,issued ,april #d1 #aiab4 ,u4,s4 ,,department ,,of ,,agriculture1 ,,bureau ,,of ,,chemistry--,,bulletin ,no4 #adh4 ,h4 ,w4 ,,wiley1 ,,chief ,,of ,,bureau4 ,,the ,,toxicity ,,of ,,caffein3 ,,an ,,experimental ,,study ,,on ,,different ,,species ,,of ,,animals4 ,,by ,,william ,,salant1 ,chief ,pharmacological ,laboratory1 ,division of ,drugs1 ,,and ,j4 ,b4 ,,rieger1 ,assistant ,chemist4 ,illustration3 ,,united ,,states ,,department ,,of ,,agriculture ,,seal ,,washington3 ,,government ,,printing ,,office4 #aiab4 ,,letter ,,of ,,transmittal4 ,u4 ,s4 ,,department ,,of ,,agriculture1 ,,bureau ,,of ,,chemistry1 ,washington1 ,d4 ,c41 ,november #ad1 #aiaa4 ,sir3 ,i have the honor to submit for your approval a manuscript on the toxicity of caffein1 which is the first of a series of reports to be made by ,dr4 ,salant on the pharmacology of this drug2 the conclusions here reported are1 therefore1 in some particulars to be regarded as tentative4 ,the data obtained are primarily of use in the execution of the food and drugs act1 but are capable of much broader application4 ,acknowledgment is made of the assistance rendered by ,dr4 ,john ,r4 ,mohler1 ,chief of the ,pathological ,division1 ,bureau of ,animal ,industry1 and his assistants1 in performing the autopsies recorded in this report4 ,i recommend the publication of the manuscript as ,bulletin ,no4 #adh of the ,bureau of ,chemistry4 ,respectfully1 ,h4 ,w4 ,,wiley1 ,chief4 ,hon4 ,,james ,,wilson1 ,secretary of ,agriculture4 ,this publication may be procured from the ,superintendent of ,documents1 ,government ,printing ,office ,washington1 ,d4 ,c41 at #ae cents per copy ,,contents4 ,page4 ,introduction #e ,historical review of the literature on the toxicity of caffein #i ,acute caffein intoxication #ah ,experiments on rabbits #ah ,subcutaneous injection #ah ,administration by mouth #bf ,injection into the peritoneal cavity #bh ,intramuscular injection #cc ,intravenous injection #cg ,summary #db ,experiments on guinea pigs #dc ,subcutaneous injection #dc ,injection into the peritoneal cavity #dg ,administration by mouth #di ,summary #eb ,experiments on cats #ec ,subcutaneous injection #ec ,injection into the peritoneal cavity #ef ,administration by mouth #eg ,summary #ei ,experiments on dogs #fj ,administration by mouth #fj ,subcutaneous injection #fj ,experiments on puppies #fa ,summary #fb ,chronic caffein intoxication #fc ,experiments on rabbits #fc ,experiments on dogs #ge ,discussion of results #ia ,general summary and conclusions #ie ,bibliography #ig ,,the ,,toxicity ,,of ,,caffein4 ,,introduction4 ,comparative physiology has established the fundamental fact that some properties are common to all forms of living matter4 ,but the same method of inquiry has also led to the recognition of marked differences in the physiological processes of various species of animals4 ,among the most important investigations which contributed to the knowledge of such variation of function are the studies in comparative metabolism4 ,it is now recognized that metabolism is in some respects quite different in herbivora and in carnivora4 ,some forms of oxidation are much greater in the rabbit than in cats and dogs4 ,nuclein metabolism presents important differences in the rabbit and in man1 while the mode of neutralizing acid in the body may be cited as another variation in the metabolism of these forms4 ,perhaps the most striking examples of differences in the metabolism of different organisms is furnished by the results of studies on the fate of certain poisons introduced into the body4 ,the classical experiments of ,bunge and ,schmiedeberg7#ae7;,a on the synthesis of hippuric acid are of interest in this regard4 ,it will be recalled that in the dog the synthesis takes place in the kidney2 the rabbit is able to form hippuric acid in the liver as well as in the kidney1 while frogs can synthesize hippuric acid even when both of these organs have been removed or excluded from the circulation4 ,observations on the fate of some of the alcohols of the fatty acid series have likewise shown that these substances may be combined with glycuronic acid in some animals but not in others4 ,according to ,thierfelder and ,von ,mering17#hd7 tertiary alcohols are combined in this manner in the rabbit but not in the dog4 ,according to ,neubauer17#fd7 the primary and secondary alcohols are so combined in the dog as well as in the rabbit1 but to a greater degree in the latter4 ,a ,the small figures refer to the bibliography at the end of this bulletin4 ,pohl7#gc7 found that amyl alcohol is largely eliminated by the lungs in the cat and in the dog4 ,the protocols of his experiments show that #fe per cent of the alcohol given these animals was thus recovered1 while he recovered only #bb per cent of this substance in the expired air of the rabbit4 ,examination of the urine showed the presence of glycuronic acid4 ,hofmeister's7#cg7 work with tellurium in the dog is of interest in this connection4 ,he made the important discovery that some animals possess the power of methylation as well as of demethylation4 ,abderhalden and ,brahm's7#a7 experiments with pyridin show that the same is true of young dogs when on a meat diet4 ,his experiments on rabbits with this substance were negative4 ,the metabolism of caffein and theobromin furnish another illustration of differences in the physiological mechanism of animals4 ,although the substances found in the urine of man1 dog1 and rabbit after the administration of caffein and theobromin were the same1 the quantities varied considerably4 ,according to ,krger and ,schmidt17#dg7 over #ad per cent of the theobromin introduced into the rabbit is eliminated as #g-methyl xanthin in the urine4 ,the dog eliminates only about #j4fg per cent4 ,on the other hand1 the amount of tri-methyl xanthin eliminated was only #c per cent in the dog and not quite #a per cent in the rabbit4 ,it appears1 therefore1 from studies in comparative metabolism1 whether endogenous or exogenous1 that well-marked physiologic and chemical differences exist in various species of animals4 ,that pharmacological action may likewise vary in different species of animals is shown by the following investigations4 ,according to ,guinard17#ca7 who made an exhaustive study of morphin1 the reaction to this alkaloid varies in different forms of life1 both qualitatively and quantitatively4 ,he established its narcotic effect in the dog1 rabbit1 guinea pig1 white mice1 and rats1 while for the cat1 horse1 ox1 sheep1 hog1 and goat it is1 on the contrary1 a stimulant4 ,moreover1 there is no evidence of cerebral effect4 ,the stimulating effect of morphin on the nervous system in some animals was also observed by ,noe7#fe7 in experiments with this substance on the hedgehog4 ,guinard7#bi71 7#cj7 has also shown that morphin has no narcotic effect in the marmot1 although this animal is very sensitive to the drug4 ,two milligrams per kilo were found to be a surely fatal dose for this animal4 ,his experiments on the comparative toxicity of morphin7#cj71 7#ca7 show a considerable range of variation in different species4 ,thus the fatal dose for the dog was found to be #j4fe per kilo1 while #g mg per kilo is the fatal dose for the horse4 ,about twice the amount is fatal for the ox and #j4b mg per kilo kills the pig4 ,experiments with other drugs has shown that a considerable range of variation in resistance exists in animals of different species4 ,noe's7#fe7 studies on the comparative toxicity of chloral brought out the interesting fact that the rabbit is more resistant to it than the hedgehog and the latter more resistant than the guinea pig4 ,perhaps the most striking example of a difference in reaction of the same substance in widely different species is that furnished by apocodein1 quinin1 and yohimbin4 ,according to ,gunn7#cb7 these substances have been found to cause vasodilation in warm-blooded animals1 but they constrict the blood vessels of the frog4 ,experiments with apomorphin likewise show that the reaction to this substance varies in different species of animals4 ,the resistance of the cat to this drug is1 according to ,guinard7#ca71 ten times greater than that of the dog1 and the latter is more sensitive than the rabbit to the crystalline form of apomorphin when given intravenously4 ,according to ,kobert7#de7 amygdalin is without effect on dogs1 but it is poisonous to rabbits4 ,lapicque7#di7 found that the toxicity of curara varies in different species of frogs1 the dose required to produce paralysis in ,rana esculenta being three times greater than in ,bufo vulgaris4 ,weir ,mitchell7#ei7 pointed out long ago that turtles stand enormous doses of curara4 ,schmiedeberg's experiments with caffein on ,rana temporaria and ,rana esculenta 7and more recently those of ,jacobi and ,golowinski7#db7 with caffein1 theobromin1 and theophyllin7 are also of interest in this connection4 ,these experimenters observed well-marked differences of reaction to methyl-xanthins in these closely allied forms4 ,experiments with quinin have shown that the action of this substance differs in some animals4 ,it causes a fall of temperature immediately after its administration in the guinea pig1 but frequently produces1 at first1 a rise of temperature1 followed by an unimportant fall1 in rabbits1 dogs1 and man4 ,the numerous investigations which have been carried out on the effect of atoxyl within recent years have contributed much to the comparative pharmacology of this substance4 ,although the symptoms and organic changes produced by this substance in a variety of animals present no great differences1 the resistance of some has been found to vary2 according to ,kster7#df7 it is more toxic for dogs than for rabbits4 ,a number of other substances have been found by various experimenters to vary in toxicity for different species of animals4 ,cantharadin1 phenol1 atropin1 and strychnin may be mentioned as illustrations4 ,pharmacological studies on lower forms of life have also revealed marked variations in the effect of some poisons4 ,observations made by ,danilewski7#ah7 with hydrochinone indicate that solutions of #a to #ajj or #bjj are toxic to ,celentrates1 causing paralysis in these organisms4 ,echinoderms are killed within one or two hours in #a to #a1jjj or #b1jjj solution1 while in ,vermes even weaker solutions cause tetanus and finally paralysis4 ,the experiments of ,drzewina7#ai7 with potassium cyanid are also interesting in this connection4 ,teleosts placed in #ajj cc of sea water containing twentieth-normal potassium cyanid showed signs of asphyxia and died in #aj to #bj minutes4 ,actinia placed in a solution of sea water containing five times as much potassium cyanid were active on the thirteenth day of the experiment4 ,similar results were obtained with other marine organisms4 ,from these data it is evident that the toxicity of a substance may vary considerably in different forms of life4 ,it has been shown also by some investigations cited by ,salant7#gh7 that the action of drugs may be modified by different conditions in the environment as well as in the subject of the experiment4 ,the recognition of the importance of these factors in determining pharmacological action has contributed much to the elucidation of the mechanism by which drugs and other substances produce physiological effects in the body4 ,moreover1 such knowledge has often enhanced the therapeutic value of pharmaco-dynamic agents and has frequently served to avert effects of an undesirable character in man and domestic animals4 ,the results obtained in one species of animals under a particular condition do not admit1 therefore1 of universal application4 ,furthermore1 the nature of the action of a drug can only be partly learned from the manifestation of its acute effects4 ,equally important1 therefore1 especially in studies on toxicity1 are the changes produced in chronic intoxication4 ,that the acute effects of a substance can hardly be considered a correct estimate of its toxicity is shown by the evidence obtained in experiments on tolerance and cumulative action of drugs2 for the toxicity of a substance may diminish when the substance is given steadily for a long time if the body acquires tolerance for it4 ,arsenic1 morphin1 and cannabis indica may be cited as illustrations of drugs1 the toxicity of which decreases with repeated doses1 while digitalis and lead show a tendency to increased toxicity when similarly administered4 ,moreover the acute and chronic effects are sometimes qualitatively different4 ,according to ,igersheimer7#da7 the symptoms in acute atoxyl intoxication are nausea1 vomiting1 and diarrhea4 ,these symptoms are absent in chronic intoxication1 in which trophic disturbances of the skin and inflammation of the mucous membranes were the effects produced4 ,that the acute action of atoxyl differs from the chronic effects was likewise shown by experiments on animals4 ,the studies of von ,anrep7#e7 on chronic atropin intoxication are of interest in this connection1 as he found that after #aj to #ae injections of atropin there is no manifestation of symptoms such as is observed in acute intoxication1 while the effects on the circulation are also less marked1 the acceleration of the pulse being less than after the same dose in a normal subject not accustomed to its use4 ,when the administration of atropin is continued for a longer time its usual effects on the pulse disappear altogether2 there is1 on the contrary a decreased frequency of the pulse4 ,if atropin has been administered for from two to three weeks1 respiration is likewise affected4 ,,historical ,,review ,,of ,,the ,,literature ,,on ,,the ,,toxicity ,,of ,,caffein4 ,caffein was discovered in #ahbj by ,runge17#gg7 ,pelletier17#fj7 and ,robiquet7#ge7 and was first analyzed by ,dumas and ,pelletier17#bj7 but its exact percentage composition was determined by ,pfaff and ,liebig17#ga71 7#gb7 while to ,herzog 7#ac71 7#ah7 belongs the credit of having established that it is basic4 ,strecker7#hb7 prepared caffein synthetically by heating theobromin silver and methyl iodid in a closed tube for #bd hours4 ,soon after its discovery in coffee ,oudry7#fg7 reported the presence of a substance in tea which he called thein4 ,its identity with caffein was established #ae years later by ,jobst7#dc7 and also by ,mulder47#fb71 7#fc7 ,according to ,brill17#ac7 ,mulder 7#ahch7 was also the first to perform experiments with caffein on animals4 ,after the administration of one-half grain to a pregnant rabbit he observed loss of appetite and kyphosis4 ,the rabbit aborted but recovered from the effects of caffein4 ,it has since been made the subject of numerous investigations which were carried out on a variety of animals4 ,observations with caffein were also made on the human subject4 ,about four years after ,mulder published his results1 ,lehmann7#ea7 7#ahdb7 reported experiments on a number of people who were given caffein4 ,the administration of from #b to #aj grains of the alkaloid was followed by headache1 palpitation of the heart1 increased frequency and irregularity of the pulse1 tinnitus aurium1 photopsia1 insomnia1 and even delirium4 ,similar experiments reported by ,frerichs7#be7 7#ahdf7 indicate that in doses of #be grains it may induce severe symptoms about #ae minutes after its administration4 ,he also observed circulatory as well as nervous symptoms and vomiting4 ,according to ,albers7#b7 7#aheb71 #d4e grains of caffein citrate injected subcutaneously into the thigh of a rabbit was soon followed by diminished motion and tremors of the operated thigh4 ,other symptoms reported were spasms of the facial muscles1 increased respiratory movements1 and mental confusion4 ,of interest in this connection are the experiments of ,cogswell7#ag7 7#aheb7 on frogs4 ,he concluded that in point of destructive action on the tissues1 caffein is far superior to morphin and may be compared to strychnin and coniin1 its action on the nervous system he believed to be principally confined to the effect on the brain and spinal cord4 ,lehmann7#eb7 7#ahec7 observed increased frequency of heart action after the administration of #d grains1 which were given with a normal diet to an adult man4 ,when the dose was doubled the frequency of the pulse was still more increased1 heart action became stronger1 and tremors and confusion of thought with excitement of the imagination made their appearance4 ,there was also an increased desire to micturate4 ,stuhlmann and ,falck7#hc7 7#aheg7 were the first to make a study of the toxicity of caffein on animals of different species4 ,the administration of #j4e gram of caffein subcutaneously or per rectum in rabbits induced tremors1 tonic and clonic convulsions1 paralysis1 and increased frequency of respiration at first followed by violent dyspnoea4 ,on autopsy he noticed congestion of the organs and in two of the three rabbits experimented upon punctiform hemorrhages of the brain with congestion of the meninges were found4 ,in the other rabbit anemia of the brain was observed4 ,experiments on cats were carried out by subcutaneous1 intravenous1 and rectal injections4 ,the symptoms observed after the administration of #j4e to #j4g gram of caffein were the same as in rabbits except that the cats developed diarrhea when caffein was given and no anatomic lesions were found on autopsy4 ,the effect of caffein on dogs indicated that in subjects of medium weight a dose of #j4e gram given by mouth might produce restlessness and increased frequency of respiration1 while the injection of the same amount intravenously into such animals may cause death4 ,large1 full-grown dogs1 however1 survived an intravenous injection of #b grams of caffein1 showing symptoms of incoordination1 salivation1 and frequent defecation4 ,these investigators also made observations on caffein1 using pigeons and other birds2 #j4e to #j4a gram introduced into the stomach caused vomiting1 diarrhea1 tonic1 but more frequently clonic1 convulsions1 incoordination1 tremors1 paresis1 and paralysis4 ,in a few1 but not in all of the birds1 there was at first increased frequency of respiration followed by dyspnoea and circulatory disturbances4 ,these amounts of caffein proved fatal in all of the experiments on birds4 ,inflammation of the intestinal mucosa and congestion of the meninges were the only changes found on autopsy4 ,stuhlmann and ,falck also studied the effects of caffein on fishes and toads4 ,mitscherlich7#fj7 7#aheh7 fed #j4d gram of caffein with bread to a rabbit and noticed lowered temperature1 fatigue1 convulsions1 first increased