. 44. fTime: Pressure min. sec. in. m. Normal ... 130 10 20 96 40 96 1 00 94 1 20 90 1 40 90 3 40 94 5 40 102 7 40 108 9 40 108 10 00 104 10 20 104 10 40 104 14 00 106 17 00 106 20 00 108 30 00 102 Experiment No. 45. Time : Pressure min. sec. m. in. Normal . . . 120 10 86 20 96 30 86 50 90 1 10 84 4 10 90 4 30 80 4 35 104 4 40 100 4 50 82 15 Animal killed by pithing. Heart in diastole ; some ecchy- moses in small intestine; blood remains fluid at the end of twenty-four hours—a few very soft clots are found. REMARKS. Injected intravenously the water-venom-globulin from 0.03 gram dried venom of the Crotalus adamanteus. Pressure falling. Clot formed in the canula. Injected water-venom-globulin from 0.015 gram dried venom. Animal killed by pithing. REMARKS. Injected intravenously 0.0033 gram water-venom-globulin (= 0.045 gram dried venom) from the dried venom of the Crotalus adamanteus dissolved by the addition of a trace of sodic carbonate. Injected 0.0066 gram as in the foregoing. Injected a similar dose. Killed by pithing. Heart arrested in diastole; few ecchy- moses ; blood remains fluid after twenty-four hours. 101 T II E V E N O M S (> 1 C E K T A I N I 11 A N A TO P II I D E .E ':xjh rime it t X o. 4(i. Time : Pressure min. sec. m. in. Normal . . 14* 10 120 20 116 30 116 50 100 1 00 92 1 30 s2 3 30 86 5 30 96 7 30 106 :i 30 118 12 30 122 14 30 126 16 30 124 17 30 100 19 3o 12S 21 3d 132 26 00 12M 2S 00 130 30 00 124 30 15 136 35 00 134 37 no 136 39 no 130 REMARKS. Injected intravenously the water-venom-globulin from one minim of fresh venom of the Crotalus adamanteus. Clot in canula. (.'lot in canula. Animal killed by pithing; no ecchymoses; blood clots. Exj n rime nt Xo. 47. 30 50 124 Time: Pressure REMARKS. min. see. in. m. Normal . . . 132 Inje-cted intravenously the water-venom-globulin from 0.001 126 gram dried venom of the Ancistrodon piscivorus dissolved in 1 c. c. distilled water by the addition of a few crystals of 1 00 136 sudic chloride. 1 30 122 1 50 114 Injected a similar dose. 2 oil 106 2 40 116 3 10 104 Experiment Xo. 4S. Time: Pressure REMARKS. min. sec. m. in. Nonual • • • 115 Injected intravenously the waler-venom-globulin from 0.015 0 • • • gram dried venom of the Crotalus adamanteus. 10 20 90 30 93 1 30 90 2 30 100 5 30 102 10 30 100 14 ;i'» . 100 Hanuaturia. 19 30 Kjy THE ACTION OF VENOMS UPON ARTERIAL PRESSURE. 105 Time: min. sec. 24 30 29 30 34 30 42 30 47 30 52 30 57 30 67 30 77 30 §0 30 85 Experiment No. 49. Normal Time: min. sec. 0 15 25 45 15 00 00 00 1 2 4 8 13 00 18 00 23 00 28 Pressure m. m. 95 85 80 75 73 60 60 57 55 38 Pressure m. m. 155 REMARKS. 158 160 158 157 153 153 153 143 153 Dead; ecchymoses in intestines ; blood incoagulable. REMARKS. Injected intravenously water-venom-globulin from 0.035 gram dried Cobra venom dissolved in 1 c. c. distilled water. Broke loose from canula. Experiment No. 50. Time: Normal 2 4 6 8 10 11 17 18 18 18 18 19 20 22 27 10 20 30 50 50 50 50 50 50 50 20 20 30 40 50 00 00 00 Pressure m. m. 126 126 126 132 126 124 126 126 124 124 120 110 114 110 118 112 112 120 116 REMARKS. Injected intravenously 0.0012 gram copper-venom-globulin (= 0.015 gram dried venom) from the dried venom of the Crotalus adamanteus. Injected double the foregoing dose. Killed. Heart in systole ; few ecchymoses in lungs and intes tines ; blood remains fluid after two hours. 14 June, 1888. 106 T H Ii V E N O M S O E C E U T A I N T II A N A I O P II I I) E .E. 1'■'..!j»:rinunf Xo. 51. N'urmal . 112 Injected intravenously 0.0023 gram eo]>per-venom-globulin (= 0.03 gram dried venom) from the dried venom of the Crotalus adamanteus. Clot in canula. Time : Pressure miu. Bee. m. in. 112 10 114 30 110 1 00 112 3 00 116 5 00 120 7 llll 122 M 00 122 10 00 124 12 00 11* 22 00 lis 24 00 12* 26 00 121 26 1(1 124 26 30 116 26 40 104 27 00 108 27 30 96 29 30 90 31 30 It* 34 30 104 39 00 Hi; 41 00 ik; 43 00 116 45 00 US 52 00 120 5* 00 122 REMARKS Injected double the dose. Killed by pithing ; no ecchymoses. Experiment Xo. u2. Normal ... 132 Injected intravenously 0.0017 gram dialysis-venom-globulin from the dried venom of the Crotalus adamanteus dissolved in 1 c. c. distilled water with a trace of sodic carbonate. Time : Pressure miu. see. in. m. 132 20 124 40 112 50 116 1 20 108 3 20 108 5 20 120 1* 20 130 18 23 18 30 96 18 45 100 19 05 94 19 25 102 19 55 96 20 25 76 20 55 60 21 25 46 22 00 42 30 00 REMARKS. Injected 0.0034 gram dialysis-venom-globulin. Dead. No ecchymoses; heart in diastole; blood remains fluid at the end of one hour. THE ACTION OF VENOMS UPON ARTERIAL PRESSURE. 107 Experiment No. 53. Normal Time: min. sec. 20 30 00 20 40 00 40 40 40 1 1 1 2 2 3 5 6 20 50 20 50 8 50 9 20 9 50 10 50 11 50 12 50 14 20 14 50 15 20 15 50 Pressure m. m. 126 120 114 110 102 102 100 100 102 110 114 118 124 126 128 128 130 134 122 112 112 84 78 62 REMARKS. Injected intravenously dialysis-venom-globulin from the dried venom of the Crotalus adamanteus (quantity unknown). Injected more of the globulin. Killed by pithing. Experiment No. 54. Normal Time: min. sec. 10 20 30 00 00 00 00. 00 30 40 30 1 3 5 7 16 17 17 18 20 30 23 30 28 30 43 30 53 30 Pressure m. m. 150 118 130 118 116 110 126 124 136 116 100 104 126 118 102 98 94 REMARKS. Injected intravenously 0.0017 gram dialysis-venom-globulin from the dried venom of the Crotalus adamanteus. Injected 0.0034 gram. Animal killed. The Action of Venom Globulins upon the Blood Pressure of Animals in which the Pneumogastric Nerves had been Severed.—Four experiments were made on animals in which the pneumogastric nerves and depressor nerves were severed. The results in these experiments do not differ in quality from those obtained in 10S T H E V E N O M S 0 E C E K T A I X T II A X A T <> P II I D E .E. normal animals ; the effects, however, appear to be less decided than in animals with the pneumogastric s intact. Here1, as in the- previous experiments, the copper- venom-globulin exhibits comparatively little effect on the pressure. Of the four experiments which were made with globulins from the Crotalus adamuidt us, one was made with the iva/t r-rcuom-g/obtdiu; two with the vopper- n uom-globtdiu, and one with the diulysis-vt nom-globulin. It will be noticed that in several instances considerable rises of pressure occurred accompanied by struggles; the former effect being, no doubt, due to the latter, and not to a peculiar action of the globulin. Exp> rtiiuid No. 55. Normal Time: min. 6ec. 10 20 30 (.0 40 40 40 Pressure m. m. 116 100 100 no 106 110 110 108 REMARKS. Injected intravenouslv 0.0011 gram water-venom-globulin from the dried venom of the Crotalus adamanteus. Clot in canula. Animal killed by pithing. Experiment No. 56. Normal Time : min. sec. 10 20 30 40 10 10 10 10 10 10 20 40 55 00 15 1 3 5 7 9 23 Pressure m. m, 130 132 132 132 132 132 132 12S 12* 128 136 130 132 132 116 116 REM AUKS. Injected intravenously 0.0024 gram copper-venom-globulin from the dried venom of the Crotalus adamanteus. Injected a similar dose. Respiration greatly slowed. Animal broke loose. Killed by pithing. Experiment X>. 57 Time : min. sec. Normal 20 40 50 2 50 4 50 6 50 * 50 Pressure m. m. 116 116 116 116 116 116 116 112 REMARKS. Injected intravenonsly 0.0012 gram copper-venom-globulin from the dried venom of the Crotalus adamanteus. THE ACTION OF VENOMS UPON ARTERIAL PRESSURE. 109 Time : Pressure min. sec. m. m. 11 50 116 13 50 118 15 50 118 16 10 100 16 20 . U8 16 30 110 16 45 108 17 45 132 19 45 114 21 45 112 23 45 106 25 45 100 26 45 88 27 00 REMARKS. Injected a double quantity. Struggles. Animal killed by pithing. Experiment No. 58. Time: Pressure REMARKS. min. sec. m. m. Normal ... 120 Injected intravenously 0.0017 gram dialysis-venom-globulin 10' 100 from the dried venom of the Crotalus adamanteus. 20 112 30 110 50 150 Struggles. 1 50 190 4 20 130 6 20 120 8 20 126 10 20 122 12 20 120 17 50 118 18 20 118 Injeeted 0.0034 gram. 18 30 100 18 40 148 Struggles. Injected a similar close. 19 00 140 " 19 15 170 19 20 176 21 50 144 22 00 140 23 00 166 25 00 122 27 00 128 29 00 114 Struggles. 34 00 82 34 30 80 38 30 60 41 00 50 47 00 28 49 00 ... Dead. The Action of Venom Globulins upon the Blood Pressure of Animals in which the Pneumogastric, Depressor, and Sympathetic Nerves and Cervical Spinal Cord had been Cut.—Four experiments were made on animals in which the nerves of the HO T II E V E X O M S OF ( E 1! T A I N T II A X A T () P II I D E A-] neck and the cord in the middle or upper cervical region (excepting one) were cut. The \ we re- all made with the globulins from the Crotalus adamautt us; one with watt r-v nom-globutiu, one with <■opper-venom-globuIin, and two with tliulysis-vcnom- glulmlin,. fhe results of this series of experiments accord with those observed when pure venom was used, and with the1 preceding experiments with the globulins. The1 primarv fall of pressure is slight, while the tendency to a secondary rise1 is very marked, since in three of the experiments the pressure rose above the normal. 'fhe action of water-venom-globulin on the primary fall was most marked, while in the1 single experiment made with coppcr-venom-globulin, in which eight times the quantity was given in two doses, the pressure rose slightly, and continued above normal. When the dose is sufficient to kill, the pressure ultimately gradually declines, accompanied by a feeble pulse. In the last experiment with diulysis-vtnom-globulin it will be noticed that tremors are accompanied with a rise of pressure during their existence. Experiment Xo. 5!). Time : Pressure min. sec. in. m. Normal . . . 48 10 38 30 3 s 1 00 4S 1 10 34 2 10 46 3 10 42 5 Id 40 7 10 38 9 10 34 11 10 30 15 10 30 17 40 30 19 00 30 21 oo 30 23 00 3d 25 00 30 27 00 30 Experiment Xo. 60. Time: Pressure min. sec. m. m. Normal . . . 29 10 32 20 30 40 32 1 00 32 3 30 38 5 30 to 7 30 42 REMARKS. Section of cord made below the 6th cervical vertebra. Injeeted intravenously 0.0011 gram water-venom-globulin from the dried venom of the Crotalus adamanteus. Artificial respiration stopped. Animal killed by pithing. REMARKS. Injected intravenously 0.0048 gram copper-venom-globulin from the dried venom of the Crotalus adamanteus. THE ACTION OF V E N O M S UPON ARTERIAL PRESSURE. HI Normal Time: Pressure min. sec. m. m. 9 30 42 11 30 42 13 30 40 16 30 44 17 00 42 17 30 38 18 00 40 20 00 44 24 00 46 26 00 44 28 00 42 30 00 40 32 00 40 34 00 40 1 No. 61. Time: Pressure min. sec. m. m. 42 10 40 30 40 1 00 46 3 00 44 6 00 40 8 30 38 10 30 38 12 30 12 50 44 13 10 48 13 30 46 13 50 48 15 00 36 16 00 46 18 00 28 REMARKS. Injected a similar quantity. Animal killed by pithing. REMARKS. Injected intravenously 0.0017 gram dialysis-venom-globulin from the dried venom of the Crotalus adamanteus. Injected 0.0068 gram. Dead. Heart arrested in diastole; no ecchymoses; blood fluid. A few fibres of the anterior columns of the cord were uncut. Experiment No. 62. Tii ne: Pressure min. see. m. m. Normal 44 10 40 20 40 30 44 40 52 50 62 1 00 62 1 10 60 1 20 58 3 20 86 3 50 52 6 50 22 8 50 8 REMARKS. 9 00 Injected intravenously 0.0068 gram dialysis-venom-globulin from the dried venom of the Crotalus adamanteus. Universal tremors persistent. Clot in canula. Blood pressure fell very low before this observation, and was raised by the tremors returning vigorously. Dead. No ecchymoses ; blood incoagulable ; heart natural, IpJ T II Ii V E N O M S O F (' E U T A I N I 11 A N A T O P II 1 D E E 1'rom this series of experiments wi'h globulins it se e nis clear that they possess the peculiar physiological effects* of pure unoius upon the blood pressure; that the water-venom-globulin is the most powerful, and the copper-vciiom-globulin the least so, and that the1 copper-venoni-globulin seems to exhibit a more marked teueii ncy than the others to cause a rise of pressure. Si;e HON 111.—TlIE ACTION OF VENOM l'PPTONES UI'ON THE BLOOD PKKSSURE. The Action of V nom Et plants upon the Blood Prtssun of Xormul Animals.— Seven experiments were made with the- peptones from different venoms: two with that of Crofu/us adamanteus ; three with Ancistrodon jn'scicorns ; and two with Cobra. The action of peptones upon the blood pressure is similar to that observed with the pure venom and the globulins, but their power to cause the primary pro- found fall of pressure is certainly much less, while the rise1 of pressure1 after the primary fall is decidedly more marked, and there is also a tendency to go above the normal. In two experiments, one with the peptone of the Crotalus and one with that of the Moccasin, the pressure was not primarily reduced, but there was a rise above the normal from the first. "Where the animal was watched until death the pressure was observed to undergo a more or less gradual decline with feeble heart- heats. In several instances a rise of prcsMire was noted which was usually due to convulsive seizures. I'xjit rimt id Xo. 63. Time : min. sec. Normal . . . 10 20 30 40 50 1 00 11 00 21 00 4'. I Exjierinteut Xo. 6-4. Time: miu. see. Normal . . . 10 30 1 00 2 00 5 00 9 00 Pressure REMARKS. m. in. 140 Injected intravenously the peptone from 0.015 gram dried 128 venom of the Crotulus adamanteus. 12s 136 128 12s 124 116 116 Clot. Dead. No ecchymoses; lungs seem congested; blood clots readily. Prcs?ure REMARKS. m. m. 114 Injected intravenously the peptone from 0.03 gram dried 130 venom of the Crotalus adamanteus. 132 120 140 144 124 Killed. Ecchymoses in the lungs : blood clots. THE ACTION OF VENOMS UPON ARTERIAL PRESSURE. 113 Experiment No. 65. Time: Pressure min. sec. m. m. Normal . . . 86 30 - 88 1 00 88 1 30 88 4 30 92 10 30 94 10 50 100 11 10 102 11 30 96 Experiment No. 66. Time: Pressure min. sec. m. m. Normal . . . 116 10 94 20 66 30 70 1 00 76 1 30 74 2 00 76 2 30 76 3 00 76 5 00 66 5 20 60 5 40 66 6 00 68 6 30 66 7 00 62 7 30 56 8 00 60 Experiment No. 67. Time: Pressure min. sec. m. m. Normal . . . 140 10 94 20 100 30 160 40 170 50 190 1 00 130 1 20 130 1 40 142 2 00 136 2 20 136 2 40 136 5 40 118 5 50 114 6 00 104 6 20 112 6 30 112 9 30 118 13 30 122 15 June, 1886. REMARKS, Injected intraveuously the peptone from 0.015 gram dried venom of the Ancistrodon piscivorus. Injected double the amount. REMARKS. Injected intravenously the peptone from 0.015 gram dried venom of the Ancistrodon piscivorus. Injected a similar quantity. Injected a double quantity. REMARKS. Injected intravenously the peptone from 0.05 gram dried venom of the Ancistrodon piscivorus. Convulsions. Injected 0.005 peptone. Killed. 