then decreased frequency of respiration1 and on autopsy congestion of all the viscera4 ,he also reported observations on two frogs1 one of which was given one-sixteenth of a grain of caffein in a pill with bread4 ,it was administered to the other frog in aqueous solution1 but the mode of administration was not published4 ,the symptoms observed were in the main the same as in rabbits4 ,in pigeons #j4abe gram introduced into the stomach caused severe vomiting1 muscular incoordination1 tonic rigidity of the limbs1 and retraction of the head4 ,respiration was increased in frequency4 ,death followed within #c hours and #ae minutes4 ,from a series of experiments on frogs which ,hoppe7#ch7 carried out 7#aheh7 by applying one-fourth of a grain of caffein to the muscles of the back1 he concluded that caffein causes paralysis of the nerves1 spinal cord1 and brain1 sensation being paralyzed before movement4 ,the injurious action of caffein proceeds1 according to ,hoppe1 from the spinal cord4 ,this was based on experiments on two frogs1 ,rana esculenta1 in which the right leg was amputated1 the nerve being left intact1 while the nerve of the other leg was ligated4 ,at the end of #cj minutes paralysis was more marked on the right than on the left side4 ,in another frog of the same species he resected the femoral nerve on the right side2 about #a hours after the administration of caffein convulsions were observed4 ,the left leg was rigid1 but the right was relaxed4 ,voit7#he7 7#ahfj7 ligated the vessels of the right lower extremity1 cut the nerves of the left leg1 and introduced a few drops of caffein solution into the stomach4 ,shortly afterwards tetanus of the right leg occurred on touching the back of the animal2 the left leg was motionless4 ,later the entire body exhibited tetanic convulsions4 ,from this and similar experiments ,voit concluded that caffein acts first and principally on the central nervous system1 and that caffein is also poisonous to nerve and muscle fibers1 as they die when a solution of caffein is applied to them4 ,the action of caffein1 according to ,voit1 is similar in great part to that of strychnin4 ,the effect on the blood vessels is particularly interesting1 as ,voit observed dilatation of the vessels1 due as he thought to muscular paralysis1 and also transudation and congestion of the capillaries4 ,kurzak7#dh7 7#ahfj7 made a study of the comparative toxicity of caffein in frogs and rabbits and came to the conclusion that the lethal dose for frogs is about one-seventh of that for rabbits4 ,caffein citrate in the form of crystals was administered in both cases by mouth4 ,the doses given to frogs were #a to #a4e grains4 ,he observed convulsions and increased respiratory activity at first2 after one hour respiration diminished and voluntary muscular activity disappeared4 ,even on the second day convulsions were sometimes noticed4 ,death occurred at the end of the first or second day4 ,experiments on only two rabbits were reported1 #j4h gram of caffein citrate causing the death of one at the end of #ac hours4 ,the symptoms noticed were the same practically as in frogs1 but it is interesting to observe that ecchymosis of the mucous membranes of the stomach near the cardia was the only lesion found on autopsy4 ,several experiments made on different days on the other rabbit indicated that the toxic dose exceeded #j4e gram1 while smaller doses caused but very mild symptoms4 ,according to ,gentilhomme7#bg7 7#ahfg71 after caffein the reflexes are at first diminished and then disappear altogether4 ,death is produced by stiffness and immobility of all the muscles1 particularly of the muscles of respiration1 thus causing asphyxia4 ,he furthermore held that caffein has no effect on cardiac or smooth muscle fiber1 its action being specific on voluntary muscle fiber1 contractions of which he observed under the microscope1 thus differing completely from strychnin1 which is a nerve poison4 ,these observations seemed to be confirmed by ,pratt7#gd7 7#ahfh71 who reported that the isolated posterior extremities and muscle fibers of the toad placed in a solution of caffein 7#a grain to a wineglassful of water7 for three minutes were contracted1 while controls placed in distilled water were relaxed4 ,this experiment is1 of course1 defective1 as normal salt solution should have been used in both cases4 ,when the muscular fibers previously immersed in caffein solution were placed under the microscope violent contractions were observed4 ,the same author administered from #b to #ah grains at a dose to five healthy young men4 ,after the administration of #ab grains he noticed mental anguish1 tremors of the hands and arms1 and insomnia4 ,doses under #e grains had no marked effect except a diminution in the frequency of the pulse and wakefulness4 ,about the same time ,amory7#d7 7#ahfh7 published the results of his studies on the toxicity of caffein in cats1 dogs1 rabbits1 and pigeons4 ,in all cases very large doses were introduced directly into the stomach by means of a temporary gastric fistula4 ,ten grains given in meat to a dog caused restlessness1 but no other symptoms4 ,doses of #cj grains and above were invariably fatal4 ,seventy-three grains given to a cat caused death within #bj minutes4 ,from observations on frogs1 guinea pigs1 rabbits1 and on one dog1 ,leven7#ec7 7#ahfh7 concluded that caffein which he gave in the form of the citrate in doses of #aj mg to frogs1 from #aej to #bjj mg to guinea pigs1 and three to four times the latter amount to rabbits1 stimulates the central nervous system and the voluntary1 cardiac1 and smooth muscles4 ,he found that #j4i gram caffein was fatal for a rabbit when injected subcutaneously1 while #a gram of the citrate was not toxic for a dog of medium size4 ,caffein applied directly to muscle fiber causes tetanus and destroys muscular contractility1 while a nerve fiber similarly treated loses its irritability4 ,according to ,johansen7#dd7 7#ahfi71 caffein acts directly on the muscular fiber4 ,after the subcutaneous injection of #j4jb gram of caffein into frogs1 he observed contraction of the muscles at the site of injection1 then contraction of the anterior extremities1 and finally the posterior extremities become rigid and extended4 ,johansen observed muscular rigidity after caffein1 even after curara was injected1 or after ligating the vessels1 or cutting the nerves which supply the muscles4 ,he also observed that large doses of caffein diminish muscular irritability4 ,when cardiac muscle was poisoned with caffein1 microscopical examination showed that the striations disappeared4 ,johansen also states that reflexes disappear after caffein poisoning4 ,he never observed tetanus in frogs1 but reported tonic and clonic convulsions as a result of caffein poisoning in mammals4 ,somewhat different effects of caffein in frogs were observed by ,buchheim and ,eisenmenger7#ad7 7#ahgj74 ,after the injection of #b per cent of the citrate the frogs soon become inactive4 ,he also observed muscular twitching of the extremities1 which gradually increased1 with rigidity of the muscles and opisthotonos1 while respiration became slow and superficial1 finally stopping altogether4 ,aubert7#f7 7#ahgb7 studied the toxicity of caffein in man and other animals4 ,after the ingestion of #j4cf gram1 he observed dizziness1 but doses of #j4ab and #j4bd gram were without any apparent effect4 ,on the other hand1 a dose of #j4e gram of caffein was followed by increased frequency of the pulse1 which soon disappeared4 ,after one hour he noticed dizziness and trembling of the hands1 which likewise passed away soon4 ,the injection of #j4af gram of a #b per cent solution of caffein into the jugular vein of a rabbit weighing #a1jij grams caused tetanus and death in two and one-half minutes1 and #j4ab gram injected into a rabbit weighing #ihj grams caused death in one minute4 ,much larger doses could be borne1 however1 when artificial respiration was resorted to4 ,a dog which was given #c grams of caffein survived when artificial respiration was performed4 ,aubert reports1 on the other hand1 a similar experiment with #j4be gram of caffein which terminated fatally4 ,that caffein may give rise to different effects in various species of animals was observed for the first time by ,bennett47#i7 ,he studied its action on frogs1 mice1 rabbits1 and cats1 and attempted to determine the minimum fatal dose in rabbits and cats4 ,he also reported experiments with thein4 ,in his first communication on the subject he states that the administration of thein to rabbits first increased and then diminished the frequency of respiration1 while the pulse was decreased in frequency4 ,caffein1 which he apparently thought was different from thein1 caused increased frequency of respiration1 while the pulse was markedly retarded after a preliminary acceleration4 ,he also noticed congestion of the ears1 muscular incoordination1 tetanus1 paralysis1 diminished reflexes1 and contraction of the pupils4 ,bennett reported the minimum fatal dose of caffein for a rabbit weighing #c4be pounds as being #e4be-e4e grains4 ,the symptoms in cats after the administration of toxic doses of thein or of caffein were great excitement1 paralysis alternating with convulsions1 and profuse salivation4 ,the minimum fatal dose for a cat weighing #e pounds was1 according to ,bennett1 #f grains of caffein and #e4e grains of thein4 ,only one experiment on a mouse is reported2 the administration of #j4a grain proved fatal4 ,the symptoms were the same as those observed in cats and rabbits after the administration of caffein4 ,the experiments on frogs indicate that the symptoms were about the same as those previously described in the case of warm-blooded animals except that the reflexes are almost completely lost after the subcutaneous injection of doses of one-sixteenth to one-twelfth of a grain4 ,the latter dose was fatal for frogs4 ,it would be of interest to know the comparative toxicity of caffein to frogs and mammals1 but unfortunately the weights were not reported4 ,schmiedeberg7#gi7 7#ahgd7 noticed that the administration of #bj mg of caffein to frogs weighing about #de grams was followed1 in ,rana esculenta1 in about #be minutes1 by increased reflexes1 #g minutes later by tetanus4 ,several attacks occurred1 but tonic spasms were never observed4 ,on the contrary1 when the same amount of caffein was given to ,rana temporaria weighing #de grams he noticed a marked diminution of the reflexes and tonic rigidity of the muscles after #bc minutes2 the reflexes were greatly increased1 however1 about #bd hours later4 ,the frogs were under observation for three days1 and although symptoms were still present at the end of this time in the subjects of both species tetanus was never observed in ,rana temporaria4 ,peretti's7#gj7 7#ahge7 studies on the effects of caffein were confined chiefly to observations on dogs4 ,he also made observations on a few rabbits and reported an experiment on one cat to which he administered1 by subcutaneous injection1 #j4ah gram of caffein per kilo and noticed increased frequency in lachrymation and crying4 ,the cat was found dead the next day4 ,the subcutaneous injection of a rabbit in which artificial respiration was instituted with #j4cf gram of caffein per kilo proved fatal soon after the injection without any manifestation of symptoms4 ,small doses of caffein1 #j4a gram1 given to a rabbit weighing #c1fgj grams1 failed to produce any visible effects4 ,doses under #j4a gram per kilo likewise failed to induce any symptoms in dogs4 ,when #j4a gram of caffein per kilo was given by mouth or subcutaneously it was followed by restlessness1 salivation1 rigidity of hind legs1 and vomiting4 ,in both instances the dogs recovered4 ,the symptoms were more severe when the dose was increased to #j4ahe gram per kilo1 but even in this case the dog recovered4 ,a dose of #j4b gram per kilo1 however1 proved fatal4 ,henneguy7#cf7 7#ahge7 experimented on three frogs to which he gave #j4ja gram of caffein citrate subcutaneously4 ,he observed mild stimulation of the nervous system and of the muscles1 as well as increased cardiac activity4 ,later1 voluntary movement and respiration disappeared and sensations diminished1 but convulsions of the extremities appeared4 ,cardiac activity was then diminished1 the heart being finally arrested in systole4 ,since the motor nerves retained their irritability even after the reflexes disappeared1 he concluded that the loss of motion was due to the action of caffein on the nerve centers4 ,binz7#aa7 7#ahgh7 reported experiments on dogs and also made some observations on man with caffein4 ,the subcutaneous injections of #j4b gram caffein may prove fatal to dogs1 although some survive such a dose4 ,the toxic dose in man varies from #j4e to #a4e grams4 ,disturbance of the circulation1 such as palpitation of the heart and fullness of pulse1 restlessness1 and diarrhea were the symptoms he observed4 ,extensive investigations on the action of caffein were carried out by ,leblond7#ej7 7#ahhc71 who studied its effect on the circulation in man and lower animals1 and its toxicity in the lower animals alone4 ,five to twenty centigrams of caffein and #j4jf to #j4be gram of salicylate of soda were dissolved and injected into the muscles of the thigh of young guinea pigs weighing a little over #cjj grams4 ,in the three experiments reported the death of the animals occurred after #bc minutes1 #dj minutes1 and #a hour and #bj minutes4 ,symptoms appeared in from #aj to #ae minutes after the injection of caffein4 ,incoordination of movements1 convulsions1 both tonic and clonic1 opisthotonos1 tremors1 increased frequency of respiration1 ataxia1 paralysis were the symptoms observed4 ,it is worthy of note that the appearance of paresis preceded the convulsions4 ,diminished sensation was reported in one pig1 but no sensory disturbances nor reflexes had been observed in the other4 ,two rabbits1 one of which received #j4e and the other about #j4c gram of caffein per kilo with equal parts of salicylate of soda1 were injected subcutaneously into the thigh4 ,diminished sensation1 paresis of the posterior extremities1 hyperexcitability1 convulsions1 opisthotonos1 dilation of the veins of the ear were observed4 ,death followed in #a hour and #bc minutes in one rabbit and in #c hours and #g minutes in the other4 ,filehne7#bb7 7#ahhf7 experimented with caffein on ,rana esculenta and ,rana temporaria4 ,the subcutaneous injection of #g mg of caffein into ,rana esculenta caused tetanus1 while #ej mg given by mouth caused tonic spasms4 ,he further stated that the difference between ,rana esculenta and ,rana temporaria as regards the reaction to caffein was one of degree only4 ,amat7#c7 7#ahhi7 reported experiments on three guinea pigs1 in which #j4d to #j4e gram per kilo injected subcutaneously proved fatal within #ch and #dd minutes4 ,one guinea pig which received #j4a gram of caffein per kilo survived4 ,the symptoms observed in the two fatal cases were general muscular rigidity and convulsions4 ,parisot7#fh7 7#ahij7 made a study of the toxicity of caffein on different species of animals4 ,unlike most of his predecessors1 however1 he reported1 at least in some cases1 the weight of the animals on which he worked4 ,after the subcutaneous and intramuscular injections of from #e to #bj mg of caffein into ,rana temporaria weighing from #ad to #af grams1 he noticed increased irritability at first2 later1 a loss of reflexes1 inability to use the muscles1 complete muscular rigidity resembling rigor mortis1 and also cessation of heart action4 ,the effect of caffein produced in the green frog was analogous to that observed in strychnin poisoning4 ,parisot found1 however1 that muscular rigidity developed1 although very gradually1 also in the green frog1 but it set in much later than in frogs of the other species and without superseding the clonic convulsions4 ,according to ,parisot1 the muscular rigidity after caffein persists after the destruction of the brain and spinal cord1 thus showing that it is not of nervous origin4 ,he further emphasized the difference in the behavior of these two species of frogs toward caffein by stating that he never observed tetanic convulsions in the red frog4 ,his experiments also indicate that the green frog is more resistant to caffein than ,rana temporaria1 as the same doses which are fatal for the latter were only toxic for ,rana esculenta4 ,the number of experiments1 however1 is too few to justify a positive conclusion on this point4 ,parisot also made some experiments on turtles4 ,the results he obtained show that caffein is at least as toxic for these animals as for the frogs he experimented upon1 #j4cc gram per kilo 7carapace not included in weight7 having proved fatal within #bd hours4 ,two experiments on one pigeon were also reported by the same observer2 two doses of #j4jf gram per kilo given at an interval of four hours caused mental depression and muscular rigidity1 but the pigeon survived4 ,experiments with caffein on the human subject made by ,parisot showed that man is far more susceptible to this substance than the other animals he investigated4 ,after the ingestion of #j4c gram of caffein symptoms of intoxication pointing to cerebral disturbance appeared1 which became more marked when the size of the doses was increased4 ,it will be noticed that the nature of the action of caffein1 whether it is a nerve or a muscle poison1 formed the subject of several investigations4 ,binz7#aa7 7#ahij7 brought forward additional evidence in support of the view that caffein acts primarily on the ganglion cells1 and not on the muscle directly4 ,this he has shown by injecting #j4e gram into each of two rabbits after cutting the sciatic nerve on one side2 in one case he also resected the obdurator and crural nerves on the same side4 ,clonic spasms developed in both subjects soon after caffein was given1 but in each rabbit the side operated upon remained paralyzed4 ,baldi7#h7 7#ahia7 studied the action of caffein on ,rana esculenta4 ,after injecting from #d to #bj mg tetanus1 such as observed in strychnin poisoning1 was noticed4 ,frhner7#bf7 7#ahib7 made observations on the comparative toxicity of caffein in domesticated animals4 ,after the administration of #e grams of caffein sodium salicylate by mouth to a dog weighing #aj kilos1 he noticed salivation1 restlessness1 vomiting1 and convulsions as in strychnin poisoning4 ,death occurred three hours after the drug was given4 ,on autopsy he noticed mild inflammation of the mucous membranes of the stomach and intestines and edema of the lungs2 the heart was in diastole4 ,a dose of #b grams of caffein sodium salicylate given to the same animal subcutaneously two days previously provoked only very slight symptoms4 ,the subcutaneous injection of #aj grams of the same preparation into a pig weighing #cj kilos caused death in two and a half hours1 with the production of symptoms of disturbance of the nervous system and of gastrointestinal irritation4 ,the same dose per kilo of body weight given to a goat likewise caused death in two and a half hours after its administration4 ,examination on autopsy revealed inflammation of the gastrointestinal tract4 ,similar lesions were found in a horse killed by #ajj grams of caffein1 in which he also noticed hemorrhage of the mucosa in the fundus of the stomach4 ,gourewitch7#bh7 7#aijg7 conducted experiments with caffein on rabbits1 pigeons1 and white rats4 ,it appears from his protocol that single doses of about #j4b to #j4be gram caffein per kilo given subcutaneously proved to be fatal4 ,he states1 however1 that the resistance to caffein was markedly diminished1 when its administration was repeated daily1 for much smaller amounts sufficed to cause death in these animals4 ,a dose of #abj mg of caffein per kilo proved fatal after the third injection4 ,when the dose was increased to #agj mg per kilo1 the animal succumbed to the effects of caffein after the second injection4 ,his experiments on the other animals do not indicate the degree of resistance to caffein1 since the weights for some were not given while for the others no attempt was made to determine the minimum toxic or fatal dose4 ,maurel7#ee7 7#aijg7 studied the influence of different methods of administration on the toxicity of caffein on frogs and rabbits4 ,he determined the minimum toxic and lethal doses of caffein hydrobromid which he employed in #a to #b per cent solutions4 ,he concluded from his experiments that the toxicity of caffein when given by mouth is twice as great for the frog as for the rabbit4 ,more recently ,hale7#cc7 carried out a number of experiments on guinea pigs in which he determined the toxicity of caffein given in the form of the citrate and made into a pill with mucilage of acacia and arrow-root starch4 ,after the pill was dried it was fed to the animal1 due precaution being taken that none of it was lost during feeding4 ,from experiments on guinea pigs which received doses of #j4c to #j4f gram caffein citrate1 the following data have been reported3 ,three decigrams per kilo given to one pig was not fatal4 ,of three pigs which received #j4d per kilo1 one died and two survived4 ,exactly the same results were obtained in three others which received #j4e per kilo4 ,two guinea pigs1 which received #j4ee and #j4f per kilo each1 died after #ae and #g hours1 respectively1 while another animal survived a dose of #j4de per kilo4 ,this review of the literature on the toxicity of caffein1 although bearing evidence of considerable investigation and extending over three-quarters of a century1 is largely qualitative in character4 ,it appears from the experiments that the main object of the investigations was to ascertain the nature of the action of caffein1 whether it is a muscle or a nerve poison4 ,the comparative toxicity in different species of animals by the accurate determination of the toxic and fatal doses received but little attention4 ,to fill the gap in our knowledge of the toxic effects of caffein1 the present investigation was undertaken4 ,this1 it will be seen1 proved to be a most laborious task1 because in the large number of experiments careful observations showed that individuals of the same species varied considerably in their reaction to the drug4 ,numerous other factors1 as will be shown1 were also found to play an important part in the determination of the toxicity of caffein4 ,,acute ,,caffein ,,intoxication4 ,the object of these experiments was to determine the resistance to caffein in various species of animals and by various methods of administration4 ,caffein was therefore given by mouth and injected subcutaneously into the peritoneal cavity1 into the muscles1 and intravenously4 ,as far as could be judged by appearance1 healthy animals were selected for the subjects of the experiments1 but as it is impossible to diagnose with any degree of accuracy the condition of the animal while it is alive1 post mortem examinations were resorted to in many cases in which the issue of the experiment was fatal4 ,since the age of the animal may modify toxicity full grown1 as well as young1 animals were employed for these experiments2 diet1 race1 and season also play an important part in determining the toxicity of a drug and these factors were also taken into account in the present investigation4 ,,experiments ,,on ,,rabbits4 ,animals of different varieties were used and were given caffein by all of the methods indicated in the preceding paragraph4 ,some of the rabbits employed in these experiments received oats1 others received a diet exclusively of carrots for several days or weeks previous to the administration of caffein4 ,the experiments were conducted at all seasons of the year4 ,,subcutaneous ,,injection4 ,from a study of the literature on the toxicity of caffein it seemed that about #aej mg per kilo is probably the lethal dose for the rabbit when the drug is injected subcutaneously4 ,preliminary observations were therefore carried out with such a dose1 but it was found1 on the contrary1 that this amount per kilo was hardly sufficient to induce symptoms in the great majority of cases4 ,,series ,a4 ,doses of #adg to #afg mg of caffein per kilo were employed in these experiments4 ,rabbit #ccb4 ,belgian hare1 female4 ,weight1 #a1jgj grams4 ,diet1 oats4 ,march #be3 #h4e cc #b per cent caffein 7#aeh mg per kilo7 injected subcutaneously at #b4ae p4 m42 #d p4 m41 reflexes increased2 #e4de p4 m41 increases of reflexes still more marked4 ,march #bf3 ,rabbit looked normal2 no symptoms observed4 ,rabbit #cca4 ,belgian hare1 female4 ,weight1 #a1agj grams4 ,diet1 oats4 ,march #be3 #b4ae p4 m41 #i cc #b per cent caffein 7#aec mg per kilo7 injected subcutaneously2 #d p4 m41 reflexes increased2 #e4de p4 m41 condition the same4 ,march #bf3 ,rabbit looks normal2 no symptoms observed4 ,rabbit #cbh4 ,belgian hare1 female4 ,weight1 #a1bjj grams4 ,diet1 oats4 ,march #be3 #i cc #b per cent caffein injected subcutaneously 7#aej mg per kilo72 #d p4 m41 reflexes increased2 #e4de p4 m41 reflexes increased but not markedly4 ,march #bf3 ,no symptoms2 rabbit looks normal4 ,rabbit #cbb4 ,white female4 ,weight1 #a1jfe grams4 ,diet1 oats4 ,march #ag3 #h cc #b per cent caffein 7#aej mg per kilo7 injected subcutaneously at #aa4ee a4 m42 #ab4ee p4 m41 reflexes increased1 but no tetanus nor any other symptoms4 ,march #ah3 ,rabbit running around in cage2 condition apparently normal4 ,march #be3 ,condition of rabbit good4 ,rabbit #bag4 ,white4 ,weight1 #a1cee grams4 ,diet1 oats4 ,october #bi3 #aj cc #b per cent caffein 7#adg mg per kilo7 injected subcutaneously at #a4ea p4 m4 #e4ae p4 m41 rabbit alive2 survived4 ,rabbit #bai4 ,maltese4 ,weight1 #a1hbj grams4 ,diet1 oats4 ,october #bi3 #ad cc #b per cent caffein injected subcutaneously at #a4dj p4 m4 7#aec mg per kilo72 #e4ae1 rabbit alive2 survived4 ,rabbit #aid4 ,white female4 ,weight1 #a1dij grams4 ,diet1 oats4 ,october #ad3 #ac cc #b per cent caffein 7#agd mg per kilo7 injected subcutaneously2 increased reflexes and tremors were observed4 ,october #ae3 ,condition of rabbit good2 no symptoms4 ,rabbit #aia4 ,brown male4 ,weight1 #a1iae grams4 ,diet1 oats4 ,october #ad3 #af cc #b per cent caffein 7#afg mg per kilo7 injected subcutaneously2 reflexes increased and tremors present4 ,october #ae3 ,condition of rabbit good4 ,a study of this series shows that about #aej mg of caffein per kilo caused increased reflexes within one to two hours after injection4 ,when the dose was increased1 as in rabbits #aid and #aia1 the symptoms were more pronounced2 #aej mg per kilo may be regarded as the minimum dose which produces symptoms of nervous irritability when caffein is injected subcutaneously4 ,experiments with larger doses were therefore carried out in order to determine the minimum fatal dose4 ,,series ,b4 ,approximately #j4b gram of caffein per kilo was employed in these experiments4 ,diet and race as possible factors which may influence the toxicity of caffein were made the subject of study in these experiments which were divided into two groups as shown in the table1 page #be4 ,rabbit #ie4 ,gray and white male4 ,weight1 #a1dgh grams4 ,diet1 oats4 ,february #bg3 #aa4cj a4 m41 #ae cc #b per cent caffein 7#baj mg per kilo7 injected subcutaneously2 #b4bj p4 m41 no symptoms1 tremors observed when handled1 but not marked1 reflexes slightly increased1 no muscular rigidity nor any other symptoms2 #b4de p4 m41 rabbit suddenly became very restless1 jumped off the table1 and had convulsions2 #c4de p4 m41 rabbit died1 rigor mortis set in almost immediately after death4 ,rabbit #if4 ,gray and white male4 ,weight1 #a1ehe grams4 ,diet1 oats4 ,february #bg3 #af cc #b per cent caffein 7#bjj mg per kilo7 injected subcutaneously at #c4dj p4 m42 increased reflexes observed about one hour after caffein was injected1 but no other symptoms4 ,february #bh3 ,rabbit found dead4 ,rabbit #aab4 ,black female4 ,weight1 #hge grams4 ,diet1 oats4 ,march #ah3 #i cc #b per cent caffein 7#bje mg per kilo7 injected subcutaneously at #c p4 m42 #c4cj p4 m41 rabbit became restless1 reflexes were increased1 tremors were observed1 but no other symptoms2 #d4ae p4 m41 rabbit had tremors1 was handled but this failed to induce tetanus1 #aj minutes later tetanus of short duration with recovery occurred4 ,march #ai3 #i a4 m41 found dead4 ,rabbit #aai4 ,yellow white female4 ,weight1 #a1jfj grams4 ,diet1 oats4 ,april #ag3 #aj cc #b per cent caffein 7#ahh mg per kilo7 injected subcutaneously at #b4aj p4 m4 ,april #ah3 ,rabbit found dead4 ,rabbit #aie4 ,white female4 ,weight1 #a1cjj grams4 ,diet1 carrots1 since ,october #g4 ,october #ad3 #ac cc #b per cent caffein 7#j4b gram per kilo7 injected subcutaneously at #aa4ae a4 m42 #b4be p4 m41 rabbit had convulsions and died4 ,note3 ,ulceration of rectum was noticed4 ,rabbit #bjh4 ,gray4 ,weight1 #a1jfh grams4 ,diet1 carrots1 ,october #g-ae1 inclusive4 ,october #ae3 #aj cc #b per cent caffein injected subcutaneously at #aa a4 m42 #a p4 m41 increased reflexes and tremors observed2 #c4de p4 m41 tremors were marked when rabbit was handled4 ,october #af3 ,rabbit found dead4 ,note3 ,looked poorly nourished4 ,rabbit #bdg4 ,belgian hare1 female4 ,weight1 #a1bie grams4 ,diet1 oats last #aj days before experiment4 ,november #aj3 #aa a4 m41 urine obtained from the bladder was acid to litmus and did not contain sugar or albumen1 #ac cc #b per cent caffein was injected subcutaneously2 #a4cj p4 m41 #ae cc urine obtained was markedly alkaline to litmus and reduced ,fehling's solution2 #b4cj p4 m41 reduction of urine considerable1 marked tremors observed but no tetanus4 ,november #aa3 #aj4cj a4 m41 #ie cc urine collected gave moderate reduction of ,fehling's solution1 no symptoms1 condition of rabbit seemed to be good4 ,rabbit #bdh4 ,belgian hare1 female4 ,weight1 #a1cje grams4 ,diet1 oats the last #aj days before the experiment4 ,november #aj3 #aa a4 m41 urine markedly acid to litmus1 no albumen1 no sugar2 #ac cc #b per cent caffein injected subcutaneously2 #a4cj p4 m41 urine was slightly alkaline to litmus1 no reduction of ,fehling's solution2 #b p4 m41 reflexes increased2 #b4cj p4 m41 #b cc urine obtained from bladder1 sugar abundant2 #d4de p4 m41 reflexes increased as before1 but no tetanus4 ,november #aa3 #aj4cj a4 m41 urine collected showed slight reduction of ,fehling's solution2 otherwise condition of rabbit was good2 rabbit did not show any effects of caffein4 ,rabbit #ccg4 ,belgian hare4 ,weight1 #a1jdj grams4 ,diet1 carrots1 ,march #ca to ,april #f1 inclusive4 ,april #f3 #c p4 m41 #aa cc #b per cent caffein injected subcutaneously in the back 7#j4baa per kilo72 #d4cj p4 m41 reflexes much exaggerated4 ,april #g3 #h4ae a4 m42 condition good1 no symptoms4 ,rabbit #ccf4 ,belgian hare4 ,weight1 #a1jdj grams4 ,diet1 carrots1 ,march #ca to ,april #f1 inclusive4 ,april #f3 #c p4 m41 #aa cc #b per cent caffein injected subcutaneously into tissues of the back4 ,april #g3 #h4ae a4 m41 no symptoms1 condition good4 ,although symptoms appeared in rabbits of ,group ,i 7see table1 page #be7 about the same time after the administration of caffein as in the rabbits of the preceding series all of them terminated fatally #b hours to #bd hours after its administration4 ,two of these rabbits 7,nos4 #aie and #bjh7 were fed carrots for several days before the injection of caffein1 the others were fed oats4 ,since symptoms and death appeared in these two rabbits about the same time as in the rest of this group it may be concluded that caffein is not less toxic when carrots are fed than when oats form the exclusive diet4 ,but since rabbit ,no4 #bjh was poorly nourished and ulceration of the rectum was observed in ,no4 #aie it is quite possible that caffein might be less toxic in normal rabbits on this diet4 ,this was tested in rabbits ,nos4 #ccf and #ccg1 both of which seemed to be free from abnormality and were well nourished4 ,since these rabbits survived and manifested mild symptoms only of intoxication it would seem that a carrot diet decreases the toxicity of caffein4 ,it was suggested1 however1 that another factor might be the cause of the greater resistance to caffein in these two rabbits1 namely1 race4 ,this was tested in rabbits #bdg and #bdh1 both ,belgian hares4 ,since the toxicity of caffein in these two rabbits was the same as in ,nos4 #ccf and #ccg1 diet as a factor in acute caffein intoxication may be disregarded4 ,the greater resistance to caffein of these four rabbits is in all probability due1 therefore1 to a difference of race4 ,this suggestion gained additional support from the experiments of the next series4 ,,series ,c4 ,the object of these experiments was to determine the minimum fatal dose for the gray rabbit and to obtain additional evidence as to the toxicity of caffein in the several varieties of rabbits4 ,eight experiments were performed1 in which from #bcf to #beb mg per kilo were given4 ,the white rabbits1 three in number1 received #bej1 #bdb1 and #bch mg per kilo4 ,all the others 7which were ,belgian hares7 received from #bcf to #beb mg per kilo4 ,two of the white rabbits were fed carrots for one week preceding the injection of caffein4 ,the other was fed oats4 ,three of the ,belgian hares were on a diet of oats1 two were fed carrots the week before the experiment with caffein4 ,rabbit #abb4 ,white1 female4 ,weight1 #b1jfj grams4 ,diet1 oats4 ,april #ad3 #be cc of #b per cent caffein 7#bej mg per kilo7 in aqueous solution injected subcutaneously in the back at #a4ce p4 m42 #d4cj p4 m41 tremors1 reflexes increased1 condition otherwise good4 ,april #af3 #i a4 m41 found dead in cage4 ,autopsy3 ,liver deeply congested2 kidneys congested in cortex and medulla2 stomach showed small hemorrhagic areas1 perforating ulcers in pyloric portion2 small intestine petechiated on mucosa2 lungs and spleen normal4 ,rabbit #bcd4 ,white1 female4 ,weight1 #a1fej grams4 ,diet1 ,november #b-i1 carrots4 ,november #i3 #aj4de a4 m41 #bj cc #b per cent caffein 7#bdb mg per kilo7 administered subcutaneously4 ,november #aj3 #i p4 m41 found dead4 ,rabbit #cce4 ,gray hare1 female4 ,weight1 #a1agj grams4 ,diet1 ,march #ca to ,april #g1 carrots4 ,april #g3 #i4cj a4 m41 #ad cc #b per cent caffein solution 7#bdj mg per kilo7 injected subcutaneously in the back2 #aj4cj1 reflexes much increased1 rabbit is extremely sensitive4 ,april #h3 #i a4 m41 found dead4 ,autopsy3 ,liver was congested and contained several coccidiosis nodules2 stomach distended with rather dry food mass2 mucosa exhibited mild catarrhal inflammation2 mucosa of intestines also slightly inflamed4 ,rabbit #bdi4 ,belgian hare1 female4 ,weight1 #a1ahe grams4 ,diet1 oats4 ,november #aa3 ,urine1 #e cc1 from bladder acid to litmus1 no sugar1 no albumin2 #aa4ej a4 m41 #ad cc #b per cent caffein 7#bcf mg per kilo7 administered subcutaneously2 #c4de p4 m41 reflexes increased1 hypersthesia marked1 but no tetanus1 even when handled2 #cj cc urine collected at #d p4 m41 reduction of ,fehling's solution considerable4 ,november #ab3 #aj a4 m41 #h cc urine collected1 reduction heavy1 only a few cubic centimeters obtained from bladder1 did not contain any sugar1 general condition of rabbit good1 no symptom of caffein intoxication4 ,rabbit #cba4 ,yellow1 female4 ,weight1 #a1ace grams4 ,diet1 oats4 ,march #af1 #aiaj3 #aa4ej a4 m41 #ad cc #b per cent caffein 7#bdf mg per kilo7 injected subcutaneously in the back2 #b p4 m41 reflexes increased1 is very sensitive1 started to run when put on floor1 no handling except what was required for removal and return to cage1 feces soft4 ,march #ag3 #i4cj a4 m41 condition good1 rabbit put on floor1 gait normal1 but does not care to walk4 ,march #ah3 #i a4 m41 walks around when put on floor1 appetite good1 condition seems to be normal4 ,march #be3 #aa a4 m41 rabbit still alive1 condition good4 ,rabbit #bej4 ,belgian hare1 female4 ,weight1 #a1dce grams4 ,diet1 oats at least two days before the experiment4 ,november #aa3 #aa a4 m41 urine obtained from bladder acid to litmus1 no albumin1 no sugar2 #aa4aj a4 m41 #ah cc1 #b per cent caffein 7#beb mg per kilo72 #c4de p4 m41 reflexes and hypersthesia1 no tetanus2 #d p4 m41 #fj cc urine1 marked reduction of ,fehling's solution4 ,november #ab3 #aj a4 m41 condition of rabbit good1 no symptoms of caffein intoxication1 #hj cc urine collected1 sugar considerable1 only a few cubic centimeters of urine obtained from bladder1 no reduction of ,fehling's solution4 ,rabbit #hcd4 ,belgian hare1 female4 ,weight1 #a1bgj grams4 ,diet1 carrots1 ,march #ca to ,april #g4 ,april #g3 #i4cj a4 m41 #ae cc #b per cent caffein 7#bdj mg per kilo7 injected subcutaneously in the back2 #aj4cj a4 m41 reflexes much increased1 rabbit extremely sensitive4 ,april #h3 #i a4 m41 condition good1 no symptoms4 ,rabbit #bcc4 ,white1 male4 ,weight1 #a1fge grams4 ,diet1 carrots1 ,november #b to #i4 ,november #i3 #aj4ej a4 m41 #bj cc #b per cent caffein 7#bch mg per kilo7 injected subcutaneously1 no symptoms observed until #e p4 m41 when increased reflexes and hypersthesia were noticed1 but no tetanus4 ,november #aj3 #i a4 m41 paralysis of posterior extremities2 died at #a p4 m4 ,analysis of the results obtained in the experiments of