11 , t H E V I! N O M S (> F C K K T A I N T II A N A T O P HIDE .E Ex/» rum N,riuul 140 Injected intravenously the peptone from 0.005 gram dried Cobra venom. /// So. UN Tim Press u re min. sec. in. 111. 140 10 130 20 14s 30 140 4 0 142 1 0(1 142 1 20 140 3 20 13S 6 20 152 11 20 224 16 20 176 16 50 134 17 50 92 is 20 M4 is 50 s| 19 00 46 19 10 46 19 30 38 19 to 36 20 10 40 20 30 40 end A o. 69. Time: Pressure miu. see. m. m. 130 10 130 15 116 30 156 50 156 3 20 140 s 20 190 10 20 176 10 30 208 10 40 ls2 10 50 136 11 00 116 11 20 102 11 40 86 12 00 66 12 20 54 12 40 38 REMARKS Convulsive twitchings. Blood is asphyxiated ; no respiration. Killed. REMARKS. Normal 130 Injected intravenously the peptone from 0.00 gram dried Cobra venom. Tonic convulsions. Convulsive twitchings; asphyxiated blood; respiration ceased. Dead. The Aetion of Venom Ptptones on the Blood Pressure of Animals with Pneumo- gastric and Dtpressor Servts Secret/.—After section of the pneumogastric and depressor nerves the results are not appreciably altered. Four experiments were made: one with Crotalus adamanteus; one with Aucistration pisd.rorus, and two with Cobra venom. In all of these experiments the pressure during the secondary rise went above the normal. THE ACTION OF VENOMS UPON ARTERIAL PRESSURE. 115 Experiment No. 70. Time: Pressure miu. sec. m. m. Normal . . 160 10 160 15 140 30 150 40 156 50 156 1 00 134 1 20 158 1 30 164 3 30 126 8 30 122 5 30 146 20 30 148 25 30 140 30 30 140 35 00 136 40 00 148 45 00 142 50 00 140 62 00 138 Experiment No. 71. Time: Pressure min. sec. m. m. Normal . 124 10 100 20 140 30 150 40 130 50 140 1 00 134 1 20 114 1 40 116 2 00 136 2 30 124 2 40 110 2 50 124 3 00 136 3 10 110 3 20 96 4 20 Experiment No. 72. Time: Pressure min. sec. m. m. Normal 138 10 142 20 136 40 134 1 00 140 1 30 138 REMARKS. Injected intravenously the peptone from 0.015 gram dried venom of the Crotalus adamanteus. Struggles. Struggles. Killed. REMARKS. Injected intra.venously the peptone from 0.015 gram dried venom of the Ancistrodon piscivorus. Respiration ceased; heart beats. REMARKS. Injected intravenously the peptone from 0.005 gram dried Cobra venom. 116 T II E V E X (IMS OF C E R T A I X T II A N A T O T II I D E .E . Time: Pressure min. hoc. m. m. 3 30 1 36 5 30 136 7 30 132 9 30 132 10 00 140 21 30 146 25 30 142 26 30 15(1 it No. 73. Time: Pressure min. see. m. m. 124 10 122 20 128 40 124 1 00 126 3 oo 120 5 00 120 16 00 lis 34 00 REMARKS. Twitchings. Killed. No ecchymoses. REMARKS. Normal 124 Injected intravenously the peptone from 0.006 gram dried Cobra venom. Dead. Asphyxiated; no ecchymoses ; blood clots in canula. The Aetion of Venom Ptptones e,u the Blood Pressure of Animals in. trhuh the Pin itinogustric, J)tpressar, and Sympathetic Serves and Cervical Spinal Cord were Cut.— In five experiments on animals in which the nerves in the neck and the spinal cord in the middle or upper cervical region were1 cut we found that but little alteration occurred in the blood pressure until late in the poisoning, excepting in one experiment with the Am is/ration piscivorus, in which the pressure sunk imme- diately and death occurred in thirty seconds. Two experiments were made with the1 peptone of the Crotalus utlanutnteus ; one with the A u,cistration piscirorus, and two with the Cobra. In all of these experiments, excepting one with Cobra, there was an immediate comparatively slight fall of pressure after injection, which was followed generally by a rise; in the excepted case of the Cobra there was a primary rise equal to 3 m. m. of mercury, which was followed by a fall, and this in turn by a rise. The pressure, as in the previous experiments, usually declines towards death. Experiment So. 74. Normal ... 50 Injected intravenously the peptone from 0.015 gram dried venom of the Crotalus adamanteus. Time : Pressure min. sec. m. m. 50 10 50 20 48 40 48 1 0(1 48 3 00 44 6 00 42 11 00 42 13 00 42 15 oo 42 REMARKS. THE ACTION OF VENOMS UPON ARTERIAL PRESSURE. 117 Time: Pressure min. sec. m. m. 17 00 50 17 30 50 19 30 48 21 30 48 23 30 46 25 30 46 27 30 44 29 30 44 31 30 42 34 30 38 REMARKS. Injected the peptone from 0.03 gram dried venom. Dead. No ecchymoses; blood fluid after Gfteen minutes. Experiment No. 75. Normal Time: Pressure min. sec. m. ID; 67 15 50 20 50 30 50 1 00 50 1 30 50 2 00 50 REMARKS. Injected intravenously the peptone from 0.015 gram dried venom of the Crotalus adamanteus. Experiment No. 76. Normal Time: Pressure min. sec. m. m. 50 10 45 18 38 30 33 1 00 REMARKS. Injected intravenously the peptone from 0.015 gram dried venom of the Ancistrodon piscivorus. Dead. Experiment No. 77. Normal Time: Pressure min. sec. m. in. 128 10 122 20 132 30 134 1 00 132 12 00 138 12 30 136 17 30 REMARKS. Injected intravenously the peptone from 0.01 gram dried Cobra venom. Dead. Blood clots readily. Ecchymoses in base of lungs. Us THE. VENOMS o 1 CERTAIN T II A N A T O P II I D E .E . Experiment S o. 7\ Tunc : I'm-mi re min. 6CC. m. m. Normal 11 39 20 41 40 40 1 40 35 5 40 35 10 40 37 15 40 38 16 00 16 06 38 16 15 3s 16 25 43 16 45 43 17 00 43 Is 00 40 20 00 25 23 00 From all of the results of these experiments it seems justifiable to conclude that the isolated principles of venoms exert the poisonous actions of pure venoms on the blood pressure, and that their toxic effects are essentially simply different in degree. These various poisons all play a part in the alterations of pressure-, acting towards the same end, but mainly with different degrees of intensity ; the water- venom-globulin appears to he the most potent in the pressure alterations, the dialy- sis-rt:u,om-globnlin next, then the peptone, and finally the copper-venom-globulin. The globulins are the more active- in the production of the diminution of pressure, and the peptone in the secondary rise. The globulins no doubt play a very important part in the poisonems phenomena of Crotalus poisoning, a less important part in Aucislration poisoning, and but very little in Cobra poisoning; these differences not depending as much upon differences in the quality of the globulins in the species of venom to which they belong as on differences in quantity. REMARKS. Injected intravenously the peptone from 0.015 gram dried Cobra venom. Injected a similar dose. > Dead. THE ACTION OF VENOMS UPON RESPIRATION. 119 CHAPTER IX. THE ACTION OF VENOMS AND THEIR ISOLATED GLOBULINS AND PEPTONES UPON RESPIRATION. Section I.—Pure Venom. In our experiments on respiration rabbits were always used, and the rate of breathing was recorded on a revolving drum by the lever of a Marey's tambour, the latter being connected with the animal by means of a tracheal tube. The injections in all of the experiments, excepting two, which were subcutaneous, were made into the external jugular vein. In experiments on normal animals we observed no qualitative difference in the several venoms used. Ten experiments were made upon normal animals: four with the venom of the Crotalus adamanteus; three with that of the Moccasin, piscivorus, and three with that of the Cobra. In eight of these experiments there was a primary increase in the respiration rate followed by a diminution far below the normal, while in two the respirations were at once diminished, and became per- sistently slower until death. In both of these cases death occurred very soon after injection, indicating a most profound action of the poison. Action of the Pure Venoms on the Respirations in Normal Animals. Experiment No. 1. Normal Length of Time: Respirations curve min. sec. pel • minute. m. m. 84 10 10 180 16 40 84 12 1 96 2 20 108 4 50 72 8 6 50 72 6 8 50 60 6 10 50 48 11 20 40 4 11 50 24 4 12 20 26 12 50 REMARKS. Injected intravenously 0.002 gram dried venom of the Crotalus adamanteus dissolved in 1 c. c. distilled water. Convulsive movements. Dead. 1 a{) T II i; V E N O M S () 1- C E K 1 A I N T 11 A N A TOPHI D E .E Exjh rimcnt Xo. 2. Length of REMARKS. N'unii;il 42 6 Injected intravenously 0 004 gram dried venom of the Crotalus adamanteus dissolved in 1 c. c. distilled water. Struggles, which prevent a count. Convulsive- movements. Conjunctival reflexes gone. Respiration ceased. Heart still beating. The respira- tory muscles respond to stimulus. The spinal cord was exposed, and the motor columns were- found to respond to electrical stimulus. The motor nerves responded after the motor columns of the cord had lost their irritability. REMARKS. Injected intravenously 0.006 grain dried venom of the- Crotalus adamanteus dissolved in 3 minims distilled water. Length of Tin lie : u.*i liratiinis curve In. sec. per minute. 4 2 m. in 6 10 43 10 40 ? 1 00 SI 12 2 10 30 25 3 40 9 23 5 00 10 14 5 10 •.xjn rinu i, d Ao. 4. Length Time: R.- l>irations I'UIVI min. sec. |)CI ■ minute. m. in. ormal . . S4 7 20 158 3 40 1 20 7 1 00 96 11 1 30 90 10 2 00 96 12 2 30 102 10 3 oo 120 7 3 3(1 35 5 4 30 60 6 5 30 35 10 6 30 10 7 7 30 4 4 Struggles. Conjunctival reflexes gone. Di'spiration ceased. Respiratory muscles irritable. The spinal cord was quickly exposed; the sensory columns give no response, the motor columns are active. The motor columns of the cord fail before the motor nerves. Ex in ri nit id Ac;. 4. Length of Time: Respirations curve REMARKS. min. sec. per minute. m. m. Normal ... 66 6 Injected intravenously 0.015 gram dried venom of the Crotalus adamanteus dissolved in 1 c. c. distilled water. 15 ... ... Arrest of respiration attended with a tetanic condition, 30 36 16 1 00 12 16 1 50 18 6 2 20 ? 5 2 25 ... ... Respiration ceased. Spinal cord rapidly exposed and tested by electrical currents; sensory columns fail first, then the motor columns, then motor nerves. THE ACTION OF VENOMS UPON RESPIRATION. 121 Experiment No. 5. Length of Time: Respirations curve REMARKS. min. sec. per minute. m. m. Normal . . . 100 9 Injected intravenously 0.004 gram dried venom of the 10 210 8 Ancistrodon piscivorus dissolved in 5 minims dis- 20 150 21 tilled water. 30 140 20 40 120 23 50 ... ... Convulsions. 1 10 ... ... Dead. Experiment No. 6. Length of Time: Respirations curve REMARKS. miu. sec per minute. m. m. Normal . . . 135 6 Injected intravenously 0.004 gram dried venom of the Ancistrodon piscivorus dissolved in 1 c. c. distilled water. 10 420 . . . Struggles. Respiration at once began to increase 20 270 6 rapidly, and reached a maximum rapidity during the occurrence of struggles. 30 65 18 Tetanic movements. 40 60 '. . . " 50 120 10 1 00 120 1 10 60 1 20 90 12 6 20 60 11 20 180 16 20 210 ... 16 30 ... ... Killed. Experiment No. 7. Normal ... 144 6 Injected intravenously 0.004 gram dried venom of the Ancistrodon piscivorus dissolved in 1 c. c. distilled water. Time: Respirations Length of curve min. sec. per minute. 144 in. m. 6 10 300 8 20 240 12 30 150 11 5 00 60 10 7 00 80 7 12 00 54 7 18 00 70 7 18 05 18 30 210 9 18 40 160 10 18 50 80 . 5 REMARKS. Injected as above 0.008 gram venom. 23 50 65 7 Killed by pithing. 16 Judg, 1886. 1 >> T II E V E N O M S O E C E R T A I N T II A N A To I' II I D E M. Ex per ina nt Xo Length of REMARKS. Injected intravenously 0.015 gram dried Cobra venom dissolved in 1 c. c. distilled water and Altered. Strut: tries. Length of Time : Re spirullons curve miu. sec. pe r minute. m. m. Normal 20 60 80 ;i 40 120 15 1 00 100 45 1 20 60 10 1 40 42 38 2 00 Respiration ceased. Expt rintent Xo. 9. Length - :.f Time: Res pirations curve REMARKS. miu. bCC. per minute. m. m. Normal 300 8 Injected intravenously 0.015 gram dried Cobra venom 10 300 9 dissolved in 1 c. c. distilled water. 20 255 11 30 285 10 40 240 10 1 1 00 30 255 200 11 9 2 00 150 7 2 10 125 7 s 20 ... Respiration ceased. Experimci nt Xo. 10. Tune: Respirations REMARKS. min. sec. pci - minute. Normal 36 Injected intravenously 0.003 gram dried Cobra venom in solution 20 39 40 39 1 00 51 1 30 52 2 00 45 4 9 00 00 48 46 12 00 36 14 Respiration ceased, The Action of Pure Venoms on the Respiration in, Animals in which the Pneu- mogastric Xerves ice re Cut.—When injections are made, after section of the pneu- mogastric nerves, the primary increase in the respiration rate does not occur, but a diminution begins at once; and, on the whole, drops irregularly until death ensues. Four experiments were thus made: one with Crotalus adumaideus, two with Ancistration juscivorus, and one with Cobra venom; the results being on the whole reasonably uniform. THE ACTION OF VENOMS UPON RESPIRATION. 123 Experiment No. 11. Time: min. sec. Normal 30 00 30 00 30 00 30 30 30 30 Respirations per minute. 42 20 28 6 6 3 12 6 6 6 Length of curve m. m. 7 18 10 22 19 25 18 21 21 15 12 REMARKS. Injected intravenously 0.002 gram dried venom of the Crotalus adamanteus dissolved in 1 c. c. distilled water. Slight struggles preceding this observation interfered with the marker. Experiment No. 12. Normal Time: min. 6ec. 10 20 30 40 50 1 00 1 10 1 15 Time: min. sec. Normal 1 2 4 10 30 00 00 00 Respirations per minute. 103 94 84 102 77 60 60 45 Experiment No. 13. Respirations per minute. 102 57 78 57 66 Experiment No. 14. of REMARKS. Injected intravenously 0.004 gram dried venom of the Ancistrodon piscivorus dissolved in 1 c. c. distilled water. Struggles. Length curve m. m. 15 15 30 25 25 28 25 30 Dead. Respiration ceased ; heart still beats. Animal dies in tetanus. REMARKS. Injected intravenously 0.003 gram dried Cobra venom dissolved in 1 c. c. distilled water. Normal Length of Time: Respirations curve min. sec. pei minute. m. m. 127 17 20 92 47 30 90 32 40 82 50 82 1 05 67 1 30 REMARKS. Injected intravenously 0.004 gram dried venom of the Ancistrodon piscivorus dissolved in 1 c. c. distilled water. Respiration ceased. 12* Til E V E N O M S 0 I C E R T A IN T II A N A T O P II I D 1. .E In none of these1 experiments do we find a primary increase in the respiration rate as in animals with intact vagi, but insatiably a diminution. It seems clear, therefore, that the hist result must be dependent upon an excitation of the peri- pheries of the pneumogastric nerves, and that the diminution of respirations is due1 to a centrally active cause. Should the lessened number of the1 respirations be central, that is, dependent upon a depression of the respiratory centres, we would expect to find that the degree of depression would depend upon the relative1 amount of venom coming in contact with these centres in a given space of time. We have accordingly made an experiment, in which this suggestion is admirably carried out by injecting the venom into the carotid artery, thus throwing the poison directly upon the respiratory centres. Experiment Xo. 15. Length of Time: Respirations curve REMARKS. min. se-c. per minute. m. m. Normal ... 78 42 Injected into the right carotid artery 0.015 gram of 15 7 38 dried venom of Ci-otalus adamanteus dissolved in 1 30 4 30 c. c. distilled water. 1 00 4 25 1 30 10 45 Convulsions. 2 00 ... ... Dead. It seems obvious from the preceding experiments that venoms exert a double aetion on the respiration; first, an irritant action on the peripherics of the pneu- mogastric nerves, by which an increase in the respiration rate is brought about; and secondly, a depression of the respiratory centres, by which the respiration rate is diminished. Since the diminution in the respirations occurs in animals with rut pneumogastrics immediately after injection, and at a time when an increase occurs in normal animals, it is apparent that these two factors are acting in normal animals at the same time to produce opposite results; consequently, whether we have an increase or a decrease in the respirations must be dependent upon the relative degree of power exerted by one or the other of these factors. In most cases we have found a primary increase of respirations followed by a diminution; it is therefore obvious that the action of the venom upon the peripheries of the pneumogastric nerves was more than able to compensate for the depressant action of the poison upon the respiratory centres; this is very clear since no increase of respirations above normal occurs in animals with cut pneumogastrics. In the two cases in normal animals in which a decline from the first was observed, and in which the animals died in a few minutes after injection, the action of the venom upon the respiratory centres was so profound that the accelerator factor was unable to cause a rise. This is also illustrated in the experiment in which the venom was injected into the carotid artery and thrown upon the respiratory centres. Since venom does not seem to exert other than a depressant action upon the respiratory centres, it does not appear probable that it would have an opposite effect upon the respiratory nerves, so that the effect of the venom upon the peri- pheries of the pneumogastric nerves is probably one of irritation rather than stimu- THE ACTION OF VENOMS UPON RESPIRATION 125 lation, and probably due to some secondary cause, which is likely to be located in the profound alteration of the blood or the destructive action of the venom upon the pulmonary tissues, as illustrated, for instance, upon capillaries. Section II.—The Action of Globulins on the Respirations. The Action of Venom Globulins upon the Respiration in Normal Animals.— Seven experiments were made with globulins upon normal animals: three with the water-venom-globulin of the Crotalus adamanteus; and one with the weder-venom- globulin of Cobra; one with the copper-venom-globnlin, and one with dialysis-venom- globidin, both from the Crotalus adamanteus. These poisons, excepting the copper-venom-globulin, all act like the pure venoms, but generally with a less degree of intensity, causing a primary acceleration of the respiration followed by a decline. In the second experiment, however, there was no diminution, but the respirations became enormously increased so that at death they were nearly trebled in frequency. The copper-venom-globulin does not cause any primary acceleration, but simply a diminution. Experiment No. 16. Normal Length of Time: Respirations curv min. sec. per minute. m. n 100 9 20 100 15 40 100 12 1 00 96 11 3 00 96 9 4 00 120 10 5 00 120 10 6 00 132 10 8 00 100 10 10 00 90 9 12 00 80 9 14 00 69 7 14 05 14 20 80 15 14 40 60 10 16 40 90 10 18 40 96 8 20 40 108 9 22 40 114 9 24 40 108 9 26 40 90 6 28 40 96 8 30 40 72 7 32 40 64 8 34 40 70 8 36 40 75 8 38 40 80 9 40 40 90 10 REMARKS. Injected intravenously the water-venom-globulin from 0.015 gram dried venom of the Crotalus adamanteus. Injected as above from 0.06 gram dried venom. Struggles. 44 00 Dead. Heart arrested in diastole ; some ecchymoses. 12(i T II E V E X 0 M S () E I'E R T A I X T II A X A TOPHI D E .E Experiment Xo. 17. Time: min. m. N ormal 1 1 6 11 16 17 27 29 15 30 00 30 30 30 30 00 00 00 Respirations per minute. 75 80 60 60 90 110 110 110 120 19(1 Experiment Xo. 18. Respirations Time : min. sec. Normal 1 2 6 11 16 26 33 56 CA\ 76 120 15 25 45 15 00 00 00 00 00 00 00 00 00 per minute. 114 126 132 150 15(1 204 114 S4 62 60 63 62 Length of curve m. m. 8 REMARKS. Injected intravenously 0.0158 gram water-venom-globtir lin (5 days old) from the dried venom of Crotalus adamaTtieus. Streitrdes. Injected the same as above. Dead. Blood remains fluid ; some ecchymoses. REMARKS. Injected intravenously the water-venom-globulin from 0.035 gram of dried Cobra venom dissolved in 1 c. c. distilled water. Killed. Animal in fair condition. Experiment Xo. 19. Time: min. see Neirmal 1 2 5 10 14 19 24 29 34 42 47 20 30 30 30 30 30 30 30 30 30 30 30 30 30 Respirations per minute. 73 84 7s 120 108 96 96 s2 70 75 78 72 69 72 96 REMARKS. Injected intravenously the woler-venom-globulin from 0.015 gram dried venom of the Crotalus adamanteus. Hematuria THE ACTION OF VENOMS UPON RESPIRATION. 127 Normal Time: Respirations min. sec. per minute. 57 30 90 67 30 84 77 30 84 80 30 12 85 Dead. E irnent No. 20. Length of Time: Respirations curve min. sec. per minute. m. m. 180 20 20 174 19 40 168 19 1 00 168 19 3 30 168 20 5 30 108 15 7 30 100 9 9 30 110 10 11 00 168 17 13 00 138 11 15 00 120 10 17 00 144 10 19 00 102 9 21 00 108 10 23 00 104 7 25 00 112 9 27 00 100 9 30 00 90 7 34 00 90 7 39 00 112 10 41 00 85 8 43 00 96 7 45 00 108 5 47 00 108 7 49 00 76 6 51 00 66 7 53 00 80 8 57 00 96 8 59 00 90 9 60 00 116 10 63 00 118 8 65 00 116 10 69 00 104 9 71 00 100 7 73 00 116 7 75 00 100 8 77 00 116 11 79 00 140 11 81 00 130 10 85 00 130 10 87 00 120 10 91 00 126 9 REMARKS. Ecchymoses generally ; blood fluid. REMARKS. Injected intravenously the copper-venom-globulin from 0.015 gram dried venom of the Crotalus adamanteus. Struggles. 92 00 Killed by pithing. Lungs very much ecchymosed; abdo- minal viscera normal; heart normal; blood coagulates. 1 Js I II E V E N (IMS O I C E R T A I N T II A X A T O P 11 I 1) E .E Expertmt nt Xo. 21 Length of Time: Rc.-piratioiis curve RKMARKS miu. sec. per miuute. m. in. Normal ... 54 18 Injected intravenously 0.0012 gram u-ater-venom- 10 60 16 globulin from the dried venom of the Crotalus ada- 26 54 15 manleus. 40 54 15 1 00 4M 16 3 00 60 17-42 Struggles. 5 uu 72 33 7 00 54 30 8 00 63 32 10 00 60 28 11 30 60 30 13 30 72 42 15 30 70 38 17 00 7s 45 Injected 0.0022 gram water-venom-globulin. 17 10 78 42 17 20 102 38 18 20 72 38-78 Struggles. 19 20 66 22 21 20 60 23 24 20 70 25 27 20 60 2!) Injected 0.0024 gram water-venom-globulin. 27 40 60 26 28 20 60 25 29 50 . . Killed by pithing; some ecchymoses. Experiment Xo. 22. Length of REMARKS Normal ... 112 9 Injected intravenously the diulysis-venom-globulin from 0.015 irram dried venom of the Crotalus adamanteus. Length i Time : Respirations curve min. SCO. per minute. 112 m. m. 9 10 120 12 20 160 16 30 140 16 40 140 15 1 00 140 16 0 00 1 26 10 5 00 156 14 10 00 174 15 12 00 130 14 13 30 142 10 13 50 150 22 14 30 132 13 19 00 130 9 24 00 120 << 29 00 110 10 39 00 SO 6 54 00 Sll 3 55 00 Injected dialysis-venom-globulin from 0.06 gram of dried venom. Dead. Respiration ceased before the heart. Ecchy- moses in the lungs and in the pericardium, in the small intestine, ureters, and bladder. THE ACTION OF VENOMS UPON RESPIRATION. 129 The Action of Venom Globulins on the Respiration of Animals in which the Pneumogastric Nerves were Cut.—Two experiments were made on animals with cut pneumogastric nerves: one with the dkdysis-venom-globidin, and one with the copper-venom-globidin, both from the Crotalus adamanteus. In neither experiment was there an- increase in the respirations; these results being in accord with the experiments made with pure venom. Experiment No. 23. Normal Length of Time: Respirations curve min. sec. per minute. m. m. 42 8 10 39 10 20 30 12 40 24 8 1 00 27 10 - 1 20 ? 3 20 20 9 5 20 35 8 8 20 24 5 18 20 30 5 23 20 32 6 36 20 42 7 36 40 42 7 38 40 24 20 42 00 Experiment No. 24. Normal Length of Time: Respirations curve min. sec. per minute. 60 m. m. 5 30 54 6 1 00 48 5 3 00 48 5 8 00 48 5 13 00 52 6 15 00 48 6 15 .30 30 4 15 40 54 15 16 00 ? 16 30 18 10 19 00 12 4 24 00 20 4 27 00 20 5 30 00 30 5 35 00 26 5 39 00 27 5 41 00 30 5 44* 00 42 6 49 00 30 6 54 00 17 June, 1886. REMARKS. Pneumogastric nerves previously cut. Injected hypo- dermically the dialysis-venom-globulin from 0.015 gram dried venom of the Crotalus adamanteus. Struggles. Injected dialysis-venom-globulin from 0.06 gram1 Struggles. Respiration ceased; heart beats feebly; blood remains incoagulable; great ecchymoses in abdominal viscera. REMARKS. Pneumogastric nerves previously cut. Injected intra- venously the copper-venom-globulin from 0.015 gram dried venom of the Crotalus adamanteus. Injected copper-venom-globulin from 0.03 gram dried venom in two doses. Struggles with very irregular breathing followed by gasping respiration. Injected copper-venom-globulin from 0.12 gram dried venom in two doses. Respiration ceased ; heart still beats; ecchymoses in heart and lungs marked. l:'»n T II E V E N O M S O F C E R T A I N T II A N A T <> P II I D E E The results of these1 experiments with the globulins indieate1 that the water- n nom-gloliulin and tlia/ysis-venom-globulin act like the pure venom, while the copinr-icnom-gUibidin lacks the property of producing the primary aceelc-ration of the respirations. Section" III.—The Action of Venom Peptones on the Respiration. The Action, of Venom Peptones on the Inspiration in Normal Animals.—Three experiments were made on the normal animals with the venom ptptones; in two with the1 peptone from the Crotalus adamanteus, and in one with the peptone from the A mist ration piscivorus. In all of these experiments the increase of the respi- ration rate was strongly marked. t.Xnert lilt td X Normal Time : 10 30 00 00 00 00 Respirations per minute. 300 270 270 270 Length of curve m. m. 68 60 60 56 50 50 55 REMARKS. Injected intravenously the peptone from 0.03 gram elrieel venom of the Crotalus adamanteus obtained by boiling. Killed. Rlood clots readily; moderate ecchymoses in the lungs. Experiment Xo. 2(V Normal Length of Time: Re spi rations curve min. sec. pe • minute. ISO in. m. 11 10 240 16 30 270 15 40 240 1 00 345 1 10 270 1 20 240 4 20 240 0 20 300 is 20 360 14 28 20 270 38 20 180 11 REMARKS. Injceteel intravenously the peptone, from 0.06 gram dried venom of the Ancistrodon piscivorus obtained by boiling. THE ACTION OF VENOMS UPON RESPIRATION. 131 Experiment No. 27. Normal Length of Time : Respirations curve min. sec. per minute. m. m. 75 9 10 120 42 3 00 30 10 6 00 75 8 11 00 50 8 18 00 48 7 23 00 50 7 28 00 45 7 33 00 00 7 37 00 60 9 49 REMARKS. Injected intravenously the peptone from 0.015 gram dried venom of the Crotalus adamanteus. Dead. No ecchymoses; lungs slightly congested. In one animal the increase was equal to one-third of the normal; in the second, in which a larger dose was used, the normal rate wras doubled; and in the third it rose to more than one-half of the normal. There was not, however, in any of the animals that marked depression which is observed in poisoning with pure venom or venom globulins. The Action of Venom Peptones on the Respiration in Animals in which the Pneumogastric Nerves had been previously Divided.—In one experiment in which the pneumogastric nerves were cut and in which the peptone from the venom of the Crotalus adamanteus was used, the well-marked primary increase in the respi- rations did not occur, there being a diminution from the first. Experiment No. 28. Normal Length of Time: Respirations curve min. sec. per minute. m. m. 80 13 10 52 18 15 37 12 20 25 8 30 22 7 1 00 30 8 1 30 30 7 3 30 40 9 8 30 60 8 15 30 36 13 20 30 48 17 25 30 50 14 30 30 52 15 35 00 55 12 40 00 48 15 45 00 45 15 50 00 45 16 62 00 44 15 REMARKS. Injected intravenously the peptone from 0.015 gram dried venom of the Crotalus adamanteus. Struggles. Killed by pithing. In this experiment, as in those with pure venom and venom globulins in which the animals had the pneumogastrics cut, the increased respiration rate seen in normal animals did not occur. 1;}'J THE VENOMS 01 CERTAIN T II A N A T O 1* HID K .E The results of the experiments with venom peptone are therefore in accord with those with the pure venom and the venom globulins. Summary.—From the results of the observations with pure venoms and their globulins and peptones upon the respiration it seems clear that the primary action of all of the above poisons, excepting the- coppcr-venoni-globulin, is to cause an increase in the number of respirations, and secondarily to diminish the respirations below the normal. Of the different principles the peptone seems to exert the most decided power in causing the acceleration, while the copper-venom-globulin seems to utterly lack this action. Since- the primary increase of the respirations does not occur in any case after section of the pneumogastric nerves, this effect must be exerted by an action of the poisons upon the peripheries of these nerves, and since after section of these nerves a diminution of the respirations always occurs this effect must be due to a depres- sion of the respiratory centres, as we have found that the motor nerves and muscles of respiration are irritable long after the cessation of this function. PATHOLOGY. 133 CH APT Ell X. PATHOLOGY. Pathology of Serpent Venoms.—The pathology of snake poisoning in man owes most of what is best in our knowledge of it to the researches of the East Indian surgeons and to American observers. In the following observations Prof. H. F. Formad has followed with great suc- cess the lines of a research which were laid down with care by the authors of this essay. They have also been at great pains to repeat, and to verify, most of the observations made by this distinguished observer. The Nature and Character of the Individual Morphological Constituents of Venom.