this series and inspection of ,table ,i1 page #be1 show that all four of the rabbits which survived doses of #bcf to #beb mg of caffein per kilo were ,belgian hares4 ,of the four which died one only was a ,belgian hare4 ,the other three were white rabbits4 ,two of these were fed oats2 the other two received carrots during seven days preceding the administration of caffein4 ,this diet does not seem to be a factor1 therefore1 in the toxicity of caffein4 ,moreover1 it may be observed that rabbit ,no4 #abb1 which was fed oats1 died after receiving #bej mg per kilo1 while rabbit ,no4 #bej received the same diet and survived the same dose of caffein per kilo4 ,experiments #bcd and #ccd offer another illustration that the toxicity of caffein is not dependent upon diet1 since both rabbits were fed carrots1 but the same dose of caffein caused only symptoms in one while it proved fatal to the other4 ,it is evident1 therefore1 that the difference in resistance to caffein shown in these experiments is in all probability due to race1 the ,belgian hare being more resistant to caffein than rabbits of other varieties4 ,rabbit ,no4 #cce seems to be an exception1 but the post-mortem examination showed the presence of coccidiosis of the liver4 ,as will be shown later1 wherever this condition prevailed even smaller doses of caffein proved fatal4 ,,series ,d4 ,to obtain additional evidence regarding the resistance of the various races of rabbits to caffein and to ascertain the smallest dose which is surely fatal to the gray rabbit or ,belgian hare was the object of this series of experiments4 ,the diet in all cases consisted of oats1 which was given ad libitum excepting to rabbit ,no4 #bce1 which received carrots for one week previous to the injection of caffein4 ,the doses administered ranged from #bfg to #cjj mg per kilo and were administered to different varieties of adult rabbits4 ,rabbit #bec4 ,brown and black1 male4 ,weight1 #a1fjj grams4 ,diet1 oats1 ,november #i to #ab4 ,november #ab3 #aa4cj a4 m41 urine from bladder acid1 no albumen1 no sugar2 #aa4ce a4 m41 #bb cc #b per cent caffein 7#bge mg per kilo7 injected subcutaneously2 #aa4de a4 m41 rabbit jumped1 off the table1 had convulsions1 retraction of head and opisthotonos1 general tremors1 anterior extremities stretched out1 posterior extremities almost normal1 frequent twitchings2 died at #ab4ae p4 m4 ,rabbit #beb4 ,black1 female4 ,weight1 #a1cce grams4 ,diet1 oats1 ,november #i to #ab4 ,november #ab3 #aa4cj a4 m41 #ah cc #b per cent caffein 7#bgj mg per kilo7 injected subcutaneously4 ,urine obtained from bladder before injection1 acid1 no albumen1 no sugar1 color normal1 tremors and great excitement noticed about #ab noon2 #d4cj p4 m41 when handled1 showed unusual restlessness and excitement followed by convulsions with opisthotonos2 occasional twitching1 condition bad4 ,died #d4ce p4 m4 ,rabbit #cbg4 ,white1 female4 ,weight1 #hbj grams4 ,diet1 oats1 ,march #h to #af4 ,march #af3 #aa4de a4 m41 #ab cc #b per cent caffein 7#bib mg per kilo7 injected subcutaneously in the back2 #b p4 m41 found dead1 but was still warm4 ,autopsy3 ,hemorrhagic area at point of injection into spinal muscles2 subcutaneous abdominal region exhibited a large area of cheesy purulent material2 liver and spleen were engorged2 bladder filled2 intestines normal4 ,rabbit #cdj4 ,white and brown male4 ,weight1 #a1dfe grams4 ,diet1 oats4 ,march #cj3 #c4bj p4 m41 #bj cc of #b per cent caffein 7#bgc mg per kilo7 injected subcutaneously in back4 ,march #ca3 #i a4 m41 found dead4 ,rabbit #cda4 ,white and brown4 ,weight1 #a1dej grams4 ,diet1 oats4 ,march #cj3 #c4bj p4 m41 #bj cc #b per cent caffein 7#bgj mg per kilo7 injected subcutaneously in back2 #d4dj p4 m41 found in dying condition1 had convulsions2 #d4de p4 m41 dead4 ,rabbit #cbf4 ,white1 male4 ,weight1 #a1fde grams4 ,diet1 oats1 ,march #h to #af4 ,march #af1 #aiaj3 #ab noon1 #bj cc #b per cent caffein 7#bdc mg per kilo7 injected subcutaneously in the back2 #b p4 m41 tremors marked1 hypersensitive1 started to run when put on floor2 rabbit was not handled any more than was required for his removal from and return to cage4 ,march #ag3 #i4cj a4 m41 tremors still present and marked1 otherwise general condition good2 no other symptoms4 ,march #ah3 #i4cj a4 m41 no appetite1 tremors still present1 general condition poor2 died about #b p4 m4 ,rabbit #bce4 ,belgian hare1 male4 ,weight1 #a1hgj grams4 ,diet1 carrots1 ,november #b to #i4 ,november #aj3 #aa4je a4 m41 #be cc #b per cent caffein 7#bfg mg per kilo7 injected subcutaneously2 reflexes increased and tremors1 but no tetanus observed2 found dead next morning4 ,rabbit #caf4 ,belgian hare1 female4 ,weight1 #hfj grams4 ,diet1 oats1 ,march #h to #af4 ,march #af1 #aiaj3 #aa4dj a4 m41 #ab cc #b per cent caffein 7#bfg mg per kilo7 injected subcutaneously in the back2 #b4ae p4 m41 reflexes somewhat increased1 but not markedly so2 walked when put on floor2 gait clumsy and slow2 tremors of head observed2 #b4ce p4 m41 rabbit lying in his cage1 posterior extremities extended and rigid1 anterior extremities flexed1 head retracted2 is still breathing2 occasional spasms observed4 ,rabbit died at #c p4 m4 ,autopsy3 ,no lesion at point of injection in dorsal spinal muscles2 liver and spleen engorged2 intestines injected2 other organs apparently normal4 ,rabbit #cie4 ,belgian hare1 male4 ,weight1 #a1daj grams4 ,august #ah3 #a p4 m41 #bj cc #b per cent caffein 7#bhc mg per kilo7 injected subcutaneously in the back2 #d p4 m41 reflexes markedly increased2 #e p4 m41 reflexes about the same1 but no tetanus4 ,august #ai1 #i4ae a4 m43 ,reflexes increased markedly4 ,august #ba1 weight1 #a1bae grams4 ,given #bge mg per kilo of caffein2 no symptoms observed4 ,august #bc1 found dead4 ,autopsy3 ,liver greatly engorged2 stomach fairly well distended and mucous membrane in a slightly inflammatory condition2 contents of small intestine liquid in nature1 but walls of same appeared normal2 other organs normal in appearance4 ,rabbit #cif4 ,belgian hare1 female4 ,weight1 #a1dge grams4 ,diet1 oats4 ,august #ah3 #a p4 m41 #bj cc #b per cent caffein 7#bgb mg per kilo7 injected subcutaneously in the back2 #d p4 m41 reflexes increased markedly2 #e p4 m41 reflexes increased markedly but no tetanus4 ,august #ai3 #aj4cj a4 m41 reflexes still increased very markedly2 rabbit jumps when touched4 ,august #ba3 ,weight1 #a1bde grams4 ,injected subcutaneously #bge mg of caffein per kilo2 reflexes increased1 posterior extremities stiff over hour later4 ,august #bb3 #i a4 m41 found dead4 ,autopsy3 ,thoracic organs normal in appearance2 stomach distended and mucous membrane affected with a catarrhal inflammation2 contents of stomach were covered with a shiny mucus2 contents of small intestine liquid in nature and bile stained2 liver showed a coccidial infestation2 kidneys and spleen normal in appearance4 ,rabbit #cig4 ,belgian hare1 male4 ,weight1 #a1cge grams4 ,diet1 oats4 ,august #ai3 #aj4cj a4 m41 #bj cc #b per cent caffein 7#bij mg per kilo7 injected subcutaneously in the back4 ,august #bb3 #i a4 m41 found dead4 ,autopsy3 ,stomach distended with ingesta2 mucous membrane exhibited a catarrhal inflammation with excessive secretions2 major portion of intestines showed a condition similar to that of stomach1 contents consisting mainly of a shiny mucus2 liver enlarged2 other organs apparently normal4 ,rabbit #cih1 ,belgian hare1 female4 ,weight1 #a1egj grams4 ,diet1 oats4 ,august #ai3 #aj4cj a4 m41 #bc cc #b per cent caffein 7#bic mg per kilo7 injected subcutaneously in the back2 #d p4 m41 found dead4 ,autopsy3 ,thoracic organs seemingly normal2 mucous membrane of stomach exhibited a catarrhal inflammation generally2 large intestines somewhat impacted but walls appeared normal2 other organs normal4 ,rabbit #cii1 ,belgian hare1 male4 ,weight1 #a1gbe grams4 ,diet1 oats4 ,august #ai3 #aj4cj a4 m41 #bf cc #b per cent caffein 7#cjj mg per kilo7 injected subcutaneously in the back2 found dead at #d4cj p4 m4 ,autopsy3 ,lungs slightly congested2 liver engorged and friable2 gall cyst well filled2 stomach exhibited catarrhal gastritis2 injection of mesenteries and intestines2 kidney showed marked cortical congestion4 ,the results of the experiments of this series likewise indicate that the ,belgian hare is more resistant to caffein than the rabbits of other varieties4 ,thus1 of the four gray rabbits 7,nos4 #bce1 #caf1 #cie1 and #cif71 which received #bfg to #bhc mg of caffein per kilo1 two died and two lived1,b one of which1 #cif1 showed the presence of coccidiosis of the liver4 ,on the other hand it will be observed that the black and white rabbits which received from #bgj to #bge mg of caffein per kilo all died from the effects of the drug2 one within #a hour and #be minutes and another within #ej hours after the administration of the caffein1 while ,no4 #cdj died in the night4 ,furthermore it will be noted that of the last three rabbits of this series1 which were ,belgian hares and received #bij1 #bic1 and #cjj mg of caffein1 two died six hours after the injection1 while the other1 ,no4 #cig1 lived three days4 ,the minimum fatal dose of caffein for ,belgian hares is1 therefore1 about #bij to #cjj mg per kilo when injected subcutaneously1 which is about #ej per cent greater than for rabbits of other varieties4 ,b ,survived first dose4 ,,series ,e4 ,it was shown in series ,a that #j4ae caffein per kilo caused symptoms of intoxication4 ,before concluding1 however1 that this is the smallest dose which causes symptoms of poisoning1 a number of experiments were performed with smaller doses4 ,it was found that in the great majority of cases #j4a caffein per kilo may cause diuresis1 but no nervous or muscular symptoms4 ,in some rabbits1 however1 even such a dose proved fatal4 ,post-mortem examinations in these cases showed the presence of coccidiosis of the liver1 and it will be recalled that similar observations were made before4 ,it is quite possible1 therefore1 that coccidiosis of the liver is an important factor in decreasing the resistance to caffein4 ,experiment #eea 7p4 #be7 shows that other conditions may likewise increase the toxicity of caffein4 ,rabbit #cbe4 ,white1 female4 ,weight1 #a1jfe grams4 ,diet1 oats4 ,march #ag3 #aa a4 m41 #f cc #b per cent 7#aab mg per kilo7 caffein injected subcutaneously in the back4 ,about #e cc of urine squeezed out from bladder before injecting caffein4 ,march #ag3 #a p4 m41 hind legs crossed and stretched out1 front legs also extended2 rabbit lying stretched out on her belly4 ,march #ag3 #e4dj p4 m41 rabbit still alive1 condition somewhat improved4 ,march #ah3 #i a4 m41 found dead1 stiff and cold4 ,autopsy3 ,hemorrhagic area at point of inoculation2 subcutaneous region of both thighs presented a hemorrhagic infiltration of the tissues2 liver contained lesions of coccidiosis2 other organs apparently normal4 ,rabbit #ccj4 ,belgian hare1 female4 ,weight1 #ice grams2 poorly nourished4 ,march #ah3 #c4ce p4 m41 #e cc #b per cent caffein 7#ajg mg per kilo7 injected into subcutaneous tissues in the back2 #e4cj p4 m41 no symptoms4 ,march #ai3 #i a4 m41 no symptoms4 ,march #be3 ,weight1 #hbe grams4 ,rabbit #cbi4 ,belgian hare1 male4 ,weight1 #gge grams2 poorly nourished4 ,received ,march #ah4 ,march #ah3 #c4cj p4 m41 #d cc #b per cent caffein 7#ajc mg per kilo7 injected into subcutaneous tissues in the back2 #e4cj p4 m41 no symptoms4 ,march #ai3 #i a4 m41 no symptoms4 ,march #be3 ,rabbit alive in good condition2 weight1 #hbe grams4 ,rabbit #cbj4 ,black1 male4 ,weight1 #a1jdj grams4 ,diet1 oats4 ,march #ag3 #aa a4 m41 #f cc #b per cent caffein 7#aae mg per kilo7 injected subcutaneously in the back2 only a few drops of urine obtained from bladder before injecting caffein2 #a p4 m41 rabbit very restless2 ran away when placed on floor2 cried when touched with a piece of paper2 no tremors observed1 but rabbit became exhausted and was unable to walk2 legs extended out2 after running for about a minute dyspnoea was very marked1 but rabbit soon raised himself on his legs2 #e4dj p4 m41 rabbit up on his legs4 ,march #ah3 #i a4 m41 found dead1 but still warm4 ,autopsy3 ,lungs studded with small grayish white nodules1 adhesions to costal pleura2 probably lesions of coccidiosis2 liver studded with coccidiosis nodules4 ,hemorrhages at point of inoculation4 ,rabbit1 #eea4 ,gray1 female4 ,weight1 ,january #bf1 #a1fej grams4 ,diet1 oats2 fed #bj cc of #be per cent alcohol daily from ,january #bf-ca4 ,january #ca3 ,weight1 #a1dej grams2 #aj4bj a4 m41 temperature #aja4f2 #aj4de1 a4 m41 temperature #aja4f2 received #g cc #b per cent caffein subcutaneously into back2 #aa4ae a4 m41 convulsions of short duration2 raised himself on posterior legs1 anterior legs wide apart2 #d4aj p4 m41 looked normal1 not hypersensitive2 #d4cj p4 m41 condition seemed to be good4 ,february #a3 #i a4 m41 found dead1 was alive at #e4cj p4 m4 of previous day4 ,autopsy3 ,lesions found involved thoracic cavity mainly2 lungs were hepatized and a fibro plastic exudate caused them to adhere to costal pleura2 liver engorged and appeared fatty2 no marked lesions affecting digestive tract1 a slight catarrh of stomach being the only noticeable feature2 kidneys and spleen normal4 ,,table #a4--,subcutaneous injections of caffein--rabbits4 ,,series ,a4 ---------------------------------------- ------------------------ ,caffein ,appearance ,duration ,no4 ,weight4 per of symptoms of life4 ,diet4 ,remarks4 kilo in-- ---------------------------------------- ------------------------ ,grams4 ,mg4 #ccb #a1jgj #aeh #a hour ,survived ,oats ,gray4 #de minutes #cca #a1agj #aec do4 do4 do4 ,do4 #cbh #a1bjj #aej do4 do4 do4 ,do4 #cbb #a1jfe #aej #a hour do4 do4 ,white4 #bag #a1cee #adg do4 do4 ,do4 #bai #a1hbj #aec do4 do4 ,maltese4 #aid #a1dij #agd do4 do4 ,white4 #aia #a1iae #afg do4 do4 ,light brown4 ---------------------------------------- ------------------------- ,,series ,b1 ,,group ,i4 ---------------------------------------- -------------------------- #ie #a1dgh #baj #b hours #c hours ,oats ,white4 #ej minutes #aj minutes #if #a1ehe #bjj #a hour ,about #ah hours do4 ,gray white4 #aab #hge #bje #cj minutes do4 do4 ,black4 #aai #a1jfj #ahh do4 do4 ,yellow white4 #aie #a1cjj #bjj #c hours ,carrots,white4 #aj minutes #bjh #a1jfh #ahh #b hours ,about #bd hours do4 ,gray4 ---------------------------------------- -------------------------- ,,series ,b1 ,,group ,,ii4 ---------------------------------------- ------------------------ #bdg #a1bie #bjj #b4e hours ,survived ,oats ,gray4 #bdh #a1cje #bjj #c hours do4 do4 ,do4 #ccg #a1jdj #baa #a4e hours do4 ,carrots ,do4 #ccf #a1jde #baa do4 do4 do4 ,do4 ---------------------------------------- ------------------------ ,,series ,c4 ---------------------------------------- ------------------------- #abb #b1jfj #bej #b hours #a4e days ,oats ,white4 #ee minutes #bcd #a1fej #bdb ,about #bd hours,carrots ,do4 #cce #a1agj #bdj #a hour do4 do4 ,gray coccidiosis4 #bdi #a1ahe #bcf #d hours ,survived ,oats ,gray4 #cba #a1ace #bdf #b hours do4 do4 ,yellow4 #aj minutes #bej #a1dce #beb #d hours do4 do4 ,gray4 #ce minutes #ccd #a1bgj #bdj #a hour do4 ,carrots ,do4 #bcc #a1fge #bch #f hours #bf hours do4 ,white4 #aj minutes ---------------------------------------- ------------------------- ,,series ,d4 ---------------------------------------- ------------------------ #bec #a1fjj #bge #aj minutes #ce minutes ,oats ,brown and black4 #beb #a1cce #bgj #cj minutes #d hours do4 ,black4 #ee minutes #cbg #hbj #bib #b hours do4 ,white4 #ae minutes #cdj #a1dfe #bgc ,about #ah hours do4 ,white and brown4 #cda #a1dej #bgj #a hour do4 ,do4 #be minutes #cbf #a1fde #bdc #b hours #ej hours do4 ,white4 #bce #a1hge #bfg #bj hours ,carrots,gray4 #caf #hfj #bfg #b hours #c hours ,oats ,do4 #de minutes #bj minutes #cie #a1daj #bhc #c hours ,survived ,do4 #cie #a1bae #bge do4 ,about #b days ,oats ,do4 #cif #a1dge #bgb do4 ,survived do4 ,do4 #cif #a1bde #bge #a hour ,about #ah hours do4 ,do4 #cig #a1cge #bij #c days do4 ,do4 #cih #a1egj #bic #e4e hours do4 ,do4 #cii #a1gbe #cjj #f hours do4 ,do4 ---------------------------------------- ------------------------ ,,series ,e4 ---------------------------------------- ------------------------- #cbe #a1jfe #aab #b hours ,less than ,oats ,white female4 #bb hours #ccj #ice #ajg ,none ,survived ,gray4 #cbi #gge #ajc do4 do4 ,gray male4 #cbj #a1jdj #aae #b hours #df hours ,oats ,black male4 #eea #a1dej #ajj #cj minutes ,less than do4 ,gray female4 #bd hours ---------------------------------------- ------------------------- ,,administration ,,by ,,mouth4 ,these experiments were carried out on two varieties of rabbits1 the white and the gray4 ,the diet consisted chiefly of oats1 but in a few cases carrots formed the exclusive diet4 ,food and water were given ad libitum4 ,a #b per cent solution of caffein was administered through a stomach tube4 ,since the resistance to most drugs is commonly supposed to be greater when given by mouth than when administered by any other path1 doses of #age to #bjj mg per kilo were fed in a series of preliminary experiments1 all of which were performed on gray rabbits weighing from #hfe to #a1ace grams1 and which were fed carrots for several days previous to the experiment4 ,three of the rabbits survived1 two without showing any symptoms2 in the other case paralysis of the posterior extremities was observed five hours after he received caffein and he was found dead the next morning4 ,unfortunately no autopsy was performed4 ,the low resistance to caffein of this animal was probably due to some abnormal condition which developed about the time of the experiment1 since this rabbit received #cbe mg of caffein per kilo two weeks previously and increased reflexes only were observed as a result of this treatment4 ,hence #bjj mg of caffein per kilo can not be considered the toxic dose when fed by mouth4 ,in the following experiments larger doses were therefore given4 ,,series ,a4 ,rabbit #bdh4 ,belgian hare4 ,weight1 #a1agj grams4 ,diet1 oats4 ,november #ag3 #a4bj p4 m41 #ai4e cc #b per cent caffein 7#ccj mg per kilo7 administered by the mouth2 #d4cj p4 m41 somewhat hypersensitive4 ,november #ai3 ,no symptoms2 at #i a4 m41 urine collected1 no reduction of ,fehling's solution2 rabbit survived4 ,rabbit #bda4 ,white male4 ,weight1 #a1chj grams4 ,diet1 oats4 ,november #ag3 #a4ae p4 m41 #bj cc #b per cent caffein 7#bij mg per kilo7 administered by the mouth2 #d4cj p4 m41 some hypersensitiveness1 but no other symptoms4 ,november #ah3 #i a4 m41 urine collected1 no reduction of ,fehling's solution2 no symptoms2 rabbit survived4 ,rabbit #bdi4 ,belgian hare4 ,weight1 #hij grams4 ,diet1 oats4 ,november #ag3 #a4cj p4 m41 #ad4e cc #b per cent caffein 7#cbe mg per kilo7 administered2 #d4cj p4 m41 hypersensitiveness2 no other symptoms4 ,november #ah3 #aj a4 m41 no symptoms2 urine collected1 no reduction2 rabbit survived4 ,,series ,b4 ,the object of these experiments was to determine the minimum fatal dose of caffein in the two varieties of rabbits1 the white and the gray4 ,all of the animals selected were approximately of the same weight4 ,rabbit #bci4 ,belgian hare1 male4 ,weight1 #ice grams4 ,diet1 oats4 ,november #ai3 #d p4 m41 #ag cc #b per cent caffein 7#cfc mg per kilo7 administered by mouth1 followed by #aj cc of #j4i per cent salt solution4 ,november #bj3 ,urine examined1 no sugar found1 no symptom noticed at any time after injection4 ,rabbit #bed4 ,belgian hare1 female4 ,weight1 #ige grams4 ,diet1 oats4 ,november #ai3 #d4je p4 m41 #ah cc #b per cent caffein 7#cfi mg per kilo7 administered by mouth1 followed by #aj cc of #j4i per cent salt solution4 ,november #bj3 #i a4 m41 rabbit found dead4 ,rabbit #bfg4 ,white4 ,weight1 #a1jej grams4 ,diet1 oats4 ,november #bc3 #ab4aj p4 m41 #ah cc #b per cent caffein 7#cdb mg per kilo7 given by mouth1 followed by #ah cc salt solution2 #a p4 m41 increased reflexes1 tremors marked but no tetanus2 #a4je p4 m41 rabbit stretched on abdomen1 posterior extremities in extended position and paralyzed1 soon after clonic spasms set in1 which recurred about every minute2 #a4ad p4 m41 tetanus and death4 ,autopsy3 ,liver showed fatty degeneration2 slight inflammation of stomach and intestines2 other organs normal4 ,rabbit #bfh4 ,white4 ,weight #a1ajj grams4 ,diet1 oats4 ,november #bc3 #bj cc #b per cent caffein 7#cfc mg per kilo7 administered by mouth1 followed by #bj cc salt solution2 #a4ae p4 m41 somewhat hypersensitive2 #d4cj p4 m41 tremors fairly marked1 no urine passed1 about #b cc of bloody looking urine obtained from bladder1 which contained albumen and a considerable amount of glycogen2 rabbit died4 ,rabbit #dai1 ,belgian hare1 male4 ,weight1 #a1fjj grams4 ,diet1 oats4 ,september #bf3 #aj a4 m41 #bh cc #b per cent caffein 7#cej mg per kilo7 given by mouth2 reflexes increased at #d p4 m42 #f p4 m41 reflexes still increased1 no other symptoms4 ,september #bg3 #i a4 m41 found dead4 ,autopsy3 ,lungs1 liver1 and kidneys congested2 other organs normal4 ,rabbit #dbj4 ,belgian hare1 male4 ,weight1 #a1bej grams4 ,diet1 oats4 ,september #bf3 #aj a4 m41 #bb cc #b per cent caffein 7#ceb mg per kilo7 given by mouth2 #aa4ce a4 m41 convulsions2 #ab noon1 found dead4 ,autopsy3 ,liver showed very extensive coccidiosis2 no other lesions4 ,rabbit #dba4 ,belgian hare1 male4 ,weight1 #a1dhe grams4 ,diet1 oats4 ,september #bf3 #aj a4 m41 #bf cc #b per cent caffein 7#cea mg per kilo7 administered by mouth2 #d p4 m41 reflexes increased2 #f p4 m41 reflexes as before1 no tetanus observed4 ,september #bg3 #i a4 m41 rabbit found dead4 ,autopsy3 ,congestion of lungs and kidneys2 liver congested and slightly fatty4 ,rabbit #dbd4 ,white1 male4 ,weight1 #a1bie grams4 ,diet1 oats4 ,september #bf3 #b p4 m41 #ai cc #b per cent caffein 7#bic mg per kilo7 administered by mouth2 #d p4 m41 reflexes increased1 no other symptoms2 #f p4 m41 no change since #d p4 m4 ,september #bg3 #ab noon1 convulsions and death4 ,autopsy3 ,congestion of the lungs2 no other lesions4 ,rabbit #dbc4 ,white1 male4 ,weight1 #a1bje grams4 ,diet1 oats4 ,september #bf3 #b p4 m41 #ah cc #b per cent caffein administered by mouth2 #d p4 m41 reflexes increased1 no tetanus2 #f p4 m41 condition unchanged since #d p4 m4 ,september #bg3 #i a4 m41 found dead4 ,autopsy3 ,lungs1 liver1 and kidneys congested2 other organs normal4 ,rabbit #dbb4 ,white1 male4 ,weight1 #a1ddj grams4 ,diet1 oats4 ,september #bf3 #b p4 m41 #ba cc #b per cent caffein 7#bia mg per kilo7 given by mouth2 reflexes increased at #d p4 m4 ,september #bg3 #c p4 m41 alive1 no symptoms2 #d p4 m41 convulsions with recovery1 this was soon followed by a violent attack of tetanus1 which lasted about one minute and was succeeded by paralysis2 rabbit died at #d4cj4 ,autopsy3 ,liver slightly congested2 a small portion of the intestine showed congestion and edema2 other organs normal4 ,a study of these experiments shows also considerable variation in the toxicity of caffein when given by mouth4 ,in some cases a dose of #cjj mg per kilo1 and even less1 caused death1 as in rabbits #dbc and #dbd4 ,in other rabbits1 however1 approximately the same doses of caffein produced increased reflexes only4 ,the same symptoms were produced in ,nos4 #bdh and #bdi after the administration of #cbe-ccj mg of caffein per kilo1 while another rabbit 7,no4 #bci7 survived a dose of #cfc mg per kilo4 ,that this is exceptional1 however1 appears from the result of the following experiments on rabbits ,nos4 #dai1 #dbj1 and #dba1 all of which died after receiving #cej mg of caffein per kilo1 and rabbits #bfg and #bfh1 to which doses of #cfc and #cdb mg1 respectively1 per kilo proved fatal4 ,it will be observed further that the gray rabbits are more resistant to caffein than the white animals1 as #cej mg per kilo was the smallest fatal dose for rabbits #dai1 #dbj1 and #dba1 all of which were gray rabbits1 while a dose of #bij mg per kilo was fatal for some of the white rabbits4 ,again1 it will be noticed that of the two gray rabbits1 ,nos4 #bed and #bci1 which received the largest doses in these experiments1 namely1 #cfi and #cfc mg1 respectively1 one survived4 ,the largest doses given to the white rabbits were #cfc and #cdb mg caffein per kilo4 ,both of these died from the effects of the drug4 ,it may be concluded1 therefore1 that the minimum toxic dose for the gray rabbit is about #cbe mg of caffein per kilo1 and the minimum fatal dose is at least #cej mg per kilo4 ,it is to be remarked in this connection that post-mortem examination showed extensive coccidiosis in rabbit #dbj and fatty liver in ,no4 #dba1 while the macroscopical examination of the organs of ,nos4 #dbd and #dbc failed to show the presence of such abnormalities4 ,since1 as was observed in the section on subcutaneous injection and elsewhere in this investigation1 pathological changes are apt to decrease the resistance to caffein1 it is quite possible that #cej mg per kilo is not the minimum fatal dose for the normal rabbit4 ,indeed1 the experiment on rabbit #bci lends support to this view1 thus furnishing additional evidence of difference in the resistance to caffein in the two varieties of rabbits4 ,,table #b4--;,administration of caffein by mouth4 ,,series ,a4 ---------------------------------------- ------------------------ ,rabbit ,caffein ,duration ,no4 ,weight4 per ,symptoms of life4 ,diet4 ,remarks4 kilo4 ---------------------------------------- ------------------------ ,grams4 ,mg4 #bdh #a1agj #ccj #c hours ,survived ,oats ,gray4 #aj minutes #bda #a1chj #bij #b hours do4 do4 ,white male4 #ae minutes #bdi #hij #cbe #c hours do4 do4 ,gray male4 ---------------------------------------- ------------------------ ,,series ,b4 ---------------------------------------- ------------------------ #bci #ice #cfc ,survived ,oats ,gray male4 #bed #ige #cfi ,about #b days do4 ,gray female4 #bfg #a1jej #cdb #ej minutes #a hour do4 ,white4 #d minutes #bfh #a1ajj #cfc ,about #c hours do4 ,do4 #dai #a1fjj #cej #f hours ,less than do4 ,gray male4 #bd hours #dbj #a1bej #ceb #a hour #b hours do4 ,do4 #ce minutes #dba #a1dhe #cea #f hours ,less than do4 ,do4 #bd hours #dbd #a1bie #bic #b hours #bb hours do4 ,white male4 #dbc #a1bje #cjj do4 ,less than do4 ,do4 #ai hours #dbb #a1ddj #bia do4 #b hours do4 ,do4 ---------------------------------------- ------------------------- ,,injection ,,into ,,the ,,peritoneal ,,cavity4 ,in a number of experiments caffein was introduced into the peritoneal cavity4 ,rabbits of different varieties receiving a diet of oats or carrots were employed for this purpose2 food and water were given ad libitum4 ,the minimum doses required to induce symptoms or cause death in these animals were determined2 tests with caffein were also made on young rabbits in order to study the influence of age on the resistance to this substance4 ,the results are shown in the following experiments3 ,,series ,a4 ,in this series large doses were administered1 approximating #j4c gram per kilo4 ,rabbit #ga4 ,gray female4 ,weight1 #a1fei grams4 ,january #bj3 #b4bj p4 m41 #be cc aqueous solution #b per cent caffein 7#cjj mg per kilo7 were injected into the peritoneal cavity2 #c4de p4 m41 when doors of cage were opened rabbit had spasm of short duration4 ,january #ba3 ,rabbit found dead4 ,rabbit #gb4 ,gray and white4 ,weight1 #a1djb grams4 ,january #ba3 #aa4ag a4 m41 #bj4b cc 7aqueous solution7 of #b per cent caffein 7#cjj mg per kilo7 injected into peritoneal cavity from burette2 #aa4be a4 m41 paralysis2 #aa4cj a4 m41 rabbit had convulsion when picked up from the floor1 followed by several spasms later2 #aa4ce a4 m41 typical tetanus2 #ab4cj noon1 found dead4 ,rabbit #fa4 ,black female4 ,weight1 #b1adc grams4 ,january #ai3 #dj cc #b per cent caffein1 aqueous solution 7#cjj mg per kilo71 injected into peritoneal cavity from burette2 tetanus when about #cj cc were injected2 when removed from holder1 repeated and violent convulsions1 terminating in death4 ,,series ,b4 ,the object of these experiments was to determine the minimum lethal dose2 #j4b to #j4ae gram of caffein per kilo was injected into the rabbits of this series4 ,rabbit #fi4 ,white female4 ,weight1 #a1gad grams4 ,january #bj3 #aj4ae a4 m41 #f cc #b per cent caffein1 aqueous solution1 injected into peritoneal cavity4 ,no symptoms1 under observation for #de minutes1 rabbit defecated rather copiously2 feces were soft2 #aa a4 m41 #f cc #b per cent caffein1 aqueous solution1 injected into peritoneal cavity1 no symptoms1 under observation for #dj minutes2 #aa4dj1 #f cc #b per cent caffein injected into peritoneal cavity2 #aa4de1 rabbit is restless1 reflexes increased4 ,rabbit #gj4 ,gray and white female4 ,weight1 #a1dhg grams4 ,january #bj3 #a4cj p4 m41 #ae cc #b per cent aqueous solution of caffein 7#j4b gram per kilo7 injected into the peritoneal cavity2 #b4bj p4 m41 no symptoms4 ,january #cj3 ,about #b p4 m4 rabbit died4 ,february #a3 ,autopsy3 ,cirrhosis of the liver2 enteritis of small intestines2 stomach and kidneys normal4 ,rabbit #ic4 ,maltese1 male4 ,weight1 #a1aig grams4 ,march #b3 #aa4cj a4 m41 #ab cc of #b per cent caffein 7#bjj mg per kilo7 injected into peritoneal cavity2 #aa4ce a4 m41 while being released from holder1 tetanus occurred1 repeated attacks later1 clonic convulsions with tonic rigidity of posterior extremities during the attacks as well as during intervals1 anterior extremities were relaxed during the intervals between the attacks1 opisthotonos of cervical region but kyphosis in lumbar region were observed1 no salivation nor dilatation of the pupils2 #b p4 m41 rabbit died4 ,rabbit #ib4 ,yellow female4 ,weight1 #a1chh grams4 ,february #be1 #d4ae p4 m41 #ad cc #b per cent caffein 7#j4b gram per kilo7 injected into peritoneal cavity2 #d4bj p4 m41 restlessness and increased reflexes1 rabbit found stretched out in cage1 but raised himself on his legs again2 #d4de1 general tremor when touched4 ,february #bf3 #i a4 m41 rabbit found dead4 ,autopsy3 ,hemorrhage into abdominal muscles at site of injection2 hemorrhage also in walls of stomach opposite similar spot in abdominal wall4 ,rabbit #cji4 ,belgian hare1 female4 ,weight1 #a1ejj grams4 ,diet1 oats4 ,march #b3 #b4je p4 m41 #b per cent caffein solution 7#j4b gram per kilo7 injected into peritoneal cavity2 #b4be p4 m41 found dead1 no urine found in bladder4 ,rabbit #cjg4 ,belgian hare1 female4 ,weight1 #a1cbj grams4 ,diet1 oats4 ,march #b3 #ab noon1 urine obtained from bladder1 clear amber colored1 no albumin1 no reduction2 #ab4jf p4 m41 #aj cc of #b per cent caffein 7#j4aea gram per kilo7 injected into peritoneal cavity2 #a4cj p4 m41 rabbit placed on floor1 runs around but anterior and posterior extremities soon extended1 in tonic condition2 #b4be p4 m41 reflexes increased1 paralysis of extremities1 dyspnoea2 #d4ej p4 m41 about #ajj cc urine collected1 no albumin1 reduction of ,fehling's solution moderate4 ,march #c3 #i4cj a4 m41 posterior extremities extended and rigid1 anterior extremities paralyzed1 respiration less frequent and deeper than normal4 ,rabbit died at #aa4ej a4 m42 urine collected since #d4ej p4 m4 previous day gave very heavy reduction of ,fehling's solution4 ,autopsy3 ,animal in good condition2 in the left axillary region was observed a hemorrhage into the subcutaneous and muscular tissue of that region4 ,the ventral portion of the large colon1 in contact with the ventral abdominal wall1 showed a hemorrhagic area about one-half inch in length1 such as might be produced by a puncture or bruise of the colon through the abdominal wall4 ,a small portion of the small intestine adjacent to the colon was affected in a similar manner4 ,all internal organs were apparently normal4 ,rabbit #cjh4 ,belgian hare1 female4 ,weight1 #a1cej grams4 ,diet1 oats4 ,march #b3 #aa4de a4 m41 urine obtained from bladder1 no albumen1 no reduction2 #aa4ej a4 m41 #aj cc #b per cent caffein 7#j4ae gram per kilo7 injected into peritoneal cavity2 #a4cj p4 m41 not very active1 no abnormal symptoms otherwise2 #c4cj p4 m41 rabbit looked depressed1 made very little attempt to move about1 remained in one position most of the time when placed on floor2 #d4cj p4 m41 #ahj cc urine collected1 no albumen1 reduction of ,fehling's solution moderate4 ,march #c3 #i4cj a4 m41 rabbit looks normal1 is able to walk but is easily fatigued when made to walk about or when placed on his side1 followed by paralysis of anterior extremities1 posterior extremities apparently normal1 about #ij cc of urine collected at noon was free from albumen1 did not reduce ,fehling's solution4 ,march #d3 #aa a4 m41 lying on his side in cage1 anterior extremities limp1 posterior extremities extended and rigid1 is in dying condition4 ,march #e3 #i a4 m41 found dead4 ,autopsy3 ,liver engorged2 spleen congested1 but not enlarged2 kidneys1 some congestion in cortex2 stomach filled1 mucosa thickened and easily pulled off2 petechial hemorrhages on serosa of colon4 ,,series ,c4 ,the experiments of this series were made to determine the minimum toxic dose4 ,rabbit #bie4 ,belgian hare1 female4 ,weight1 #a1bje grams4 ,diet1 carrots4 ,march #a3 #aj4dj a4 m41 #f cc #b per cent caffein 7#j4a gram per kilo7 injected into peritoneal cavity2 about #b cc of urine obtained before injecting caffein2 #b p4 m4 #ajj cc urine1 bloody in appearance1 collected1 a moderate quantity of albumen present1 no reduction2 #c4dj p4 m41 no symptoms4 ,march #d3 #b p4 m41 rabbit looks well4 ,rabbit #bic4 ,belgian hare1 female4 ,weight1 #a1fje grams4 ,diet1 carrots4 ,march #a3 ,urine from bladder clear1 alkaline2 #aa4ee a4 m41 #h cc #b per cent caffein 7#j4a gram per kilo7 injected into peritoneal cavity2 #c p4 m41 #ij cc urine normal in color collected1 no albumen1 no reduction2 #c4dj p4 m41 no symptoms4 ,march #d3 #a4ae p4 m41 rabbit looks normal4 ,rabbit #bib4 ,belgian hare1 male4 ,weight1 #a1eie grams4 ,diet1 carrots4 ,march #a3 #aj4aj a4 m41 #h cc #b per cent caffein 7#j4a gram per kilo7 solution injected into peritoneal cavity2 #aj4dj a4 m41 rabbit urinated1 reflexes increased1 but no other symptoms2 #aj4ej a4 m41 no urine obtained from bladder2 #b p4 m41 #aje cc of clear pale urine collected2 no albumen1 no reduction2 #c4dj p4 m41 no symptoms4 ,march #d3 #b p4 m41 rabbit looks well1 urine collected1 did not contain sugar4 ,rabbit #bih4 ,belgian hare1 female4 ,weight1 #a1bje grams4 ,diet1 carrots4 ,march #a3 #d4jf p4 m41 #g4e cc #b per cent caffein solution 7#j4abe gram per kilo7 injected into peritoneal cavity1 urine obtained from bladder immediately after injection1 no albumen1 no reduction2 #e4cj p4 m41 reflexes increased1 rabbit was able to run around1 but became paralyzed soon2 #e4dj p4 m41 rabbit is again able to run around4 ,march #c3 #aj a4 m41 anterior extremities paralyzed1 is able to use posterior extremities4 ,march #d3 #a p4 m41 rabbit looks normal4 ,rabbit #bbc4 ,belgian hare1 male4 ,weight1 #a1afe grams4 ,diet1 carrots4 ,march #a3 #c4ej p4 m41 urine obtained from bladder clear1 amber colored1 no albumen1 no sugar2 #c4eb p4 m41 #g4e cc #b per cent caffein 7#abe mg per kilo7 injected into peritoneal cavity2 #e4dj p4 m41 rabbit makes little attempt to run when put on the floor1 weakness of extremities marked4 ,march #d3 #a4ae p4 m41 rabbit normal4 ,,series ,d4 ,the object of the experiments of this series was to study the effect of age on the resistance to caffein4 ,half-grown rabbits were1 therefore1 used in the following experiments4 ,rabbit #caj4 ,belgian hare1 female4 ,weight1 #hhj grams4 ,diet1 oats4 ,march #b3 #c4be p4 m41 #i cc #b per cent caffein 7#j4b gram per kilo7 injected into peritoneal cavity4 ,march #c3 #i4cj a4 m41 no symptoms1 rabbit looks normal4 ,march #d3 #aa a4 m41 posterior extremities abducted1 walked when placed on the floor1 made no attempt to change attitude when placed on its side1 remained some time in this position4 ,march #e3 #i a4 m41 found dead4 ,autopsy3 ,liver showed areas of degeneration2 kidneys congestion and petechial hemorrhage on cortex2 small and large intestines1 inflammation marked2 bladder distended4 ,rabbit #ge4 ,gray and white1 female4 ,weight1 #hdb grams4 ,january #be3 #c p4 m41 #h4e cc #b per cent caffein solution 7#j4b gram per kilo7 injected into peritoneal cavity2 #c4ae p4 m41 anterior extremities weak and reflexes increased4 ,january #bg3 ,rabbit paralyzed but is able to turn over when placed on back4 ,rabbit #gd4 ,gray and white1 female4 ,weight1 #fib grams4 ,january #be3 #c p4 m41 #g cc #b per cent caffein 7#j4b gram per kilo7 solution injected into peritoneal cavity2 #c4ae p4 m41 reflexes increased and anterior extremities paralyzed4 ,january #bg3 ,rabbit recovered and is able to walk about in the room4 ,rabbit #cab1 maltese1 female4 ,weight1 #gdj grams4 ,diet1 oats4 ,march #c3 #aa4dg a4 m41 urine obtained from bladder1 appearance normal1 no albumen1 no reduction of ,fehling's solution2 #aa4ej a4 m41 #g4e cc #b per cent caffein 7#j4b gram per kilo7 injected into peritoneal cavity2 #b4cj p4 m4 anterior extremities paralyzed1 posterior extremities rigid and extended2 #e p4 m4 7about71 rabbit died4 ,rabbit #caa4 ,belgian hare1 female4 ,weight1 #fej grams4 ,diet1 oats4 ,march #c3 #aa4bf a4 m41 urine obtained from bladder normal in appearance1 albumen considerable1 reduction of ,fehling's solution none2 #aa4bg a4 m41 #f cc #b per cent caffein solution 7#j4b gram per kilo7 injected into peritoneal cavity2 #b4cj p4 m41 rabbit seemed to be normal1 no symptoms had developed2 urine collected contained a large amount of sugar1 reduction was very heavy1 but no albumen was found4 ,march #d3 #aa a4 m41 condition good1 moves about when put on floor2 gait1 normal4 ,rabbit #gh4 ,yellow and white4 ,weight #fei grams4 ,january #bf3 #a4cj p4 m41 #h4e cc #b per cent caffein 7#bej mg per kilo7 injected into peritoneal cavity1 under observation the rest of the afternoon1 no symptoms4 ,january #bg3 #d p4 m41 no symptoms developed4 ,rabbit #cag4 ,belgian hare1 female4 ,weight #fce grams4 ,diet oats4 ,march #ae3 #aj4ce a4 m41 #h cc #b per cent caffein 7#j4beb gram per kilo7 injected into peritoneal cavity2 #ab noon1 marked abduction of hind legs1 was unable to walk after a little exertion1 rabbit died between #ab4cj and #ab4ej p4 m4 ,autopsy4 ,right lung hepatized and showed adhesions to costal and mediastinal pleura2 liver studded with nodules of coccidiosis2 spleen congested2 stomach filled1 mucosa normal2 intestines injected2 colon hemorrhagic on serosa in ventral region1 near point of injection2 kidneys normal4 ,rabbit #cbc4 ,white1 female4 ,weight #hbj grams4 ,diet oats4 ,march #ae3 #aj4de a4 m41 #aj cc #b per cent caffein 7#bej mg per kilo7 injected into peritoneal cavity2 #ab noon1 reflexes increased1 hind legs abducted but is able to walk1 symptoms are mild2 #a4dj p4 m41 tremors1 weakness1 and abduction of head and legs much more marked than at #ab noon4 ,march #af3 ,condition good4 ,march #ag3 ,condition good1 recovery apparently complete4 ,since the experiments of ,series ,a1 which were intended as preliminary tests1 have shown that #j4c gram of caffein per kilo when introduced into the peritoneal cavity is rapidly absorbed and is fatal1 much smaller doses were employed in subsequent trials with the drug4 ,this is shown in series ,b1 which may be divided into two groups4 ,group ,i1 consisting of rabbits #fi1 #gj1 #ib1 #ic1 and #cji1 which received #j4b gram of caffein per kilo1 and ,group ,,ii1 ,nos4 #cjg and #cjh1 into which #j4ae gram of caffein per kilo was injected4 ,three rabbits of ,group ,i 7,nos4 #ib1 #ic1 #cji7 died from the effects of caffein2 rabbit #cji twenty minutes after injection1 and rabbits ,nos4 #ib and #ic1 twenty hours and two and one-half hours1 respectively1 after the administration of caffein4 ,in both of these rabbits symptoms appeared within five minutes after the injections were made4 ,rabbits #fi and #gj1 it will be noticed1 survived the same amount of caffein in proportion to body weight as was given to the other members of this group4 ,increased peristalsis and the distribution of the dose may account for the greater resistance of rabbit ,no4 #fi4 ,the case of rabbit ,no4 #gj is evidently one of exceptional resistance to caffein1 since both the rabbits of ,group ,,ii died from the effects of a much smaller dose1 namely1 #j4ae gram of caffein per kilo4 ,moreover1 macroscopical examination at the autopsy of ,nos4 #cjg and #cjh failed to show any lesions which might tend to lessen the resistance to caffein4 ,that a dose of #j4ae gram per kilo is therefore in all probability the minimum fatal dose for the rabbit when injected into the peritoneal cavity appears from the results of the experiments in series ,c1 in which smaller doses1 #j4abe gram of caffein per kilo caused mild symptoms only1 while #j4a gram per kilo rarely induced any symptoms4 ,it may be remarked that the rabbits of series ,c were fed carrots while rabbits ,nos4 #cjg and #cjh received oats4 ,their resistance to caffein may be different1 but1 as was pointed out in the earlier part of this investigation1 diet does not seem to influence the toxicity of the single dose of caffein4 ,doses of #aej and of #ajj to #abe mg per kilo1 when injected into the peritoneal cavity1 may be considered1 respectively1 as the minimum fatal and minimum toxic doses for the gray rabbit4 ,analysis of the experiments in series ,d shows much greater resistance to caffein than in the other rabbits which received it intraperitoneally4 ,thus1 after the administration of #j4b gram per kilo to each of five rabbits1 no effect was observed in two cases 7,nos4 #caj1 #caa71 while in two others 7,nos4 #gd1 #ge7 symptoms developed1 but they survived4 ,only one rabbit1 ,no4 #cab1 died from the effects of this dose2 the autopsy showed the presence of degeneration of the liver and petechial hemorrhages on the cortex of the kidneys in the case of ,no4 #caj1 which was probably the cause of death rather than the caffein4 ,two decigrams of caffein can not be considered1 therefore1 the fatal dose for rabbits4 ,this is further corroborated by the results obtained in experiments with larger doses4 ,rabbit #gh1 which received #beg mg per kilo1 failed to show any symptoms4 ,the same amount in proportion to body weight in ,no4 #cbc caused mild symptoms only1 while the rapid death of rabbit ,no4 #cag after the same dose of caffein may be explained by the lesion found at autopsy1 thus affording additional evidence that disease may decrease the resistance to caffein4 ,it will be observed that all the members of this series were young rabbits and1 as will be shown later1 young animals of other species are likewise more resistant to caffein than adult animals4 ,similar results were obtained by von ,anrep1 who observed that atropin is less toxic in young than in full-grown animals4 ,observations were also made on the diuretic effect of caffein when injected into the peritoneal cavity4 ,the results shown in the following table indicates the stimulating effect on renal secretion whether the diet consisted of oats or of carrots4 ,the urine of some rabbits contained moderate amounts of sugar after from #j4b to #j4ae gram of caffein per kilo was given2 albumen was observed in one case1 but in none of the others4 ,in rabbit ,no4 #caa albumin was found before the injection of caffein1 but none in the urine which was collected three hours after caffein was injected4 ,effect of caffein on renal secretion4 ---------------------------------------- ------------------ ,no4 ,weight4 ,caffein ,urine4 ,time4 ,diet4 per kilo4 ---------------------------------------- ------------------ ,grams4 ,gram4 cc4 #cjg #a1cbj #j4aej #ajj #d4e hours ,oats4 #cjh #a1cje 4#aej #ahj do4 ,do4 #bie #a1bje 4#ajj #ajj #b hours #bj minutes ,carrots4 #bic #a1fje 4#ajj #ij #c hours ,do4 #bib #a1eie 4#ajj #aje #d hours ,do4 ---------------------------------------- ------------------ ,,note4--,the amount of urine secreted in three hours by control rabbits1 on a carrot diet1 varied between #ce and #ej cc1 the average weight of the animals being a little above #a1fjj grams4 ,the secretion of urine on an oat diet was much less for an equal period of time4 ,,table #c4--;,intraperitoneal injections4 ,,series ,a4 ---------------------------------------- ------------------------- ,caffein ,time of ,duration ,no4 ,weight4 per appearance of life4 ,remarks4 kilo4 of symptoms4 ---------------------------------------- ------------------------- ,grams4,gram4 #ga #a1fei #j4c #he minutes #bd hours ,gray4 #fa #b1adc 4#c ,at the end of ,black4 injection #gb #a1djb 4#c #h minutes #a4be hour ,gray and white4 ---------------------------------------- ------------------------- ,,series ,b1 ,,group ,i4 ---------------------------------------- ------------------------- #gj #a1dhg #j4b #aj days ,gray and white4 #ic #a1dib 4#b #e minutes #b4e hours ,maltese2 given second dose after #c days1 died #b4e hours later4 #fi #a1dib 4#b ,about ,survived ,white4 #e minutes #ib #a1chh 4#b #e minutes #bd hours ,yellow4 #cji #a1ejj 4#b #bj minutes ,belgian2 oats4 ---------------------------------------- ------------------------- ,,series ,b1 ,,group ,,ii4 ---------------------------------------- ------------------------- #cjh #a1cej #j4ae #c hours and ,about #b4e days,belgian2 oats4 #dj minutes #cjg #a1cbj 4#ae #a hour #bd hours ,do4 #bd minutes ---------------------------------------- ------------------------- ,,series ,c4 ---------------------------------------- ------------------------- #bbc #a1afe #j4abeb hours ,survived ,belgian2 carrots4 #bic #a1fje 4#a do4 ,do4 #bie #a1bje 4#a do4 ,do4 #bib #a1eie 4#a do4 ,do4 #bih #a1bje 4#abea4e hours do4 ,do4 ---------------------------------------- ------------------------- ,,series ,d4 ---------------------------------------- ------------------------- #caj #hhj #j4b #b days7#a7 ,about ,belgian2 oats4 #b4e days7#a7 #caa #fej 4#b ,survived ,do4 #cab #gdj 4#b #dj minutes #d4e hours ,maltese2 oats4 #gh #fei 4#begae minutes ,survived ,yellow and white2 oats4 #ge #hdb 4#b do4 do4 ,gray and white4 #gd #fib 4#b do4 do4 #cag #fce 4#beba hour ,about #b hours ,belgian2 oats4 #be minutes #cbc #hbj 4#be #a hour ,survived ,white2 oats4 #ae minutes ---------------------------------------- ------------------------- 7#a7 ,not due to caffein4 ,,intramuscular ,,injection4 ,well-fed rabbits1 which received a diet exclusively of oats1 were used for these experiments4 ,the injections were made into the lumbar or into the gluteal muscles4 ,,series ,a4 ,in this series the caffein was injected into the gluteal muscles4 ,rabbit #bhd4 ,brown and white1 female4 ,weight1 #a1ajj grams4 ,december #ad3 #b p4 m41 #aa cc #b per cent caffein injected into the gluteal muscles 7#j4b gram per kilo71 under observation until #e p4 m41 had frequent convulsions2 at #e p4 m4 in a comatose condition4 ,rabbit was found dead the next morning4 ,rabbit #bhf1 white and black1 female4 ,weight1 #a1cae grams4 ,december #ae3 #b4cj p4 m41 #ac cc #b per cent caffein injected into the gluteal muscles 7#j4aigg gram per kilo71 tremors and increased reflexes observed during the next two hours1 but no other symptoms4 ,december #ag3 ,rabbit alive4 ,rabbit #bhe1 yellow and white1 female4 ,weight1 #a1che grams4 ,december #ad3 #aj4ae a4 m41 #ad cc #b per cent caffein injected into the gluteal muscles 7#j4b gram per kilo71 general tremors1 but no convulsions observed4 ,rabbit survived4 ,december #ag3 ,rabbit still alive4 ,rabbit #bhg4 ,belgian hare1 female4 ,weight1 #a1adj grams4 ,december #ae3 #b4ae p4 m41 #aa cc of #b per cent caffein injected into the gluteal muscles2 #b4cj p4 m41 tonic contractions of posterior limbs4 ,paralysis and death at #b4dj p4 m4 ,,series ,b4 ,in series ,b the caffein was injected into the lumbar muscles4 ,rabbit #cjg4 ,belgian hare1 female4 ,weight1 #a1age grams4 ,february #af3 #aa4je a4 m41 #h cc #b per cent caffein injected 7#j4acf gram per kilo7 into the lumbar muscles2 under observation until #d p4 m41 no symptoms2 #d p4 m41 allowed to walk on the floor2 after walking a short distance loss of coordination and paralysis of posterior extremities2 #e4bj p4 m41 found dead4 ,rabbit #cjf4 ,belgian hare1 female4 ,weight1 #a1hfj grams4 ,february #af3 #aa a4 m41 #ab4e cc #b per cent caffein injected into the lumbar muscles2 #ab noon1 no symptoms2 #b p4 m41 walked about #aj feet1 exhaustion and paralysis2 #c p4 m4 found dead4 ,rabbit #aha4 ,belgian hare4 ,weight1 #a1bcj grams4 7,was experimented on some time previously47 ,february #af3 #aj4ee a4 m41 #h cc #b per cent caffein injected into the lumbar muscles2 7#j4acj gram per kilo72 #ab noon1 no symptoms2 #b p4 m41 no symptoms2 #c p4 m41 put on the floor1 walked about #aj feet and was exhausted1 posterior extremities paralyzed2 #d p4 m41 found dead4 ,,series ,c4 ,in the fall of the same year additional experiments were carried out with doses ranging from #ajj to #bjj milligrams of caffein per kilo1 which were injected into the lumbar muscles4 ,the results are given in the following abbreviated protocols3 ,rabbit #dbe4 ,belgian hare4 ,weight #a1ebj grams4 ,september #bg3 #aj4cj a4 m41 #g4e cc #b per cent caffein injected into the lumbar muscles2 #b p4 m41 reflexes increased4 ,september #bh3 ,rabbit normal4 ,october #e3 ,weight1 #a1fbj grams2 #b4ej p4 m41 #aj cc #b per cent caffein injected into lumbar muscles2 #c4je p4 m41 reflexes increased4 ,october #ac3 ,weight1 #a1ebj grams2 #aj4cj a4 m41 #aj cc #b per cent caffein 7#aca mg per kilo7 injected2 #aa a4 m41 no symptoms2 #aa4cj a4 m41 reflexes much increased4 ,october #ad3 ,alive1 no symptoms4 ,rabbit #dbf4 ,belgian hare1 female4 ,weight1 #a1dbe grams4 ,september #bg3 #g cc #b per cent caffein injected into the lumbar muscles at #aj4cj a4 m42 #b p4 m41 reflexes increased4 ,september #bh3 ,rabbit normal4 ,october #e3 ,weight1 #a1dbe grams2 #b4ee p4 m41 #i cc #b per cent caffein injected into lumbar muscles2 #c4je p4 m41 reflexes increased4 ,october #ac3 ,weight1 #a1dje grams2 #aj4cj a4 m41 #aj cc #b per cent caffein 7#adb mg per kilo7 injected2 #aa a4 m41 no symptoms2 #aa4cj a4 m41 reflexes increased4 ,october #ad3 ,rabbit alive1 no symptoms4 ,rabbit #dbg4 ,belgian hare1 female4 ,weight1 #a1ghj grams4 ,september #bg3 #i cc #b per cent caffein injected into the lumbar muscles2 #b p4 m41 reflexes increased4 ,september #bh3 ,rabbit normal4 ,october #e3 ,weight1 #a1hej grams2 #c p4 m41 #aa4e cc #b per cent caffein injected into lumbar muscles2 #c4aj p4 m41 reflexes increased4 ,october #ac3 ,weight1 #a1hcj grams2 #aj4dj a4 m41 #ad cc #b per cent caffein 7#aec mg per kilo7 injected into lumbar muscles2 #aa a4 m41 no symptoms2 #aa4cj a4 m41 reflexes increased4 ,october #ad3 ,rabbit alive1 no symptoms4 ,rabbit #dec4 ,belgian hare1 male4 ,weight1 #a1afj grams4 ,october #ab3 #c4de p4 m41 #aa4e cc #b per cent caffein in aqueous solution injected into lumbar muscles2 #d4ae p4 m41 reflexes increased2 #d4cj p4 m41 paralyzed4 ,october #ac3 #i a4 m41 found dead4 ,autopsy3 ,gastric mucosa hemorrhagic2 liver darkened2 other organs normal4 ,rabbit #dee4 ,belgian hare1 gray1 female4 ,weight1 #a1ahe grams4 ,october #ab3 #c4cj p4 m41 #aa4e cc #b per cent caffein injected into the lumbar muscles2 #d p4 m41 reflexes increased4 ,october #ac3 ,rabbit weighed #a1jgj grams1 no symptom of caffein poisoning1 reflexes normal2 #aj4cj a4 m41 #aj cc #b per cent caffein injected into the lumbar muscles2 #aa4cj a4 m41 jumped off the table1 had attack of convulsions and died4 ,autopsy3 ,findings same as in ,no4 #dec4 ,rabbit #dbh4 ,belgian hare1 gray1 male4 ,weight1 #a1fej grams4 ,october #e3 #d p4 m41 #ad4h cc #b per cent caffein 7#j4ah gram per kilo7 injected into the lumbar muscles4 ,october #f3 ,found dead4 ,rabbit #dbi4 ,belgian hare1 male4 ,weight1 #a1cdj grams4 ,october #e3 #d p4 m41 #ac4e cc #b per cent caffein 7#j4b gram per kilo7 injected into lumbar muscles4 ,october #h3 ,rabbit found dead4 ,,series ,d4 ,further experiments making injections into both the lumbar and the gluteal muscles1 were made in this series4 ,rabbit #egg4 ,gray male4 ,weight1 #a1chj grams4 ,february #ad3 #c p4 m4 #ad cc #b per cent caffein injected into the gluteal muscles of the right side2 #c4aj p4 m41 restless1 jumped off the table and walked about1 reflexes increased2 #c4de p4 m41 passed #cj cc clear1 straw-colored urine2 #d4de p4 m41 allowed to walk about1 ran across the room1 about #bj feet1 looked tired1 stretched himself out on the floor1 then raised himself and walked about showing no disturbance of gait4 ,february #ae3 #i a4 m41 found dead4 ,rabbit #egh4 ,gray1 female4 ,weight1 #a1fgj grams4 ,february #ad3 #c4je p4 m41 #ah cc #b per cent caffein solution injected into the gluteal muscles of the right side2 #c4ae reflexes increased1 but not restless2 #e p4 m41 allowed to walk about1 no symptoms observed4 ,february #ae3 ,found dead4 ,rabbit #egi4 ,white and gray1 male4 ,weight1 #a1dij grams4 ,february #ad3 #c4ae p4 m41 #ae cc #b per cent caffein solution injected into the gluteal muscles of the right side2 put in cage2 #c4cj p4 m41 reflexes increased2 #e p4 m41 taken out of cage and allowed to walk across the room1 no special symptoms noticed4 ,february #bc3 ,still alive4 ,rabbit #ehj4 ,gray male4 ,weight1 #a1eaj grams4 ,february #ad3 #c4ce p4 m41 #ae cc #b per cent caffein solution injected into lumbar muscles4 ,february #bc3 ,still alive1 in good condition4 ,rabbit #eha4 ,gray female4 ,weight1 #a1fhj grams4 ,february #ad3 #c4de p4 m41 #ag cc #b per cent caffein solution injected into the lumbar muscles of the right side2 #d p4 m41 reflexes increased2 #d4ae p4 m41 jumped off the table and had wild convulsions1 became very restless1 walked about the laboratory2 #d4be p4 m41 had convulsions occasionally2 #d4cj p4 m41 extremities extended and quite rigid2 #d4ce p4 m41 convulsions and death4 ,rabbit #ehb4 ,gray male4 ,weight1 #a1hgj grams4 ,february #ad3 #d4ae p4 m41 #ah cc #b per cent caffein solution injected into the lumbar muscles of right side2 #e p4 m41 reflexes increased2 walked about in the room1 then rested2 #e4ae p4 m41 had short spasm when handled4 ,february #bc3 ,alive2 good condition4 ,the data presented in these experiments show that the toxicity of caffein when injected into the muscles of the lumbar regions is the same as when injected into the gluteal muscles4 ,the rabbits of series ,a received approximately #j4b gram caffein per kilo and two died as a result of this treatment4 ,the other two survived but symptoms of caffein intoxication were observed4 ,in series ,b smaller doses proved fatal1 from which it would appear that caffein is more toxic when injected into the lumbar muscles4 ,further observations1 however1 failed to corroborate the results obtained in this series4 ,thus1 in series ,c1 #acj to #aej mg of caffein per kilo injected into the lumbar muscles produced mild symptoms only4 ,experiments with larger doses showed that #j4ahj gram caffein per kilo may cause death4 ,it will be noticed1 on the other hand1 that rabbit ,no4 #dee survived a dose of #j4b gram per kilo4 ,new experiments were therefore carried out in which the same amounts of caffein in proportion to the weight of the animals were injected into the lumbar muscles as into the gluteal muscles4 ,as shown in the experiments of series ,d1 one rabbit 7,no4 #eha7 died shortly after caffein was injected into the lumbar muscles2 two recovered4 ,two of the three which received injections into the gluteal muscles were found dead the next day2 one recovered4 ,post-mortem examination failed to indicate the presence of any abnormalities4 ,the rate of absorption of caffein from the gluteal and from the lumbar muscles seems to be1 therefore1 the same1 or not to differ very much4 ,the observations of ,auer and ,meltzer7#g7 are of interest in this connection4 ,according to their investigations adrenalin is more rapidly absorbed from the lumbar than from the gluteal muscles4 ,this is in all probability due to the greater delicacy of