—Having seen that fresh venom consists morphologically of a liquid and of a solid part, it was necessary to ascertain the exact nature and character of each. The following means were resorted to:— 1st. The separation of the granular material (of fresh venom) by filtration and the submission to physiological tests of the liquid filtrate and of the solid residue, each separately. 2d. The exposure of fresh venom to a temperature high enough to kill organized life, and then submitting it to physiological tests. 3d. Studying the effects of venom and of its isolated morphological constituents upon dead animal substances. (Putrefaction and other experiments.) 4th. The isolation and culture of the organisms contained in venom and the testing of the physiological effects of these isolated and washed organisms (viz., of pure cultures of micrococci). 1st. Filtration Experiments with Fresh Venom.—On account of its viscid and glutinous character venom could not be satisfactorily filtered except under a high pressure through a vacuum filter. About two drachms of fresh Crotalus adamanteus venom were forced by means of a hydraulic air pump through a porous clay cylin- der such as is employed in certain small galvanic batteries, or else the venom was filtered through a thin layer of plaster of Paris moulded in the neck of a small glass filter. The liquid filtrate obtained was perfectly clear, and examined under the microscope showed no organic or solid particles of any kind. The solid residue left upon the filter consisted of granular material, such as has been described before, of bacteria and a few cells. This residue was diligently and repeatedly washed with boiled distilled water, by passing the latter through the filter. The amount of residue (about three grains) just obtained was dried and intro- duced subcutaneously into the pectoral muscle of a pigeon, but without effect. l;j| Till: VENOMS OF CERTAIN T 11 A N A T O P 11 I P E E T\\<> pigeons wen injected in the pectoral muscle, one with five, and the- other with two niiniins of the liquid filtrate1 above drseribod, and both died promptly within six minutes and twenty-five1 minutes respectively. 2d. Exia rintents tilth United Venom.— Fiv^h ('retains venom rapidly dried was put. in a covered watch-glass and subjected for one hour to a temperature of 115 0. in the- dry-heat oven. The venom was thereby converted into a dense resinous opacpie brown mass. Two grains of this mass, upon the addition of distilled water forming a turbid liquid, were divided into thirds and injected hypodermatically into a rabbit, a rat, and a pigeon, respectively. The rabbit died in 15 minutes, the rat in 12 minutes, and the pigeon in ~i minutes, after the operation, with results and le;sion similar to those obtained by the use of fresh venom. This experiment also shows that the virulence of venom does not reside1 in any of its organized constituents. 3d. Putrefaction Exju rimt ids.—The testing of the effc-cts of venom on various dead animal substances was particularly desirable on account of the remarkable capacity of the venom to induce rapid putrefaction in the tissues of living animals. It was necessary to learn whether this property of bringing about speedy necrotic changes was an action inherent in ve-nom or due to any of its accidental constituents. Put r< faction Ex pt rim cuts irith Sterilized Bouillon and Fresh Venom and its Active. Priu.c'tples (not Sterilized).—This bouillon was prepared from chicken in the same manner as that ordinarily used for culture liquids for bacteria, and the experiments were executed in a room at a temperature of about "HP F. About two drachms of sterilized bouillon were1 put in each of sixteen ordinary test tubes which were1 then treated as follows :— Tubes 1 and 2. added to bouillon one drop of fresh Crotalus venom; mouth of tubes plugged with cotton. Tubes 3 and 4. prepared same as last, but tube left open (no cotton plug). Tubes 5 and (i, added one grain of Crotalus peptone. Tube closed by cotton plug. Tubes 7 and S. same as last, but tubes left open. Tubes \) and 10, added one grain of Crotalus globulin. Tubes closed. Tubes 11 and 12. same as last. Tubes open. Tubes 13 and 14, a pure bouillon, nothing added to it. Tubes closed. Tubes 15 and 16. same as last. Tubes open. Twenty-four hours later the bouillon in all the test tubes which originally was perfectly clear had become cloudy except tubes 13 and 14 (which contained the sterilized pure bouillon plugged well with cotton). On the third clay of the experiment tubes 3 and 4 (fresh venom, tubes open) showed well-pronounced putrefaction of the bouillon. Slight putrefactive changes were subsequently observed in the remaining tubes (except 13 and 14) in the following order:— On the fourth day, tubes 7 and s. On the fifth day, tubes 11 and 12, also in tubes 15 and 16. On the seventh day all the plugged specimens were examined, and all showed PATHOLOGY. 135 more or less putrescence except the tubes with the pure bouillon as stated. Of these closed test tubes, however, tubes 1 and 2 (the fresh venom) showed the putrefactive changes to be much more pronounced than in the remaining tubes ; but as we have seen putrefaction ensued much sooner in the tubes that were open (tubes 3 and 4). As all the tubes showed putrefaction more or less, it is presumable that the peptone and globulin accidentally contained bacteria, these substances not having been sterilized at the commencement of the experiment. The contents of the tubes examined microscopically during and at the end of the experiment showed the presence of bacteria of putrefaction in direct proportion to the putrefaction changes. Imperfect as this experiment may be, it appears to establish the fact that fresh venom promotes putrefactive changes comparatively more rapidly than the venom peptone and globulin, but it also shows further that this power to produce putres- cence is very much aided by the action of the air, and depends upon the presence of bacteria contained in that air or in the venom. It was also evident that putre- faction was considerably retarded in all the tubes that were plugged by the cotton, and further that unplugged tubes containing sterilized soup, and exposed to contami- nation from air showed also putrefaction but at a later date. Putrefaction Experiment with Muscular Tissue and Venom.—The following rough experiment also appears to show that putrefactive changes develop, in dead animal tissues much more rapidly in the presence of venom than without it. Experiment.—A few drops of a solution of dry Crotalus venom were poured upon a small piece of fresh muscle just removed from the thigh of a rabbit and placed in a covered glass beaker. A similar preparation but without the addition of venom was made in a second covered beaker. Temp. 70° to 80° F. Putrefactive changes began to appear in the specimen treated by the venom after twenty-four hours, and after seventy-two hours were quite far advanced. Under the microscope the muscular tissue showed necrotic alterations very similar to those (to be described later) as occurring in experiments upon the living muscle. A multitude of dumb-bell-shaped rod bacteria, some large bacilli and the micrococci of the venom enormously multiplied, were seen in the decaying muscular substance. In the specimen of muscle not treated by venom, putrefactive changes were delayed to the fifth day and then appeared to be much less conspicuous, showing but few bacteria. The muscle fibres were uniformly cloudy and degenerated but not broken down in the peculiar manner caused by venom. Experiments with Bouillon and Venom in Sealed Glass Bidbs, Venom being thoroughly Sterilized.—More satisfactory and conclusive results were obtained from the following experiments: — A number of small glass bulbs were filled with sterilized bouillon after the well- known method of Dr. Sternberg, and after being thoroughly resterilized by boiling the following preparations were made:— * To each of six bulbs was added one grain of dry Crotalus venom, the venom havin^ been previously subjected to sterilization in a dry heat at 110° C. for one 1H<; THE VENOMS 0 1 (M-UTAIX T II A N A T () P II I D E /E hour. The bulbs wore then hermetically sealed by molted glass. The1 bouillon in flu m- tubes (with sterilized venom) remained perfectly clear and free1 from bacteria. Microscopical examination was made at various periods, the last time after eighteen months when it was still perfectly clear and showed no signs of putrefaction. A similar result was obtained in an experiment with another set of six glass bulbs filled with bouillon, and to which some Moccasin peptone, previously sterilized, was added. These bulbs looked somewhat cloudy, but on examination of the con- tents eighteen months later no bacteria, and no putrefactive changes were noted. As a control experiment six bulbs filled with pure sterilized bouillon were kept for a similarly long period, and they all remained clear and free from change1; while a few bulbs filled with unsterilized bouillon showed great cloudiness, bacteria, and putrefactive1 change. 4th. Culture Experiments.—The study of the morphology of the bacteria inhabit- ing the venom was next undertaken. To this end numerous culture experiments to isolate the bacteria from the venom were made. As stated before, the perfectly fresh venom contained only one form of these vegetable organisms, the micrococci, and only to these latter attention was paid; the rod bacteria and bacilli not appearing except in venom which had began to putrefy. The micrococci contained in the venom showed the following behavior in pure cultures: Of culture soils, the peptonized gelatine prepared after the formula of Koch proved to be quite suitable. The isolation of the micrococci was made after the1 methods of Sternberg and of Koch, as adopted in the pathological laboratory of the University of Pennsylvania. For gelatine culture a minute quantity of venom was smeared on the surface of the solidified jelly contained in a sterilized, small, fiat, well covered glass vessel. The micrococci liquefied the jelly, an effect not peculiar to all bacteria. After twenty-four hours all over the inoculated surface of the jelly were seen small turbid drops which contained the micrococci. With a ste!rili/e-d platinum wire the micrococci from one of the liquefying specks upon the first culture1 were transplanted to the jelly in a second culture vessel. From this second generation a minute quantity was transplanted to a third and fourth culture vessel. The fourth and all the later generations yielded usually a pure crop of micrococci. In impure cultures dumb-bell-shaped bacteria and sometimes large bacilli were met with. These, however, could not be said to be peculiar to venom, as they are never found in fresh venom. It may, therefore, be concluded that these cultures represent the micrococci peculiar to, or at least those constantly inhabiting venom. More- over, the micrococci in these cultures whenever they were successful, were the only bacterium seen and were fully identical as to shape, measurement, and be- havior to aniline dyes with those found in the fresh venom. Much better crops of the venom-micrococci were obtained in bouillon cultures in Sternberg's glass-bulbs. The micrococci grow more rapidly and better in these bulbs, because the bouillon can be heated up to the more suitable temperature of 40° C.; while the jelly cultures could not be warmed to such a degree without melt- ing solid gelatine. A variety of other culture soils and methods of isolation were PATHOLOGY. 137 employed in these experiments, but their description here is unnecessary as not being sufficiently related to the points at issue. In relation to the morphology of the micrococci it may be added, that they measure on the average ^ootTo °f an mcn m diameter; they often appear in pairs, but most commonly in zooglcea masses. They show a distinct aureole, such as is met with in various forms of micrococci.1 These aureoles have lately been erroneously described by Friedlander, as peculiar to certain " specific" micrococci in croupous pneumonia. In conclusion, it might be said that the venom micrococci do not appear to differ from the micrococci found in the saliva of men and other animals. In order to test whether the venom-micrococci were in any way specific or patho- genetic, and whether they form, or contribute to, the virulence of the venom, inocu- lations with pure cultures of the micrococci were made upon animals. As these experiments gave entirely negative results, it is superfluous to enter into details. Suffice it to say that large quantities of the pure micrococci from a sixth generation were injected, in various manners, into rabbits, cats, pigeons, and white rats, but without fatal results; or without producing any other lesion than occasionally local abscesses, or later on, metastatic abscesses. Sometimes the so- called "miliary tuberculosis of animals" was produced by inoculating with the venom-micrococci. No signs of any lesions resembling those of venom poisoning were observed. Experiments made to Study the Anatomical Changes produced by the Venom in liv- ing Animals. Naked Eye Appearances.—Very many years ago Dr. Weir Mitchell described two forms of venom poisoning—rapid or acute, and slow or chronic. To the latter appear to be relegated by him all those cases in which death is protracted beyond a few hours. This convenient division is justified by certain differences in the mode of termination of venom poisoning, and by the macroscopic and micro- scopic appearances of the lesions induced. In the most rapid poisoning, there is frequently nothing appreciable to the naked eye beyond the slight local lesion or here and there minute capillary hemorrhages, when death has been delayed beyond a minute. In examples of chronic poisoning both the local and the systemic changes are enormously more extensive. When animals were subjected to chronic poisoning they were kept under the influence of narcotics, since it had been learned that these agents did not affect the results. No Cobra venom was employed in this series, but only the pure or dried venoms of our own serpents, or else some one or other of the constituents of these poisons. The following tables relate the experiments made, and the more striking mor- phological changes: — 1 See "Memoir on Diphtheria," Report to the Xational Board of Health, 1882, by H. C. Wood and II. P. Formad. 18 June, 1886. T II E V E N O M S () 1 C E R T A I N T II A N A T O P II I D E A-] RAPID POISONING E(iry Crotalus venom, ^ grain in watery solution, into peritoneum Dry CrotalusJ venom, i grain in watery solution, into peritoneum Local lesion. Killed Moderately sized, after 5 j dark hemorrha- minutes gic swelling Died in 15 minutes Died after 1 hour and .r>(i minutes Very dark colored hemorrhagic swelling Profuse hemor- rhage all over peritoneal cavity Same as last Died in 25 minutes 9 Subperitoneal minutes hemorrhages 35 | Hemorrhagic minutes swelling 5 minutes 43 minutes Killed at the end of 1 hour 20 minutes 40 minutes 40 minutes 1 hour and 20 minutes Killed in 10 minutes Killed in 10 minutes Died 1 hour and 25 minutes Hemorrhages in arachnoid and brain tissue Lung infarcted by blood Ecchymosis locally only Condi- tion of blood. Coagu- lable and red Changes in thorax, abdomen, brain, and membranes. All internal organs congesh no other changes visible ; ecchymoses perceptible Less co- Organs only moderately con- agulable, gested, but there were inl- and | uierous small subpleural, quite j subperitoneal, and slight dark subpericardiai ecchymoses Liquid very dark Liquid dark Coagu- lable on exposure Liquid Slightly coagu- lable Ninie as last Liquid dark Slight subperito- Dark neal ecchymoses but co- agulable Local ecchymoses Ditto slight The same as last Profuse ecchy- mosis Same as last, but le=s marked Same as last Same as last Same as last Ditto Slightly coagu- lable Liquid Red and coagu- lable Same as last Very dark, liquid Ecchymoses in nearly all or- gans, quite marked in arach- noid and at base of brain ; some so small as to be visi- ble only by microscope. Ex- treme congestion Hemorrhages only subperito- neal, other organs merely congested Xo changes beyond local lesion No visible changes, except all organs congested Membranes of brain and brain substance peripherally soak- ed with blood ; other organs congested No changes, except in lung and some subpericardiai ec- chymoses Other organs not visibly affected No systemic changes. No notable changes in other organs Hemorrhage only local Hemorrhage only local, also extreme congestion of all organs Nothing peculiar beyond the local lesion Same as last Ecchymoses in all organs ex- amined. Profuse ecchymo- ses in peritoneum, also sub- pleural, subarachnoid, and subpericardiai. Liver, which was injured by the syringe. showed a large hemorrhagic infarction KliMAKk:- This animal was killed before the full effects of the venom. For the details and the his- tological appearances, see the next chapter. The studies of the changes ill muscular tissue were mostly made from this experiment. Changes in muscular tis- sue similar to those pro- duced by fresh venom, but far less blood effused. See specimen and descrip- tion in chapter on histo- logical changes. ' Histological changes similar to those pro- duced by fresh venom. Microscopic examination \- made of every organ. The details will be given hereafter. Some of the ecchymoses were so small as to be visible only on micro- scopical examination. PATHOLOGY. 139 RAPID POISONING.—Continued. No. of Animal Form and quantity Time of Local lesion. Condi- Changes in thorax, abdomen, Remarks. expt. used. of venom, and where introduced. death. tion of blood. brain, and membranes. 18 Cat Dry Crotalus Died Same as last Same as Peritoneal cavity contains a Cats appear to resist the venom, 1 grain in 5£ hours last good deal of liquid blood; effects of venom much watery solution, hemorrhage at base of brain longer than the other into peritoneal (subarachnoid); no other animals used in this re- cavity lesion noted; organs rather anaemic. Heart empty, con-tracted search . 19 Cat Peritoneum opened, Died Hemorrhagic in- Partly Peritoneal hemorrhage; or- It appears that when the (chlor- mesentery exposed after 4 filtration, quite coagu- gans anaemic mesentery is exposed and alized) uninjured, in hours extensive, but lable not injured the animal moist chamber, and 35 came on very survives much larger ap- and smeared re- minutes slowly plications of venom than peatedly with a if venom be injected into solution of dry an unopened peritoneal venom, using not cavity. Very small quan- less than 5 grains tities of venom appear to of venom kill in the latter case. For further experiments of this character, see Mechanism of Hemor-rhages. None of the cases in the table exhibit instances of the greatest possible rapidity of death. Dr. Mitchell has seen a pigeon die within ten seconds from a hypodermatic injection of pure Crotalus venom. In such a case there is positively no lesion, and the blood is solidly coagulated. In most cases very soon after injection of the venom in either of its forms, the time varying from a few minutes to a few hours, according to the kind of animal and the quantity of venom used, there appears a swelling at the point of injection with intense violet-black discoloration of the skin, which gradually extends over an area of several square inches. On making an incision into the tissues in the immediate neighborhood of the injection, they are found to be soaked with extravasated blood. This is often all that is visible if death has occurred soon; but if it has been postponed for a short time, then in tissues distant from the place of the injection, extravasations to a smaller extent were often found. Most pro- nounced and most frequent are the ecchymoses below serous membranes (subpleural, subperitoneal, and subpericardiai); in fact the whole organism is deeply affected, the tissues being congested and presenting a much darker appearance than normal. The blood does not seem to coagulate readily within cavities or interstices of the body unless death follows edmost instantaneously. In cases which live longer, the blood remains commonly in a liquid state, or coagulates imperfectly, and then only after being exposed to the air, resembling in this particular the state of that fluid observed in conditions of asphyxia. 1 t() T II E V E N <> M S O I C E Ii T A I N T II A N A T () P II I D E .1 Animal Form and quantity Time of used. { of venom, and : death. where introduced, j SLOW POISON I N(J. Eficis of Vtnam upon the Tissues of tin Living Animal. i Local lesion. Pigeon Copper globulin, , 13 2 c. c. (equal to 1 hours gram fresh venom) injected into pec- toral muscle Rabbit 1'nknown, but very minute quantity of Crotalus venom injected in back White rat Pigeon Crotalus venom, dry, £ grain in- jected into abdo- Crotalus venom, dry, 1 grain in- jected into right thigh Quantity unknown, injected into pec- toral muscle 9 days 2 days and 7 hours 9 days and 2 hours 14 days Condi- tion of blood. Large, dark gan- grene like swell- ing of chest ; muscle disinte- grated Dark gangren- ous swelling Hemorrhagic peritonitis Skin slough over local lesion, which is dark, hemorrhagic, and gangrenous Atrophy, with pigmentation of tin? pectoral muscle injected Liquid and dark Liquid and dark Changes In internal organs. Subpericardiai ecchymoses and pericardial effusion. Red tinged serum in peritoneal cavity. Heart empty. Lungs and pleura full of ecchymoses. All the organs congested Numerous minute hemorrhages be- low serous membranes, seen also at base of brain in right posterior fossa. The organs rather anaemic and softened Kkmaiik." All these autopsies wore made immedi- ately or quite shortly after death. Slightly Organs congested, softened; noth- For changes in bl.....1, coagu- ing else peculiar found; small, see details in text. lable, | loose, red clot in right side of dark heart Liquid All internal organs softened and dark, ill highly ecchymosed and congested. smelling Feces ami, urine bloody. Hemor- rhage at base of brain, and min- ute blood specks in pericardium. Heart quite atrophied and softened Liquid Hemorrhages indicated by deposits and of blood pigment in the tissues. very All the organs in a state of atro- dark phy and softened, resembling acute! yellow atrophy in man. Serous sacks all distended with bloody serum. Heart empty, and although contracted quite soft For further details of the histological changes, see text. N. B.—Gangrenous changes in the local lesion are usually more pronounced in the " Slow" than in the Rapid form of venom poisoning. The following lesions may be mentioned as peculiar to retarded or slow poison- ing: Rigor mortis often absent. The blood, usually diffluent, is very dark and docs not readily acquire the scarlet-red color when exposed to the air. There are prominent blood-stained effusions in all the serous sacks. (Plate V.) Urine and licces often bloody. Hemorrhages beyond the local lesion much more conspicu- ous than in the rapid poisoning. The remote lesions of slow poisoning resemble very much (morphologically) the primary local lesion, but are not so extensive or so well defined. In general the conditions of slow venom poisoning resemble those of acute septic poisoning. It is very often impossible to draw a distinct line between the manifestations of rapid and slow poisoning, nevertheless the division is in prac- tice convenient. One case- of very protracted slow poisoning was observed in a pigeon which had been injected with venom in the pectoral muscle. (See Experiment 24, 'fable Slow Poisoning.) In>tead of the usual gangrenous change there was seen in this case after the lapse- of two weeks a decided dry atrophy of the muscular tissue about the wound. Its fibres were greatly diminished in size as compared with the opposite unaffected PATHOLOGY. 141 muscle, and many of them were entirely disintegrated, as was evident from the remnants of the muscular fibres and the granular material which took their place between the interstices of the connective tissue. This granular material was seen throughout the specimen, some of it being of a brown tint, and probably repre- senting disintegrated blood corpuscles. The internal organs were all in a state of atrophy, more particularly so the liver, the tissues of which under the microscope bore a striking resemblance to acute yellow atrophy. The serous sacks were all largely distended by blood stained serum. The heart muscle was also in a condi- tion of atrophy, its chambers empty, and the blood dark and not coagulable. Blood examined microscopically showed appearances to be mentioned shortly. The Effects of certain Venoms on the Coagidability of the Blood.—One of the most interesting differences in the action of the venoms of the Rattlesnake and Cobra and which was pointed out some years ago by more than one observer, is that the former venom partially or completely destroys the coagulability of the blood, while the venom of the Cobra has no such marked effect. The blood of animals poisoned with Crotalus venom is usually thin and dark, the clots form slowly, and are very soft and easily broken up. Some direct studies were made to test more accurately this interesting property of the Crotalus venom, and it was thus observed that it is not peculiar to the poison of this genus, but is also a characteristic of the Moccasin. Several of these observations which were made with the venom of the Crotalus adamanteus we record in detail. Experiment.—Five test-tubes were used :— No. 1 empty. No. 2 contained £ grain dried venom dissolved in 0.5 c. c. distilled water. No. 3 " \ " " in 1.0 " No. 4 " | " in 1.0 " No. 5 " 2 drops glycerine solution of venom, equal parts. These test-tubes were packed in snow, to retard coagulation and to give the venom a better opportunity to act, the tubes remaining in this condition for about half an hour. The main artery in the leg of a large etherized rooster was exposed, and a canula placed in it. The blood was allowed to flow into the tubes in the order of their numbers, the tubes being gently shaken to mix the venom and blood. The operation began at 3:55 and ended at 4:00 p. m. At 4:35 the tubes were ex- amined. The blood in No. 1, which contained no venom, was firmly clotted, in all the others the blood was fluid. At 4:55 the test-tubes were all taken from the snow. Blood in No. 1 was firmly clotted and of a bright-red color; blood in Nos. 2, 3, and 4 was fluid and venous in appearance; blood in No. 5 was fluid and of a brighter red than No. 1. The tubes were then corked with raw cotton and set aside. Twenty-four hours later blood in No. 1 was firmly clotted, in Nos. 2 and 3 tarry, in No. 4 tarry, but thinner than in Nos. 2 and 3, in No. 5 perfectly fluid; in the lower half of the tube was a mass of corpuscles, while the upper half had the appear- ance of pure serum. Forty-eight hours—no appreciable alteration. 1 |;> I II E V E N O M S () F C E R T A I N T II A N A T () P HIDE JR. Seventy-two hours—no appreciable alteration; the blood in tube No. 1 had no unpleasant odor, but all the rest gave decided odors of putrefaction, and were \crv dark. Comparative observations were also made at the1 same time with different venoms, using as before a fowl to furnish us the blood and the snow pack to retard coagu- lation. In test-tube No. 1 was placed ', grain dried Moccasin venom in 1 c. c. distilled water. In test-tube Xo. 2 was placed \ grain dried Moccasin venom boiled and filtered through clay. In test-tube No. 3 was placed \ grain of dried Crotalus venom in 1 c. c. distilled water. In test-tube No. 4 was placed \ grain of dried Crotalus venom in 1 c. c. distilled water, heated gradually to 70: C. In test-tube No. 5 was placed \ grain dried Cobra venom in 1 c. c. distilled water. In test-tube No. 6 was placed \ grain dried Cobra venom in 1 c. c. distilled water, boiled and filtered through a clay filter. In test-tube No. 7 nothing was placed but the pure blood. Into each of the test-tubes about 10 c. c. of blood was allowed to flow; at the end of 15 minutes the blood in Nos. 2, 5, 6, and 7 was clotted firmly, and the blood in Nos. 1, 3, and 4 was perfectly fluid. After one hour and a quarter the blood in No. 1 was clotted in a quite remarkable clot, which was exceedingly elastic—the clot when picked up and suspended drew out into a long worm-like thread, and could then be further pulled out to at least double its length, resuming its natural size when placed upon the table. The blood in No. 3 had some very .soft clots. In Ne>. 4, the blood was clotted soft. On the second day all of the bloods were firmly clotted except Nos. 1, 3, and 4, which were perfectly fluid and had a putrefactive odor, which was absent in the others. On the third day these bloods were clotted and had some dark serum, but the pure blood was clotted firmly and perfectly dry on the surface. From these observations it seems clear that the Cobra venom exerts no appreciable effect on the coagulability of the blood of a chicken when thus circumstanced, and that Crotalus and Moccasin venoms act powerfully. Moreover, that the effect of the Crotalus venom is the more efficient, and that if the solutions of venom have: been subjected to a degree of heat sufficient to coagulate the venom-globulins, the effect is lessened very greatly. It thus appears that the principle affecting the coagulability of the blood is most largely the globulin. It would seem therefore that venom-peptone, although not without power to lessen the coagulability of blood, has not the full efficiency of the globulins. Neither can it be said as to this capacity, that the small percentage of Cobra globulin has even relatively the anti-clotting capacity of the globulins of Crotalus. These differences between Cobra and Crotalus show themselves strikingly in the slighter local disorders caused by the Indian serpent. The singular formation of an elastic clot was observed in other cases. It ap- peared to be a temporary condition, and to be in a measure due to the great increase in the adhesiveness of the blood corpuscles. PATHOLOGY- 143 Microscopical Changes in the Various Tissues of the Body from the Effects of the Venom of Crotalus. Effects of Fresh Venom upon the Blood Corpuscles.—A series of experiments were made to study the direct as well as the remote effects of the venom upon the blood corpuscles. The result of these observations was the discovery of some changes which have not been heretofore fully described. A drop of blood from man or any mammal treated with a minute quantity of fresh venom, presented the following appearances under the microscope: Upon the white blood corpuscles, the venom did not appear to have any other effect than to stop the amoeboid motion, which in presence of venom could not be kept up, even by the use of the warm stage. The cells appeared somewhat larger than usual and also more granular. The red blood corpuscles appeared unchanged when observed, but for a moment, and superficially, yet prolonged and careful study revealed very remarkable alterations. The alterations in the red blood cor- puscles are essentially these :— The blood disks lose their biconcavity and assume a spherical form, but without parting with their coloring matter. They exhibit also great adhesiveness, arrang- ing themselves into various sized and shaped aggregations. The corpuscles com- prising these groups sometimes appear to fuse so that their outlines cannot be determined, even by high amplification. In addition the corpuscles seem to soften and acquire a peculiar ductility and capacity to be stretched without fracture. By inclining the stage of the microscope, or making gentle pressure upon the cover- glass, allowing thereby the liquid to flow, the red blood corpuscles may be seen to elongate themselves into spindle-shaped or even into fine thread-like bodies. (Figs. 1 and 2, Plate III., and Plate IV.) Such masses of corpuscles appear to act like colloid material. One drop of human blood was mingled with one of fresh snake venom by the application of the cover-glass. The three fields photographed were found in the zones of contact between the blood and venom ; they occurred within a small area— almost adjacent. Fields 1, 2, and 3, Plate IV., were photographed respectively within 15, 30, and 40 minutes after the first application of the venom to the blood. As the masses of corpuscles were slowly changing form and position, the exposure was, necessarily, but for a part of a second. The lens employed was Spencer T\ immersion, giving 400 diam. with the low power eye-piece. This remarkable condition seems, however, to be only temporary, and in fact often escapes observation. After a short time, which in about 100 observations was found to vary from a few seconds to a quarter of an hour, the apparently homogeneous blood-cell masses break up anew into individual corpuscles, which then continue isolated or in bead-like rows, but remain spheroidal, i. e., do not regain their biconcal shape. Those corpuscles which arrange themselves in rows present an appearance strik- ingly different from the ordinary rouleaux arrangement of normal blood-disks, an appearance which may better be designated as "beaded," because the corpuscles are here spheroidal aiid not disk-like. 1U THE VENOMS OI CERTAIN T II A N \ T O P II 1 D E .E Liquids in general variously modify the1 shape of the red blood-disks, but no liquid or reagent tried in control experiments produces the effects described above. Waterv solutions of dried venom did not exhibit the immediate influence upon the red blood corpuscles as well as the1 fresh venom, although the corpuscles very promptly became spheroidal as they do from most watery liquids; but did not lose the coloring matter as when exposed to pure water without venom. The- blood of birds, upon being mixed with venom, docs not show the above described changes in as striking a manner as mammalian blood. The nuclei of the oval corpuscles of the pigeon appear, however, to undergo a rapid necrotic change which finally gives rise to a granular albuminoid material to be seen floating in large quantities between the corpuscles. A number of experiments were made to study the changes in the corpuscles of the- living animal. Fresh venom or solutions of dry Crotalus venom were injected hypodermatically, and then the blood taken at intervals from the local lesion as well as from the- general circulating fluid and examined under the microscope. The blood taken from local lesions presented quite often alterations in the cor- puscles similar to those observed in a direct mixture of blood and venom under the microscope, as described above. It was not possible, however, to trace all the modifications of the red blood corpuscles in specimens of the circulating blood; only one change being constant, viz., the spheroidal transformation of the blood disks. The red blood corpuscle retained the acquired spherical shape after the death of the animal.1 All the experiments made in orele-r to study the ultimate changes in the blood- corpuscles gave nearly similar results varying slightly in degree with the quantity of the venom and the animal employed. The record of one observation will suffice for all. Experiment.—Young cat. Injected at 2 p. m. 3 m. m. fresh Crotalus venom in left thigh. Hair of part being previously clipped away. 2 minutes later. Animal well. Blood microscopically examined. Local lesion ; blood-disks assuming spherical-shape. Blood from auricular artery showed no changes in the blood-disks. o minutes later. Animal well. Local lesion; blood-disks all spherical showing also gelatinoid behavior and ductility on pressure. Auricular artery, blood-disks normal. S minutes later. Animal restless. Local lesion shows only spherical shape of red blood-disks. Auricular artery also shows partial change of red blood-disks to spherical shape. 12 minutes later. Animal ill. Blood of local lesion as well as blood taken from jugular vein shows same changes as when last examined. 1 Errors in distinguishing the spheroidal shape of the red blood-corpuscles from the round shape which the normal disk-like corpuscles exhibit when viewed in a certain position are easily eliminate-el wlieu the blood is brought into current by gentle pressure upon the cover-glass, or by inclining the stage- of the microscope. The disks assuming spheroidal shape are decidedly reduced in diameter and appear smaller. PATHOLOGY. 145 20 minutes later. Animal quite ill. lied blood-disks all spheroidal when exam- ined in the local lesion and in several other parts of the body. 25 minutes later. Animal dead. 30 minutes later. Blood examined from heart. All the red blood-disks spherical. 24 hours later. The dead animal being kept in a cool place. lied blood-disks all spherical and many disintegrated. The blood, in sections of tissues from animals poisoned with venom, also presents decided alterations. The corpuscles in tissues hardened with preserving fluid are seldom seen intact. When, however, the parts in question are placed in preser- vative fluid immediately after the death of the animal the spheroidal (altered) red blood corpuscles may be distinguished; and still more likely are they to be intact if the animal was killed before the venom had asserted its fatal effect. The corpuscles as a rule appear disintegrated in animals dead from slow Crotalus venom poisoning, and present themselves as a granular debris of a yellowish or dark brown color. The tissue elements of the part into which the venom had been directly injected are as a rule profusely saturated with the coloring matter of the blood. The microscope further reveals blood crystals and numerous bacteria between and within the tissue elements. This indicates the profound altera- tion which takes place in the blood in venom poisoning, and accounts for the black appearance and the rapid putrefactive changes which are seen in the local lesion. " Quite recently Lacerda, in lectures1 on snake poisons, speaks of alterations of the blood, which differ much from those observed by us. He does not state the serpent venom employed. It was presumably from the Bothrops urutu, Lacer. In slow poisoning, he says, the blood globules become indented like a toothed wheel. Some are elongated, deformed, or broken up; others present shining points and then break up into minute fragments. Some undergo a change of tint to chesnut brown, others become entirely discolored. " The consequences of mixing pure blood and pure venom, he says, are these: The red blood-globules unite in mass, adhere one to the other and begin thereon to lose their normal forms. In a few minutes the dissolution is complete. There remains only an amorphous protoplasmic matter, semi-liquid, diffluent, of a uni- form yellow color, with well-marked red striations. After some minutes the hema- tine or coloring matter quite disintegrated is seen under the form of granular substance of a deep vermillion red. Whilst the globules thus break up bubbles of iras rise here and there." We have quoted this account nearly in full to point out that it describes a sequence of appearances very unlike those which we have delineated. Effects of the Venom upon certain Tissues.—Direct observations were further made us to the effects of venoms upon the various solid tissues, such as the bloodvessel walls; muscular tissue, unstriated and striated; nervous tissue (brain and medulla 1 Lecons sure le Yenin des Scrpentes du Brdsil, etc. J. B. De Lacerda, pp. 87-88. Rio de Janeiro, 1884. 19 June, 1886. 1 pi T II E V E MIM S O I C E 11 T A I \ T II A N A T () P II I D E .E. oblongata" ; lumxs. liver, skin, mucous membranes, the cornea, spermatozoa and ciliated epithelium, and most extensively upon the- mesentery and other serous membranes. If fresh venom be injected into any organ or applied to any internal part of the hod v. one of the chief effects is. as Dr. Weir Mitchell shelved twenty-two years ago, the production of minute hemorrhages. The studies re-ported here thoroughly confirm Dr. Mitchell's observations. Above- all, it was further evident that, as a general rule, // teas everywhere the pun lulnpnuious eh mi ids of the organ, or parts that undcrwt ul necrotic changes (which wi/l be described below), while the interstitial elements of organs ur tissues acted upan, by the, cen,om, remained usually uutrffectetl, or were merely tvjiltrati eye a diape-desis of blood-corpuscles and a leakage of serum occurs, and this process is sometimes amazingly rapid. As will be described later with more details, the following arc the essential points in the action of the venom upon its direct application to a vascular membrane viewed under the microscope. The blood current appears at first to be accelerated, and the color of the blood becomes darker. Then in a few moments while the circulation still continues in the veins and arteries, in many of the capillaries stagnation occurs. From these latter vessels, and apparently only from them, the blood oozes, first forming pin-point ecchymoses which gradually increase, and which by fusion give rise at last to a general hemor- rhagic infiltration of the neighboring tissues. Changes in the Striped Muscular Tissues.—Venom directly applied to living striped muscular tissue produces changes which become apparent immediately after the death of the animal. The ultimate muscular fibrillar readily break up into their sare ems elements, these becoming easily separable in transverse layers, the so-called Bowman's disks. A granular change1 of the elements, not however uniform in character and distribution, is quite conspicuous. (Fig. 3.) It should be noted that all these changes occur without the addition of any other reagent than venom and become conspicuous when the poisoned tissue is teased out in water. The alterations just referred to are most manifest in muscular fibres near or around which the capillaries are affected by the venom, localities apt to be marked 1 Figured by Dr. Mitchell, in his first essay. PATHOLOGY. 147 by the presence of extravasated blood. The changes described are not uniform, even in an individually affected fibre, but are bounded by small abrupt layers of normal sarcous elements, the whole being surrounded by an unaffected sarco- lemma. The latter, which is beautifully demonstrated on such occasions, shows constrictions in those places where the sarcous elements are disintegrated. (See Figs. 3 and 4.) All muscular fibres of the part where the poison was injected are more or less granular, and arc often stained by hematin. The granular material between the fibres has very much the appearance of micrococci, but by appropriate tests only a small proportion of the granules can be identified as bacteria. The remaining granular matter can be identified as particles of necrosed sarcous elements, dis- integrated blood, and granular substances which have been described as constituents of the fresh venom and introduced from without. These granular muscle changes occur only in or near the wound, and not also in remote muscles. They demand for their production a certain length of time, and are most decided in cases of long survival. Changes in the Lungs.—As has been seen from the table of experiments, the injection of venom into the lungs was followed by nearly instantaneous death. The local lesion was an hemorrhagic infarction throughout the whole of the paren- lis T II E V E N O M > O E C E II T A I N T II A N A TO P II I I> E .E e-hvma. filling alsei all of the air vesicas. The-p- were extrusive sub-pleural ecchy- inoses. both parietal and visceral, as well as sul>-pericaidial ecchymoses. Under the mieroM-i'pc wish high an,plication see lions ot the lung tissue showed a peculiar clogging, fusion, and due'ility of the red blood-corpuscles not unlike- that which fellows the application of fresh venom to the blood. This appearance is. however, not uniform, as in many places the corpuscles are men-ly spheroidal, or have undergone a granular disintegration. The bloodvessels are all highly congested, the air vesicles seem to be distended by extravasate-d blood. The micrococci introduced with the venom appear to have rapidly multiplied, numerous masses being seen in the air vesicles and in the* more necrosed parts of the lung tissue. In general the tissue is deeply stained by the coloring matter of the blood. Brain ami Mululla 'orm a. The following experiments were made: — Expcrinuut.— Adult albino rabbit, etherized. A drop of an aqueous solution of the dried venom Crotalus adamanteus was dropped on the cornea and conjunctiva of the left eye. In a few minutes the conjunctiva became ecchymosed and cede- matous to such an extent as to close the eyelids. Animal died in five hours. After death the conjunctiva and eyelids were seen to be soaked with extravasated blood, while tin- cornea remained perfectly transparent and colorless, showing no trace of inflammatory change when removed and examined under the microscope. Post-mortem e x;.mination showed extensive sub-pleural, sub-peritoneal, and slight sub-arachnoid ecchymoses. Experiment.—Young kitten, etherized. A drop of fresh venom was placed on the cornea. Results, similar to those of foregoing experiments, the cornea remain- ing transparent, but exhibiting a certain roughness upon the surface, which under the microscope proved to be due to slight desquamation of the epithelium. PATHOLOGY. 149 Esrper-iment.—Yoxmg kitten, etherized. Abdominal cavity and stomach opened and fresh venom applied to surface of mucous membrane. Specimen watched for half an hour failed to reveal any decided visible changes, beyond a slight corruga- tion and congestion. No ecchymoses. The Effect of Crotalus Venom upon Ciliary Motion.—Fresh venom applied to ciliated epithelium taken from the edge of the tunic of a fresh oyster seemed to exert no effect upon ciliary motion, The specimen was watched and compared with the control experiment side by side. The cilia: still kept up their movement at the end of three hours in both specimens. Fresh venom was applied to ciliated epithelium taken from the pharynx of a live frog. The specimen was carefully observed and compared with similar preparations in which venom was not used. In the latter the ciliary motion, as a rule, kept up longer. Yet after one hour specimens treated with venom continued to exhibit motion though less vigorous than in the control specimens. The Effect of Venom upon Spermatozoa.—Fresh venom applied to spermatozoa taken from a live rabbit seemed to exert a decided influence. Specimens treated with the venom were examined side by side with control specimens, and while in the presence of venom the spermatozoa ceased to exhibit their-peculiar movements in from one-quarter to three-quarters of an hour, unpoisoned spermatic particles con- tinued to move for many hours. The venom did not appear to produce any changes in the substance or the bodies of the individual spermatozoa.1 The Mechanism of the Hemorrhages as Observed in Venom Poisoning. In order to study the mechanism of the hemorrhages Dr. Mitchell's original ob- servations were repeated as follows: — The animals used were cats, rabbits, pigeons, white rats, and frogs. The frogs do not give satisfactory results as they withstand the effects very strenuously and if peritoneal hemorrhages occur at all they are very scanty. The most satisfactory observations were obtained when cats were employed, as these animals lived longest after the application of the venom, the latter also acting more slowly, thus permit- ting satisfactory study of the effects under the microscope. Anaesthetics were always used. Ether was found to give the best results. Chloral appeared to retard the effects of the venom. While in an etherized animal peritoneal hemorrhages appeared at once upon the application of the venom, in a chloralized animal they occurred much later, and sometimes failed to appear. A few drops, three to six, of a saturated solution of chloral hydrate were usually sufficient to anaesthetize a small kitten or rabbit, two drops for a white rat, one drop for a mouse. It was administered hypodermatically. In administering ether the animal was placed under a bell-glass, with a sponge kept saturated with the agent until the animal was rendered powerless. In experiments upon the mesentery to be examined under the microscope, the 1 The observations wc:re made under an amplification of one thousand diameters. 1;,() T II E VENOMS O 1 C 1. \\ I A I N T II A N A T (> I' II I D E .E animal was placed on its right siele upon a thin oblong wooden board. On one side of tin- board near the middle- was rut a triangular opening, each side being about one inch in length. An incision was then made in the median line through the abdominal integuments, sufficiently large to allow a loop of the intestine to be extracted. Care was taken that pressure should not interfere with the circulation. The loop being drawn out. it was stretched over the hole in the board above described, and kept in position by means of pins. The venom was applied to the uninjured surface of the mesentery. A saturated aqueous solution of the dried venom was most commonly used. The moist chamber was not required, as the experiments were of short duration. The warm stage seemed onlv to hasten the process and otherwise was observed to have no special influence, being rather disadvantageous. Experiment 1.—A young kitten was secured by means of ether as above- de-scribed, and placed upon the microscopic stage. .V few drops of an aqueous solution of the venom were- allowed to flow over the mesentery. The part being carefully watched with the inked eye, it was noticed that after one minute tiny hemorrhagic points made their appearance here and there, all over that part of the mesentery which was uncle r the direct influence of the venom. These- hemorrhages increased rapidly in size, and in a few minutes the whole surface became the seat of one diffused hemorrhagic infiltration. (Plate III., Figs. 3, 4, 5, b\ 7.) Pxpt riuttid 2.—Young white rat. Ether. Aqueous solution of venom applied as before to the mesentery. The loop of the mesentery acted upon was quickly cut out bv means of scissors after the lapse of one minute and subjected to drying. A beautiful preparation was thus obtained, in which the minute hemorrhages were permanently fixed by drying, preserving their natural appearance.1 Experiment 3.—Young kitten. Chloral. Mesentery spread upon microscopical stage. An aqueous solution of dried venom applie-d in the same manner as above. In this case- the hemorrhages did not appear so promptly and were not so rapid in their development. Nearly five minutes elapsed before they began to form. Expt rimiut 4.—Young white rat. Chloral. Venom applied as in pie-ceding experiments; there seemed to be delay in the appearances and development of the hemorrhages. Further enumeration of this class of observation is unnecessary, as more than fortv experiments exhibited the characteristic hemorrhages, except in the ease of frogs. Five of the latter were used. It was noted that chloral always retarded the production of hemorrhages, at least they did not appear as rapidly as when ether was used. Microscopical Detail*.—It being necessary to study the exact location of the In •niorvliages and the mode of the escape of blood, the following modifications of methods were adopted in repetition of the older experiments of Dr. Mitchell. 1 After much experimentation this method of preparing permanent specimens was found to be the onlv available one. Specimens of mesentery mounted in any kind of licpiid ve'ry soon lose their proper appearanee-, as the hemorrhagic specks in the membrane gradually vanish, or get blurred from the effects ol the prcservini: fluid. PATHOLOGY. 151 Experiment 5.—Cat. Ether. Mesentery exposed and placed on the stage of the microscope. The aqueous solution of venom was applied, and the experiment watched under a magnifying power of 60 diameters. In thirty seconds minute hemorrhagic points were noticed as in all the previous experiments first along the sides of the smallest capillaries. It was also observed that the hemor- rhages occurred first in those small capillaries which were in the neighborhood of larger vessels. In vascular plexuses which started from the greater arteries the hemorrhages appeared much sooner than in those which took their departure from smaller arterioles. In each case, however, it was only the capillaries from which the hemorrhages proceeded, the arteries and veins remaining intact. The hemorrhages being seen to proceed from capillaries in the vicinity and along the route of larger vessels, one may erroneously get the impression that it is the latter from which the bleeding arises. No actual breech of continuity in the capillaries was observed, and it appeared as though the blood filtered through the walls of these minute channels. Experiment 6.—Kitten. Ether. Mesentery exposed in the usual manner. The mesenteric vessels, both the main artery and the veins, were ligated near the root of the mesenteric attachments. A salt solution stained by aniline blue was injected into the vein. The venom was applied, and the field closely watched under the microscope. No extravasation of the injected solution or of blood could be observed. Experiment 7.—Kitten. Ether. Vessels ligated and salt solution with aniline injected as in previous experiment. Applied aqueous solution of the dry venom. No extravasation of the colored liquid or blood observed. Experiment 8.—Kitten. Animal secured as before, but no salt solution injected. Mesenteric veins and the artery ligated near root of mesentery. Solution of dried venom applied. Hemorrhage as usual, but slow and scanty. Experiment 9.—Kitten. Ether. Animal fixed as in last, experiment upon microscopical stage. Fresh venom applied and watched for one-half hour. Hemor- rhages were seen to develop more slowly. Experiment 10.—Kitten. Ether. Mesenteric vein and artery ligated as in pre- ceding experiments. Fresh venom applied as before, and a marked delay in de- velopment of hemorrhages again observed. Experiment 11.—Kitten. Ether. Mesenteric vessels tied not only at the root of the mesentery, but also peripherally at the convex portion of the loop, thus almost entirely cutting off the circulation. Fresh venom applied. Hemorrhages were scarcely appreciable with the naked eye. Experiment 12.—Kitten. Ether. Mesenteric vessels tied at both root and peri- phery of mesentery. Venom applied immediately. Hemorrhage hardly perceptible. The above experiments were subsequently repeated, especially those in reference to the effects of the venom upon bloodvessels when blood had been substituted by a 0.75 per cent, saline solution. These experiments, however, gave the same results as those just described, and hence it is unnecessary to occupy space in multi-* plying similar records. Yet some studies in the same direction have been left undone. It might be desirable to elaborate the methods of experimentation, e. g., by application of artificial blood pressure, etc. In all the experiments above quoted, 1 ;,o T II I! V E N O M S OF ( E K T A I X T II A N A T O P II I I) I! .E . \« opt in experiments (> and 7 (where the blood was substituted by another liquid), the peculiar extravasations of blood followed the- application of the venom. When the mesenteric vessels were tie d as in experiments S, !>, and 10, there- was a delav in the appearance of the hemorrhages. When the- vessels were1 tied in two places, as in experiments 11 and 12. so as to cut off the circulation in a great measure, the hemorrhages appeared hardly appreciable to the naked eye. And as we have seen above, there was no extravasation at all when the blood was substi- tuted by an artificial liquid, as in experiments 6 and 7. Therefore, the hi inorrlmyi s Income b ss marked in proportion to the interfere nee with the circulation of the blood in the part. GENERAL CONSIDERATIONS. l,3;j CHAPTER XT. GENERAL CONSIDERATIONS. It seems desirable at the close of a research such as we here record to offer a few brief and general considerations in connection with some of the methods and plans pursued in parts of the work, to group some of the conclusions, and to bring together deductions which are necessarily scattered. A summary is also desirable that we may set forth succinctly the essential actions of venom so as to make clear the important differences in the toxic influences of globulins and peptones, to facili- tate the application of what we have learned to the treatment of snake bite, and to indicate new lines of research in the most promising directions. Our discovery of the existence of two distinct classes of poisons in venoms, that both are doubtlessly represented in all venoms, only differing in relative propor- tions and slightly in chemical and physiological properties, that they possess activities akin but yet readily distinguished, and that they are proteids and closely related to principles normally existing in mammalian blood, seems to us as of grave importance. Our methods, however, for the separation of the poisonous substances in venoms are open to improvement, because the processes are slow, and since possibly one of the poisons at least is injured. It does not seem from the results of our physiological studies with these poisons that any of them except- ing the copper-venom-globidin have suffered, but that this has been affected seems probable from its altered solubility, its comparatively low toxic power, and its physiological peculiarities compared with the other globulins. Doubtless the ordinary methods for the separation of the globulins from other proteids in solu- tion could be used to advantage, but how far successful they may prove in isolating the globulins from each other can only be determined by extended and careful investigation. The plan we adopted in studying venoms and their active principles on the arterial pressure, pulse, and respiration is probably open to much criticism, but any other course seemed unavoidable. Instead of studying all venoms together as though they were absolutely identical compounds, although from different sources, and each of the active elements, as for instance the peptones, together as identical, it would doubtless have been preferable to have made a detailed investigation of each venom, and of each of the active principles of that specimen. But this course could not have been pursued satisfactorily because of the meagre supply of poison. It was then simply a question as to whether we would take a very limited number of experiments with each venom and each of its active principles, and base conclu- sions thereon, or study the actions of all pure venoms together, of all the watcr- 20 June, 1886. 1.", | T II E V I! N «» M S O E C E II TAIN I II A N A T O P II I D E .E . venom-globulins together, etc., and then form our conclusions. The latter course seeineel preferable: first, because of the similarity in the actions of all pure venoms ami of the ready interpretation of any differences, and of the resemblance in the actions of members of each of the classes of poisons; second, because in senile of the ae tions such diverse factors are at work as to give apparently contradictory results, so that conclusions founde d upon a very limited number of experiments would likely be more misleading than in the plan we- adopted. We summarize the following important points, deduced chiefly from our studies of Crotalus venom, to which arc added a few comments:— 1. Venoms bear in some respects a strong resemblance to the saliva of other vertebrate s. 2. 'fhe active principles of venom are contained in its liquid parts only. The solid constituents, such as we observed suspended in the poison, consist of epithe- lium cells, semie minute rod-like animal organisms and micrococci, etc., which, when separated from the liepiid fresh venom by means of filtration and well washed by water are harmless. Micrococci arc constantly present in fresh venom, but have nothing to do with its virulence. 3. Venoms may be dried and preserved indefinitely in this condition with but very slight impairment of their toxicity. In solution in glycerine they will also probably keep for any length of time. I. There probably exist in all venoms representatives of two classes of proteids, globulins and jupfouts, which constitute their toxic elements; the former may be re-presented by one or more distinct principles. 5. When venom is taken into the stomach in the intervals of digestion, enough of the poison may be absorbed to produce death, especially in the case of those venoms which contain a larger proportion of the more dialysable peptone; but during active- digestion the venom undergoes alteration and is rendered harmless. (i. Potassic permanganate, ferric chloride in the form of the liquor or tincture, and tincture of iodine seem to be the most active1 and promising of the generally available local antidotes. 7. Venom exerts a powerful local effect upon the living tissues, and induces more rapid necrotic changes than any known organic substance. It causes oedema, swelling, attended with darkening of the parts by infiltration of incoagulable blood, breaking down of the tissues, putrefaction, and sloughing. S. It renders the blood incoagulable. !). When brought in contact with a vascular tissue of a warm-blooded animal it produces such a change in the capillary bloodvessels that their walls are unable to resist the normal blood pressure, thus allowing the blood-corpuscles to escape into the tissues. These lesions are, however, not analogous to those of inflamma- tion, since in the latter process it is principally the white blood-corpuscles which emigrate from the vessels, and the blood is highly coagulable, while here the blood exudes en masse and coagulates with difficulty, if at all. Free- access of air (probably of oxygen) appears to lessen the virulent effects. The mesentery exposed to air. and on which the venom is merely brushed, endures the venom longer and in much larger quantity than when the poison is injected into the unopened and GENERAL CONSIDERATIONS. 155 uninjured peritoneal cavity, or when directly thrown into the blood. There may be here also a question of temperature and other conditions. The following facts as elicited in these investigations seem to be sufficient to explain the mechanism of the hemorrhages: the blood pressure has been shown to play a most important part; a watery salt solution substituted for the blood does not extravasate, hence, blood seems to be necessary; there always occur molecular changes in the bloodvessel walls from the effect of venom. That blood pressure is an important factor has been established by the observation that the hemorrhages as a rule occur first in the capillaries which are immediately next to or nearest the large bloodvessels. The hemorrhages take place soonest where the force of the blood current is first felt and cannot be sufficiently resisted, and in no case do hemor- rhages seem to originate from vessels with strong walls like the arterioles or veins. Cutting off the circulation of a part, as, for instance, by ligation of the vessels of the mesentery, destroys the blood pressure, and, as a consequence, the hemorrhages are so slight as scarcely to be seen by the naked eye though venom was freely applied. Finally, the colloid, softened, diffluent condition of the red corpuscles must inevitably facilitate extravasations. It is impossible to have seen numerous cases of venom poisoning without noting a variety of symptoms often abrupt or unexpected. These often are due, as Dr. Mitchell long since pointed out, to acci- dental hemorrhages into brain, kidney, and heart tissues. They explain much which might otherwise seem inscrutable, and serve sometimes to give a marked individuality of symptoms to cases which survive long. 10. Among the most remarkable effects of venom is that upon the red blood- corpuscles. These bodies undergo substantial modifications, i. e., they lose their bi-concave shape, become spherical and softened, and fuse together into irregular masses acting like soft elastic colloid material. This jelly-like condition of the corpuscles is no doubt doubly important: in connection with the extravasation of the blood, and in its probable interference with the normal respiratory functions of the blood-cells. * 11. The direct action of venom upon the nervous system save as concerns the paralysis of the respiratory centres is of but little importance. 12. The alterations in the pulse-rate are dependent chiefly upon two antagonistic factors which are active at the same time, the one tending to increase the rate and the other to diminish it. The former is found in the increased activity of the accelerator centres and the other in a direct action on the heart. When we have the action on the accelerator centres removed by isolation of the heart from any centric influence we almost invariably find a diminution of the heart beats. Occasionally after this operation the pulsations are increased, but this alteration is attended, as in the case of the diminution of the pulse, by feeble heart beats, and accordingly is but a manifestation in another way of a depressed condition of the heart. 13. The variations in arterial pressure are due chiefly to three causes, depression of the vaso-motor centres, depression of the heart, and irritation and consequent constriction or blocking up of the capillaries. It seems not improbable that all of these are consentaneously active, and it therefore follows that such alterations are de- pendent upon the relative degree of power exerted by any one of these factors. Our |.,li THE VENOMS OF CKI5TA1N T II A N A I O P II I D E .E results inelicate1 that the profound primary fall of arterial pressure is chiefly due to depression of the vase>-motor centres and is in part cardiac-, that the subsequent recowry is capillary, while the final fall is cardiac, 'fhe initial fall does not con- tinue, because1 the constriction of the capillaries is, for a time- at least, capable of compensating the1 depressed action of the central organ of circulation. 14. Ibe respirations are1 primarily increased and secondarily diminished. Here again we have two antagonistic factors at work together, one tending to increase and the other to diminish the rate. The former is an irritation of the peripherics of the vagi nerves and the latter a depression of the respiratory centres ; whether we have an increase followed by a decrease or a decrease from the first will depend upon the relative intensity of the action of the venom on these two parts. When the- action of the venom is sufficient to profoundly depress the centres the excitation of the peripherics may prove futile. 15. Death in venom-poisoning may occur through paralysis of the respiratory centre s. paralysis of the heart, hemorrhages in the medulla, or possibly through the: inability of the profoundly altered red corpuscles to perform their functions. There can be no question, however, that the respiratory centres arc the parts of the system most vulnerable to venom, and that death is commonly due to their paralysis. A general survey of the chief physiological actions of venoms leads us to believe- that the most important effects are upon the respiratory and circulatory appara- tuses-, and that in the production of these- results antagonistic factors are at work so that we sometimes have observations which seem directly contradictory. \\ hen it is remembered that there are two classes of poisons in venoms, that each class possesses certain distinguishing physical, chemical, and physiological differ- ences, although closely related, it is easy to conceive1 of the cause of the existence of antagonistic actions and the necessarily varying results. A comparative study of the actions of the globulins and peptones indicates that the glohulins produce swelling and blackening of the parts by infiltration of incoagu- lable blood; they are the more potent in producing ecchymoses, in destroying the coagulability of the blood, in modifying the red-corpuscles, and in the production of molecular changes in the capillary walls ; their action on the accelerator centres of the heart is more notable than that of the peptone, hence they are more active in causing the increased pulse-rate; they exert, too, a more marked action on the vaso- motor centres in producing the primary fall of pressure and are the greater depres- sants of the heart; they also act more powerfully upon the respiratory centres to paralyze them. The ptptones are more active in the production of oedema, in the breaking down of the tissues, in the production of putrefaction and sloughing ; they have little power to produce ecchymoses, to prevent coagulation or modify the cap- illary walls or the blood-corpuscles; they have less tendency to accelerate the pulse ; they tend to increase the blood-pressure by irritating the capillaries, and are the prin- cipal factor in exciting the peripheries of the vagi nerves in the production of the increased respiration-rate. A knowledge of these peculiarities in the actions of globulins and peptones coupled with the fact that the two classes exist in different proportions in the various species of venoms is of great importance in explaining the diverse pathological GENERAL CONSIDERATIONS. 157 appearances in cases of poisoning in different kinds of snake-bite—and suggests immediately the cause of the frightful local changes which are seen after the bite of the Crotalidse but scarcely at all in Cobra-poisoning. It must not, however, be supposed that the peptones or globulins for instance are absolutely identical physio- logically in every venom, as they are probably modified physiologically as well as chemically, although we do not doubt that on the whole the type of action is carried throughout all species. Cobra venom does not produce the marked lesions of Crotalus-poisoning because it is so lacking in globulins; it is weak in the pro- duction of the local swelling and blackening of the parts, of the ecchymoses, of the altered corpuscles and of the non-coagulability of the blood, but the effects of Cobra venom are closely in accord with the actions peculiar to peptones. The peptone of Cobra seems to have a more decided power in producing convulsions than that of the rattlesnake. The fact that the active principles of venom are proteids, and closely related chemically to elements normally existing in the blood, renders almost hopeless the search for a chemical antidote which can prove available after the poison has reached the circulation, since it is obvious that we cannot expect to discover any substance which when placed in the blood will destroy the deadly principles of venom without inducing a similar destruction of vital components in the circu- lating fluid. The outlook then for an antidote for venom which may be available after the absorption of the poison lies clearly in the direction of a physiological antagonist, or, in other words, of a substance which will oppose the actions of venom upon the most vulnerable parts of the system. The activities of venoms are, how- ever, manifested in such diverse ways and so profoundly and rapidly that it does not seem probable that we shall ever discover an agent which will be capable at the same time of acting efficiently in counteracting all the terrible energies of these poisons. It is now most desirable that our discovery of the complex chemical nature of venoms should be made the groundwork in India of a study of the poison of the Bungarus, the Daboia, and especially of the dangerous Hydrophidese. 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