the test they employed 7since they judged the rate of absorption by the effect of adrenalin on blood pressure7 as well as to the much greater activity of the substance4 ,,table #d4--;,intramuscular injections4 ,,series ,a4 ---------------------------------------- ------------------------ ,caffein ,no4 ,weight4 per ,symptoms ,duration ,site of ,remarks4 kilo after-- of life4 injection4 ---------------------------------------- ------------------------ ,grams4,gram4 #bhd #a1ajj #j4bjj #c hours ,less than ,gluteal ,white and #bj hours brown female4 #bhf #a1cae 4#aigg #b hours ,survived do4 ,white and black female4 #bhe #a1che 4#bjj ,present do4 do4 ,yellow and white female4 #bhg #a1adj 4#baj #ae minutes#be minutes do4 ,gray female4 ---------------------------------------- ------------------------ ,,series ,b4 ---------------------------------------- ----------------------- #cjg #a1age #j4acf #e hours #f hours1 ,lumbar ,gray female4 #bj minutes #cjf #a1hfj 4#acd #c hours #d hours do4 ,do4 #aha #a1bcj 4#acj #d hours #e hours do4 ,gray4 ---------------------------------------- ----------------------- ,,series ,c4 ---------------------------------------- ----------------------- #dbe #a1ebj #j4aca #a hour ,survived ,lumbar ,gray4 #dbf #a1dje 4#adb #cj minutes do4 do4 ,gray female4 #dbg #a1hcj 4#aec #ej minutes do4 do4 ,do4 #dec #a1afj 4#bjj #cj minutes,less than do4 ,gray male4 #bj hours #dee #a1ahe 4#bjj do4 ,survived do4 ,gray female4 #dbh #a1fej 4#ahj ,less than do4 ,gray male4 #bj hours #dbi #a1cdj 4#bjj do4 do4 ,do4 ---------------------------------------- ----------------------- ,,series ,d4 ---------------------------------------- ----------------------- #egg #a1chj #j4bjj #aj minutes,less than ,gluteal ,gray male4 #ah hours #egh #a1fgj 4#baj do4 do4 do4 ,do4 #egi #a1dij 4#bjj #ae minutes,survived do4 ,white and gray male4 #ehj #a1eaj 4#bjj do4 ,lumbar ,gray male4 #eha #a1fhj 4#bjj #ae minutes#ej minutes do4 ,do4 #ehb #a1hgj 4#aib #de minutes,survived do4 ,do4 ---------------------------------------- ----------------------- ,examination of ,table #d shows that #ad rabbits received from #ahj to #baj mg caffein per kilo4 ,the appearance of symptoms in these rabbits varied considerably4 ,in some increased reflexes could be noticed in #aj to #ae minutes after the injection of caffein2 in others it was delayed #b or #c hours4 ,it might be added that the onset of symptoms occurred in many cases very soon after the administration of the drug--on an average about #aj to #cj minutes after the drug was injected4 ,after smaller doses were administered by injection into the lumbar muscles the appearance of symptoms was delayed several hours in some cases4 ,the duration of life in these #ad rabbits varied considerably4 ,eight of them died within #a to #bj hours2 six survived4 ,about #j4b gram caffein per kilo may be regarded as the minimum fatal dose1 while the minimum toxic dose is somewhere between #acj and #aej mg per kilo4 ,,intravenous ,,injection4 ,these experiments were carried out on well-fed1 full-grown gray rabbits4 ,the diet for several days preceding the experiments consisted of oats or carrots1 which were given ad libitum4 ,the injections were made into the ear veins from a burette or by means of a syringe1 the temperature of the caffein solution being about #dj ,c4 ,attention was also directed to the effect of the rate of injection and of the concentration on the toxicity4 ,the minimum toxic as well as lethal doses were determined as shown in the following experiments4 ,,series ,a4 ,in these experiments the rate of injection was about #a cc of #b per cent caffein solution per minute4 ,rabbit #aid4 ,white1 female4 ,weight1 #a1caj grams4 ,october #ai3 ,injected #g4e cc #b per cent solution caffein 7#aae mg per kilo7 into the ear vein4 ,rabbit showed stiffness2 paralysis of extremities appeared soon after4,c ,rabbit survived4 ,c ,time of injection inadvertently omitted1 but was probably not slower than in the other cases of this series4 ,rabbit #eef4 ,gray1 female4 ,weight1 #a1fce grams4 ,january #ca3 #b p4 m41 #aa cc #b per cent caffein 7#acd mg per kilo7 injected into ear vein1 in about #aa minutes2 #b4aj p4 m41 convulsions1 rabbit remained lying on its side2 during the rest of the hour it had convulsions occasionally2 #c4bj p4 m41 convulsions and died4 ,rabbit did not urinate after the injection of caffein4 ,rabbit #eeg4 ,gray1 female4 ,weight1 #a1ehj grams4 ,january #ca3 #b4cj to #b4cg p4 m41 #g cc #b per cent caffein injected from the burette at the rate of #a cc per minute2 #b4cg p4 m41 flow of liquid ceased1 veins were engorged and bled freely1 injection was continued by means of a syringe2 #b cc #b per cent caffein injected in two minutes2 injections discontinued as convulsions appeared2 #b4ej p4 m41 rabbit raised itself but fell over2 #c4aj p4 m41 rabbit assumed normal attitude1 walked about the floor without manifesting any signs of the effects of caffein2 #d4cj p4 m41 walked about1 gait normal1 condition seemed to be good4 ,february #a3 #b p4 m41 condition good1 appetite good1 total amount of caffein injected1 #i cc #b per cent solution1 or #aad mg per kilo4 ,rabbit #eeh4 ,gray1 female4 ,weight1 #a1eij grams4 ,january #ca3 #c p4 m41 given #h cc #b per cent caffein in eight minutes2 #c4aj p4 m41 violent convulsions2 #c4bj p4 m41 rabbit was stretched out on his abdomen1 extremities extended1 urinated2 #d4cj p4 m41 looked normal2 was able to walk about4 ,february #a3 #b p4 m41 condition good1 appetite good4 ,rabbit #bib4 ,belgian hare1 male4 ,weight1 #a1ggj grams4 ,february #ah3 #d4bf to #d4ci p4 m41 #ab4e cc warm caffein solution 7#j4ada gram per kilo7 injected into ear vein1 convulsion followed when this quantity was injected1 tonic rigidity of limbs followed soon after2 #d4eb p4 m41 condition unchanged1 rabbit on floor1 limbs stretched out1 and lying on abdomen4 ,rabbit #bid4 ,belgian hare1 female4 ,weight1 #a1cej grams4 ,carrot diet for about #aj days before the experiment4 ,february #ai3 #ab4bj p4 m41 #e cc #b per cent caffein 7#gd mg per kilo7 injected into ear vein in five minutes1 edema of the ear1 other ear used1 #c4e cc injected in #aj minutes1 repeated convulsions2 #a4be p4 m41 rabbit still alive1 frequent attacks of convulsions2 #b4cj p4 m41 found dead4 ,total amount injected in #ae minutes1 #h4e cc1 or #j4abf gram per kilo4 ,it will be observed in the preceding experiments that symptoms of severe intoxication were present in all of the six rabbits1 but only two of these 7,nos4 #bid and #eef7 died from the effects of caffein4 ,of those which survived1 three received doses of #ajj to #aad mg caffein per kilo1 and another 7,no4 #bib7 received #ada mg of caffein per kilo4 ,the death of rabbits ,nos4 #bid and #eef may be regarded therefore as a case of exceptionally low resistance to caffein4 ,,series ,b4 ,doses of #afj to #bjj mg caffein per kilo were employed in these experiments4 ,the rate of injection was #a cc per minute1 with the exception of ,experiment #bed1 in which #aj4h cc #b per cent caffein were introduced in #ag minutes and #be seconds4 ,rabbit #efb4 ,gray female4 ,weight1 #a1fej grams4 ,diet1 oats4 ,february #a3 ,injection began at #c p4 m41 injected #aj cc in #ab minutes2 #c4ja p4 m4 to #c4ji p4 m41 #c cc injected1 convulsions2 #c4ji p4 m4 to #c4ad p4 m41 #c cc injected1 followed by violent convulsions1 marked opisthotonos2 #d4cj p4 m41 rabbit died2 total quantity injected1 #af cc4 ,rabbit #efa4 ,gray female4 ,weight1 #a1dej grams4 ,diet1 oats4 ,february #a3 ,injection began at #aa4dj a4 m42 #aa4dh1 rabbit struggled1 #g cc #b per cent caffein injected2 #aa4ej1 convulsions1 #aj cc #b per cent caffein total amount injected2 #aa4ee a4 m41 injections stopped2 injections resumed #aa4eh1 violent convulsions1 injections discontinued1 total quantity received1 #ad4e cc #b per cent caffein solution2 #a4cj p4 m41 found dead1 did not urinate1 #be cc urine found in the bladder4 ,rabbit #efj4 ,gray male4 ,weight1 #a1fbj grams4 ,diet1 oats4 ,february #a3 ,injection began #aa a4 m42 #aa4aj a4 m41 #g cc #b per cent caffein injected1 rabbit struggled2 #a cc was injected during the next three minutes1 rabbit struggled but there were no convulsions1 injection stopped2 resumed at #aa4ae a4 m4 and continued #aj minutes1 #h cc #b per cent caffein introduced during this time2 total amount caffein injected1 #af cc2 reflexes markedly increased2 #ab noon1 tetanic convulsions off and on until #b p4 m41 then remained stretched out on abdomen1 extremities extended4 ,february #b3 #i a4 m41 found dead4 ,rabbit #eei4 ,gray female4 ,weight1 #a1hge grams4 ,diet1 oats4 ,january #ca3 #d p4 m41 convulsions after injection of #i cc #b per cent caffein in #ad minutes2 #d4jh p4 m41 convulsions after injection of #g cc caffein in #h minutes2 #d4aj to #d4ab p4 m41 injected #b cc more1 rabbit lying stretched out on abdomen1 extremities extended2 total amount of caffein injected1 #ah cc 7#aij mg per kilo74 ,february #a3 #b p4 m41 condition good1 walked about1 appetite good1 passed #aee cc dark1 reddish-brown urine since #e4cj p4 m4 previous day4 ,rabbit #bgi4 ,gray and white female4 ,weight1 #a1cbj grams4 ,february #bd3 #aj4ji a4 m41 #f cc #b per cent caffein passed rapidly into jugular vein2 #aj4ae a4 m41 involuntary twitching of muscles of legs1 but no other symptoms2 #aj4bc to #aj4bf1 #c cc of #b per cent caffein injected2 #aj4bg to #aj4bh1 #b cc #b per cent caffein injected1 convulsions2 #aj4bi1 convulsions stopped2 #aj4cb1 convulsions2 #aa a4 m41 rabbit lying on its side1 anterior extremities paralyzed1 posterior extremities contracted1 no clonic convulsions1 breathed deeper and more slowly than normal2 #aa4aj a4 m41 rabbit died1 had no convulsions immediately before death2 amount of caffein injected1 #aa cc #b per cent solution1 or #j4aff gram per kilo4 ,rabbit #bed4 ,belgian hare1 female4 ,weight1 #a1bhe grams4 ,diet1 oats4 ,november #ab3 #a4cj-a_/c to #a4dg p4 m41 received #aj4h cc #b per cent caffein from burette into ear vein1 after injection of #f4b cc dyspnoea1 #f4g cc struggling1 convulsions2 at #a4ej p4 m41 released from holder1 paralysis especially marked in the anterior extremities2 #a4ej p4 m41 recovered1 survived2 total amount injected1 #aj4h cc #b per cent caffein in #ag minutes and #be seconds1 or #j4af gram caffein per kilo4 ,rabbit #bee4 ,belgian hare1 male4 ,weight1 #a1aje grams4 ,diet1 oats4 ,november #ab3 #b4ca to #b4ce p4 m41 received #c4g cc2 from #b4cg-a_/f to #b4df-a_/f p4 m41 #e cc injected2 after injection of #f4a cc convulsions followed by dyspnoea1 then continuous struggling2 when #h4c cc were injected rabbit had another convulsion2 #b4dg p4 m41 tonic contraction of anterior extremities2 amount injected1 #h4g cc 7#aeh mg per kilo7 in #ae minutes and #ce seconds4 ,rabbit #efg4 ,gray female4 ,diet1 oats4 ,february #f3 ,injection began at #d4aa p4 m42 #d4ah1 convulsions after injection of #e cc #b per cent caffein2 #d4ba1 convulsion after total injection of #h cc2 #d4bd p4 m41 injection resumed and #b cc more introduced2 #d4bh p4 m41 convulsions1 injected #b cc more2 total caffein injected1 #ab cc1 or #afb mg per kilo2 #d4dj p4 m41 rabbit paralyzed in posterior extremities2 #e p4 m41 found dead4 ,in the eight experiments comprising series ,b rabbits ,nos4 #efg1 #bed1 #bgi1 and #bee1 which may be designated as ,group ,,ii1 received doses of #afb1 #afj1 #aff1 and #aeh mg1 respectively4 ,nos4 #efb1 #efa1 #efj1 and #eei1 which may be designated as ,group ,i1 received about #bjj mg caffein per kilo4 ,in ,group ,,ii1 which received the smaller doses1 one 7,no4 #bed7 survived4 ,this may be regarded as exceptional1 since1 as was shown in the experiments of the preceding series1 even smaller doses may be fatal4 ,about #afj mg per kilo is1 therefore1 the smallest surely fatal dose4 ,this might be regarded as a contradiction of the results obtained for rabbit ,no4 #eei1 but it will be noticed that in this case diuresis was very marked4 ,the results of experiments ,nos4 #bid and #bee are of interest in this connection1 since they indicate that a moderate difference in the rate of injection is without any effect on the toxicity of caffein4 ,the greater resistance to caffein of rabbit ,no4 #eei is in all probability due1 therefore1 to increased diuresis4 ,,series ,c4 ,in these experiments the minimum toxic dose was determined4 ,the conditions were the same as in the experiments of the other series4 ,rabbit #bic4 ,belgian hare1 female4 ,weight1 #a1faj grams4 ,diet1 oats4 ,february #ah3 #c4dj to #c4dc p4 m41 #d cc #b per cent warm caffein solution injected into ear vein1 convulsions when #c cc were injected1 repeated attacks2 #d p4 m41 raised itself on legs1 but fell over immediately and lay stretched on abdomen4 ,february #ai3 #i a4 m41 rabbit looked normal1 apparently recovered4 ,rabbit #bbg4 ,white male4 ,weight1 #b1cbj grams4 ,october #bf3 #c4bi to #c4cg p4 m41 injected into ear from burette #f4g cc #b per cent caffein1 no symptoms2 experiment discontinued2 survived4 ,rabbit #efc4 ,gray female4 ,weight1 #a1fej grams4 ,diet1 oats4 ,february #f3 ,injection began at #a4jb p4 m41 injected #c4e cc #b per cent caffein 7#db mg per kilo7 in four minutes1 #j4f cc more within the next two and one-half minutes1 total amount injected #d4a cc2 #a4aj p4 m41 hypersensitive1 some disturbance of muscular coordination2 restlessness2 #a4ce4 p4 m41 reflexes decreased1 urinated and walked about1 gait normal4 ,under observation for several days2 no symptoms noted4 ,rabbit #efd4 ,gray female4 ,weight1 #a1eae grams4 ,february #f3 ,injection began at #a4bf p4 m41 #c4e cc #b per cent caffein 7#df mg per kilo7 injected at the rate of #a cc per minute2 #a4cj p4 m41 reflexes increased2 #a4cd p4 m41 marked paresis of the extremities1 rabbit stretched out on abdomen1 legs abducted and partly extended1 able to hop about but gait disturbed1 no untoward symptoms noticed1 under observation for several days after experiment4 ,rabbit #efe4 ,gray female4 ,weight1 #a1ede grams4 ,diet1 oats4 ,february #f3 ,started to inject at #c4dj p4 m41 received #b4e cc #b per cent caffein intravenously in two minutes or #cb mg per kilo1 under observation all afternoon1 no symptoms4 ,rabbit #eff4 ,gray female4 ,weight1 #a1ijj grams4 ,diet oats4 ,february #f3 ,injection began at #c4je p4 m41 received #c cc #b per cent caffein intravenously in three minutes or #ca mg per kilo1 no symptoms observed4 ,these experiments show that a dose of about #ej mg per kilo when injected intravenously produces mild symptoms1 such as increased reflexes4 ,in the four experiments with this amount of caffein these effects were observed in each case4 ,in the experiments in which smaller quantities1 #cj mg per kilo1 were given intravenously there was no manifestation of symptoms4 ,a dose not over #ej mg per kilo may1 therefore1 be regarded as the minimum toxic dose when injected intravenously under the conditions stated4 ,,series ,d4 ,a #j4e per cent caffein solution was used in these experiments in order to test the effect of concentration on its toxicity2 the rate of injection was #a cc per minute4 ,rabbit #efi4 ,gray male4 ,weight1 #a1dge grams4 ,diet1 oats4 ,february #f3 #aa4ej a4 m4 to #ab4ja p4 m41 injected #aj cc #j4e per cent caffein2 #ab4jc to #ab4ab p4 m41 injected #aj cc of #j4e per cent caffein2 #ab4ac to #ab4bf p4 m41 injected #aj cc of #j4e per cent caffein1 total amount injected1 #cj cc2 #ab4bj1 passed #ce cc of urine2 #ab4cj1 increased reflexes1 but no convulsions2 #d p4 m41 reflexes increased4 ,february #aa3 ,alive1 condition good4 ,rabbit #egd4 ,gray female4 ,weight1 #a1eee grams4 ,diet1 oats4 ,february #h3 #aj4be to #aj4cc a4 m41 injected #d cc of #j4e per cent caffein in salt solution1 injection discontinued for five minutes2 #aj4ch to #aa4aj1 injected #cj cc1 total amount of caffein solution received1 #cd cc2 #aa4ee a4 m41 very sensitive2 reflexes markedly increased4 ,february #i3 ,alive1 condition good4 ,rabbit #ega4 ,gray female4 ,weight1 #a1ecj grams4 ,diet1 oats4 ,february #g3 ,injection #c4ah to #c4ej p4 m41 received #cj cc in #cb minutes1 not hypersensitive2 #c4ee1 restlessness and weakness of extremities2 #d4aj p4 m41 control of anterior extremities impaired1 distinctly paretic but tried to walk about1 died the same afternoon4 ,rabbit #efh4 ,gray male4 ,weight1 #a1fje grams4 ,diet1 oats4 ,february #g3 ,injection #aj4ec to #aa4ja a4 m41 injected #aj cc #j4e per cent caffein2 #aa4jc1 injection resumed after two minutes interval2 #aa4ad1 received #aj cc #j4e per cent caffein intravenously in #aa minutes2 #aa4af1 injection resumed2 #aa4ce1 received #ab cc #j4e per cent caffein1 total amount of caffein solution received1 #cb cc2 #ab4cj p4 m41 urinated #ad cc of bloody urine2 #ab4ee p4 m41 convulsions and death a few minutes later4 ,autopsy showed congestion of viscera1 but no other lesions4 ,rabbit #egj4 ,gray female4 ,weight1 #a1bbe grams4 ,diet1 oats4 ,february #g3 #b4jf to #b4ce p4 m41 injected #bd4e cc #j4e per cent caffein1 reflexes increased but no convulsions1 paresis especially marked in the anterior extremities2 #c p4 m41 passed urine which was normal in appearance1 reflexes not increased but rabbit was weak4 ,february #i3 ,found dead4 ,autopsy3 ,liver1 spleen1 and kidneys congested2 large intestines hemorrhagic2 omentum congested and showed the presence of small caseous nodules2 liver showed adhesion to diaphragm2 viscera presented the appearance of intraabdominal infection4 ,of the five rabbits of this series three died as a result of the administration of caffein4 ,the other two which survived showed mild symptoms only1 such as increased reflexes1 but no evidence of severe poisoning such as was observed after the injection of the same doses of caffein in series ,a when a #b per cent solution of caffein was injected4 ,convulsions were noticed in one case only 7,no4 #efh72 paresis in two cases 7,nos4 #egj and #ega74 ,the nervous symptoms even in this group1 therefore1 were much milder than in series ,a4 ,the percentage of death1 however1 was greater than in series ,a1 in which the concentration of caffein was four times as great4 ,it is quite probable that the strain on the heart due to the sudden increase in volume of the blood and its dilution might be an important factor in increasing the toxicity of caffein4 ,it is conceivable that doses just sufficiently large to depress the normal heart may cause paralysis of an already overstrained organ4 ,,series ,e4 ,in the two experiments of this series the rate of injection as a possible factor influencing the toxicity of caffein was tested4 ,a #b per cent caffein solution was injected at the rate of #a cc in two and one-half to three minutes4 ,rabbit #egb4 ,gray male4 ,weight1 #a1ggj grams4 ,diet1 oats4 ,february #h3 ,injection began at #c p4 m41 discontinued at #c4cg p4 m41 and resumed at #c4ch p4 m42 rabbit was restless2 injection finished at #c4eb p4 m4 ,total quantity received1 #ag4d cc #b per cent caffein intravenously in #eb minutes2 struggled intermittently during the injection2 anterior legs paralyzed4 ,february #i3 ,found dead4 ,rabbit #egc4 ,gray male4 ,weight1 #a1haj grams4 ,diet1 oats4 ,february #h3 ,started to inject at #a4ce and discontinued at #b4bg p4 m42 received #ah cc #b per cent caffein intravenously in #eb minutes2 reflexes markedly increased soon after2 #b4de1 passed bloody urine2 #d4cj p4 m4 reflexes increased2 no other symptoms4 ,february #i3 #i a4 m41 found dead4 ,it will be observed that some retardation of the onset of symptoms was caused by slower injection1 but the final result was the same as when the injections were made more rapidly4 ,it is quite probable1 therefore1 that a much slower rate of injection may lessen considerably the toxicity of caffein4 ,from the results of the experiments by intravenous injection summarized in the table1 it appears that the minimum toxic dose for rabbits of a #b per cent caffein solution1 injected at the rate of #a cc per minute1 is about #ej mg per kilo4 ,twice the dose induces severe symptoms and may be fatal2 #afj mg per kilo are surely fatal4 ,if the rate of injection is diminished1 the toxicity of caffein is lessened1 but this effect is not marked unless the injections are very slow4 ,dilution of the caffein solution suppresses to some extent the nervous symptoms1 but the toxicity1 on the contrary1 seems to be increased4 ,,table #e4--;,intravenous injections4 ,,series ,a4 ---------------------------------------- ----------------------- ,caffein ,duration ,no4,weight4 per ,symptoms4 of life4 ,diet4 ,remarks4 kilo4 ---------------------------------------- ----------------------- ,grams4 ,mg4 #aid #a1caj #aad ,present ,survived ,oats ,white female4 #eef #a1fce #acd #aj minutes #bj minutes do4 ,gray female4 #eeg #a1ehj #aad ,present ,survived do4 ,do4 #eeh #a1eij #ajj do4 do4 do4 ,do4 #bib #a1ggj #ada do4 do4 do4 ,do4 #aid #a1cej #abf do4 #aj minutes ,carrots ,do4 ---------------------------------------- ----------------------- ,,series ,b1 ,,group ,i4 ---------------------------------------- ----------------------- #efb #a1fej #bjj #a hours ,oats ,gray female4 #efa #a1dej #bjj do4 do4 ,do4 #efj #a1fbj #bjj ,present ,less than do4 ,do4 #bd hours #eei #a1hge #aij do4 ,survived do4 ,do4 ---------------------------------------- ----------------------- ,,series ,b1 ,,group ,,ii4 ---------------------------------------- ----------------------- #bgi #a1cbj #aff #a hour ,gray and white female4 #bed #a1bhe #afj ,survived ,oats ,gray female4 #efg #afb ,about #de ,do4 minutes #bee #aeh ,died ---------------------------------------- ----------------------- ,,series ,c4 ---------------------------------------- ----------------------- #bic #a1faj #ejj ,present ,survived ,oats ,gray female4 #bbg #b1cbj #egj ,none do4 ,white male4 #efc #a1fej #ejj ,present do4 do4 ,gray female4 #efd #a1eae #dfj do4 do4 ,do4 #efe #a1ede #cbj ,none do4 do4 ,do4 #eff #a1ijj #caj do4 do4 do4 ,do4 ---------------------------------------- ----------------------- ,,series ,d4 ---------------------------------------- ----------------------- #efi #a1dge #ajj ,present ,survived ,oats ,gray male4 #egd #a1eee #aab do4 do4 do4 ,gray female4 #ega #a1ecj #ajj do4 ,about do4 ,do4 #b hours #efh #a1fje #ajj #bj minutes do4 ,gray male4 #egj #a1bbe #ajj ,less than do4 ,do4 #bj hours ---------------------------------------- ----------------------- ,,series ,e4 ---------------------------------------- ----------------------- #egb #a1ggj #bjj ,present ,about ,oats #bd hours #egc #a1haj #bjj do4 do4 ---------------------------------------- ----------------------- ,,summary4 ,the results of the experiments on rabbits show considerable variation in the toxicity of the single dose4 ,individuals differed so widely in their resistance to this drug that the same experiments had to be repeated many times with each method of administration before satisfactory conclusions could be drawn4 ,this is strikingly illustrated in the experiments by intravenous injection in which a dose of nearly #j4b gram per kilo was not fatal4 ,similar instances of exceptional resistance or of sensitiveness to caffein were observed when it was given in other ways4 ,a comparison of the toxicity of caffein administered by different methods in this investigation shows well-marked differences in its activity1 although they are not quite so striking as similar experiments with other alkaloids reported by several observers4 ,the toxicity of caffein in these experiments on the rabbit indicates that it is greatest when given by vein and least when given by mouth4 ,the ratio of the minimum toxic doses by these two methods of introduction of caffein was about #g4a2 the relation of the minimum fatal dose was about #c4a4 ,the toxicity when given subcutaneously is about #ae to #bj per cent greater than when given by mouth4 ,the difference between the intramuscular and subcutaneous injection is even more marked4 ,the toxicity of caffein when injected into the muscles is about midway between that administered by the subcutaneous and intraperitoneal routes1 and is about half that injected intravenously4 ,meltzer and ,auer17#eh7 who experimented with a number of drugs found that the intramuscular method of administration is as effective as the intravenous1 fluorescin forming the only exception according to their observations4 ,in the experiments of ,sollman and ,brown7#ha7 with ergot1 the effect was quite different from those obtained by ,meltzer and ,auer7#eh7 with the drugs they used4 ,it is quite possible that the result obtained with ergot is merely illustrative of a difference in the behavior of various substances in this regard4 ,this appears probable on account of the difference in the rate of absorption for various substances4 ,thus1 according to ,achard1 ,gaillard1 and ,ribot 7,compt4 rend4 ,soc4 biol41 #aijg1 #fb3 #ij71 absorption from the peritoneal cavity varies with the concentration of the solution and the size of the molecule4 ,the smaller the molecule and the greater the concentration the more rapid the absorption4 ,that the rate of absorption from the intramuscular tissues is unequal and varies for different substances appears from the experiments of ,meltzer and ,auer47#eh7 ,the difference was very striking between intramuscular and subcutaneous administration of curara or adrenalin2 the results were somewhat different with morphin and with fluorescin4 ,as shown in their protocols1 the onset of the symptoms after the intramuscular injection of morphin was sooner than after subcutaneous injection1 but in time the difference diminishes and disappears altogether4 ,the absorption of fluorescin is much faster when the intramuscular path is used than when given subcutaneously1 but the writers state that the rate falls far behind that of the intravenous administration4 ,the difference in toxicity we observed between feeding by mouth and subcutaneous injection1 although distinct1 was not very great4 ,it was much less than ,maurel7#ee7 obtained with the hydrobromid of caffein in the rabbit4 ,whether this difference between his results and ours is due to the use of the pure alkaloid in our experiments and the hydrobromid employed by ,maurel can not be stated at present with any degree of accuracy4 ,it is hoped that the work in progress in the laboratory will throw some light on the subject in the near future4 ,but ,maurel's7#ef7 experiments show that various substances behave differently in this regard4 ,thus the toxicity of strychnin1 he states1 is three times as great when given subcutaneously as when given by mouth and six times that of the minimum fatal dose by vein4 ,it may be remarked1 however1 that examination of his data shows that his doses are much too large for the rabbit4 ,in experiments with other drugs little or no difference between the two modes of administration was noticed4 ,thus1 digitalin was but slightly more active when given subcutaneously than by mouth1 while the toxicity of emetin hydrochlorid was just the same1 whichever one of these methods of introducing the substance was used4 ,differences in the toxicity of substances have also been observed between subcutaneous and intravenous modes of administration1 but here1 too1 the differences for various substances were unequal4 ,,experiments ,,on ,,guinea ,,pigs4 ,the toxicity of caffein was studied in a large number of individuals4 ,the experiments were conducted on full-grown animals and were carried out at different seasons of the year in a variety of ways4 ,special attention was given to diet as a possible factor influencing resistance to caffein1 and the effect of different modes of administration on toxicity4 ,some animals were therefore fed oats1 some carrots1 others received both hay and oats4 ,caffein was introduced subcutaneously1 intraperitoneally1 and by mouth4 ,,subcutaneous ,,injection4 ,,series ,a4 ,preliminary experiments carried out on three guinea pigs1 which received #cfj1 #cjj1 and #bij mg of caffein per kilo subcutaneously have shown that such doses were rapidly fatal4 ,two of the animals were seized with convulsions half an hour after the introduction of caffein and died during the attack4 ,the other had tetanus two minutes after the injection of caffein4 ,repeated attacks followed1 which terminated in the death of the animal two and a half hours later4 ,the fatal and toxic doses must therefore be considerably under #j4c gram of caffein per kilo when introduced by this path and smaller doses were therefore injected4 ,the results are shown in the experiments of the next series4 ,,series ,b4 ,experiments with #b decigrams per kilo constituted this series4 ,guinea pig #bj4 ,female4 ,weight1 #dig grams4 ,diet1 oats4 ,april #b3 #e cc #b per cent caffein injected subcutaneously at #aa4cj a4 m42 #a4ej p4 m41 spasm of short duration4 ,died at #c p4 m41 three and one-half hours after injection4 ,guinea pig #ch4 ,brown male4 ,weight1 #egj grams4 ,diet1 carrots and oats week previous to injection4 ,february #aa3 #c4ej p4 m41 #f cc #b per cent caffein injected subcutaneously in back 7#baj mg per kilo72 #d4ae1 reflexes increased1 had convulsion of short duration when disturbed2 #d4de p4 m41 on handling1 repeated convulsion and paralysis2 #e p4 m41 guinea pig lying on his side1 respiration difficult and labored4 ,february #aa3 #e4je p4 m41 guinea pig found dead1 #b hours and #ae minutes after injection4 ,guinea pig #cg4 ,male4 ,weight1 #hbj grams4 ,diet1 carrots and oats during week preceding the injection of caffein4 ,february #aa3 #c4ce p4 m41 #h4e cc #b per cent caffein injected subcutaneously in the back2 #e p4 m41 pig very sensitive1 anterior extremities paralyzed when handled1 frequent spasms of posterior extremities1 no symptoms noticed before #e p4 m41 although watched all the time2 #e4je p4 m41 guinea pig on his legs and looked normal4 ,no attack on handling4 ,february #ab3 #i a4 m41 found dead2 died within #ah hours4 ,guinea pig #ac4 ,female4 ,weight1 #fah grams4 ,diet1 oats4 ,march #bi3 #b4de1 #f cc #b per cent caffein injected subcutaneously 7#j4aid grams per kilo74 ,march #cj3 ,died at #d p4 m41 #be hours after injection4 ,guinea pig #cf4 ,male4 ,weight1 #hej grams4 ,fed oats and carrots for one week previous to injection4 ,february #aa3 #c4cj p4 m41 #h4e cc #b per cent caffein injected subcutaneously into back2 #e p4 m41 somewhat more sensitive than normal1 no other symptoms1 no effect on handling2 #e4je p4 m41 no symptoms4 ,february #ab3 #i a4 m41 found dead1 about #ah hours after injection4 ,the results of these experiments1 as observed in five guinea pigs1 indicate that two decigrams of caffein per kilo of animal produce symptoms within a half to about two and a quarter hours after injection4 ,death followed in two guinea pigs #gj minutes to #a hour after the first manifestations of symptoms4 ,two others died during the night1 while one lived #be hours after the injection of caffein4 ,even #b decigrams caffein per kilo weight might therefore be fatal to the guinea pig4 ,experiments carried out later have shown1 however1 that the resistance to caffein is appreciably greater in some guinea pigs4 ,this is indicated by the following experiments1 in which doses of #j4b to #j4bd gram caffein per kilo were administered by the same path4 ,,series ,c4 ,guinea pig #ff4 ,yellow and dark brown male4 ,weight1 #eaj grams4 ,diet1 oats4 ,october #d3 #e cc #b per cent caffein 7#j4b gram per kilo7 injected subcutaneously in the back at #c p4 m42 #e p4 m41 no symptoms4 ,october #e3 #i a4 m41 alive2 condition good4 ,october #i3 ,found dead4 ,autopsy3 ,congestion of liver1 kidney1 and small intestine4 ,guinea pig #fe4 ,white and black male4 ,weight1 #eaj grams4 ,diet1 oats4 ,october #d3 #e cc #b per cent caffein 7#j4b gram per kilo7 injected subcutaneously in the back at #c p4 m42 #e p4 m41 no symptoms4 ,october #e3 #i a4 m41 condition good4 ,guinea pig #fj4 ,white and gray female4 ,weight1 #cbj grams4 ,diet1 oats4 ,october #c3 #b4be p4 m41 #c4e cc #b per cent caffein 7#j4bai gram per kilo7 injected subcutaneously in the back2 #c4dj p4 m41 convulsion with recovery2 #c4ej p4 m41 frequent spasms with paralysis1 especially of anterior extremities2 #e4cj p4 m41 tetanus when removed from cage and put on floor4 ,october #d3 #h4ej a4 m41 found dead4 ,autopsy3 ,congestion of small intestines1 lungs1 liver4 ,guinea pig #eg4 ,white and gray female4 ,weight1 #cej grams4 ,diet1 oats4 ,october #c3 #b4ae p4 m41 #c4e cc #b per cent caffein injected subcutaneously in the back 7#j4b gram per kilo72 #c4dj p4 m41 convulsions with recovery2 #e4cj p4 m41 no marked symptoms4 ,october #d3 #h4ej a4 m41 alive1 active4 ,october #f3 ,found dead at #i a4 m4 ,autopsy3 ,congestion of lungs and liver2 kidneys petechiated2 severe gastro-enteritis4 ,guinea pig #fh4 ,yellow male4 ,weight1 #ghe grams4 ,diet1 oats4 ,october #f3 #aa4ce a4 m41 #g4h cc #b per cent caffein 7#j4b gram per kilo7 injected subcutaneously2 #ab noon1 reflexes increased markedly2 #d4bj p4 m41 reflexes the same as at #ab noon4 ,october #g3 #i a4 m41 dead4 ,autopsy3 ,lungs congested2 liver congested and fatty2 spleen congested1 kidney showed hemorrhagic spots2 gastric mucosa necrotic2 small portion of small intestine inflamed4 ,guinea pig #fi4 ,white male4 ,weight1 #ehe grams4 ,diet1 oats4 ,october #f3 #aa4dj a4 m41 #e4h cc #b per cent caffein injected subcutaneously2 #ab noon1 reflexes increased1 but not as much as in ,no4 #fh2 #d4bj p4 m41 guinea pig hypersensitive1 reflexes increased more than at #ab noon4 ,october #g3 #i a4 m41 alive4 ,october #ae3 #i a4 m41 found dead4 ,guinea pig #fa4 ,brown and black female4 ,weight1 #ccj grams4 ,diet1 oats4 ,october #c3 #d p4 m41 #d cc #b per cent caffein 7#bdj mg per kilo7 injected subcutaneously2 #e4cj p4 m41 reflexes increased2 runs1 but drags posterior extremities4 ,october #d3 #h4ej a4 m41 found dead4 ,guinea pig #fb4 ,white1 yellow1 and black female4 ,weight1 #cce grams4 ,diet1 oats4 ,october #c3 #d4je p4 m41 #d cc #b per cent caffein 7#bch mg per kilo7 injected subcutaneously in the back2 #e p4 m41 convulsions2 #e4bj p4 m41 convulsions1 alternating with paralysis of anterior and posterior extremities4 ,october #d3 #h4ej a4 m41 found dead4 ,guinea pig #gj4 ,white and brown male4 ,weight1 #ede grams4 ,diet1 oats4 ,october #g3 #c p4 m41 #f4e cc #b per cent caffein 7#bch mg per kilo7 aqueous solution injected subcutaneously2 #c4ej p4 m41 reflexes increased4 ,october #i3 #i a4 m41 found dead4 ,guinea pig #ga4 ,brown and white male4 ,weight1 #edj grams4 ,diet1 oats4 ,october #g3 #c p4 m41 #f4e cc #b per cent caffein solution 7#j4bd gram per kilo7 injected subcutaneously2 #c4de p4 m41 reflexes increased1 tetanus4 ,october #i3 #i a4 m41 found dead4 ,guinea pig #gb4 ,brown and white male4 ,weight1 #efj grams4 ,diet1 oats4 ,october #g3 #c p4 m41 #f4e cc #b per cent caffein 7#j4bcb gram per kilo7 aqueous solution administered by subcutaneous injection2 #c4ce p4 m41 reflexes increased4 ,october #aj3 found dead4 ,autopsy3 ,nos4 #gj1 #ga1 #gb showed congestion of organs4 ,the reaction to caffein in the experiments of this series 7,c7 showed considerable variation4 ,the appearance of symptoms1 as well as the final outcome of the experiments1 differed markedly in a number of cases1 notwithstanding the fact that the conditions were the same2 thus the administration of #j4b gram per kilo to guinea pigs1 all of which received the same diet1 induced no symptoms in two of the animals 7,nos4 #ff and #fe71 while marked symptoms were observed in the other four2 in two of these the symptoms appeared in one hour and a quarter after injection1 and in two others 7,nos4 #fh and #fi71 mild symptoms only appeared in #bj or #be minutes4 ,the last two were under observation for #d hours longer1 but there was no visible change in their condition4 ,the duration of life in all of these guinea pigs1 as indicated in the table1 likewise varied4 ,two 7,nos4 #fj and #fh7 died during the night after they received caffein1 one survived 7,no4 #fe71 and three others 7,nos4 #eg1 #ff1 and #fi7 lived #b1 #e1 and #i days1 respectively4 ,experiments with larger doses likewise showed differences in the behavior of these animals toward caffein1 but they were not quite so marked4 ,as shown in the table1 symptoms appeared in from #ce minutes to #a4e hours after injection4 ,the duration of life was less than #a day in two pigs1 about twice as long in two others1 and in one case between #b and #c days4 ,a comparison made with results obtained in the preceding series shows a striking difference in the resistance to caffein4 ,as #b decigrams per kilo proved more rapidly fatal to the guinea pig than the larger doses employed in the later experiments1 this difference in the resistance to caffein may be due to several factors4 ,as pointed out in the experiments on rabbits1 age might be an important factor influencing the toxicity of caffein4 ,unfortunately1 no accurate data were available on the age of the guinea pigs1 but they were all apparently full grown1 although they differed in weight considerably4 ,the difference in their ages was in all probability not very great4 ,moreover1 it will be observed that the resistance in series ,b and ,c differed in animals of approximately the same weight4 ,this is evident on comparing experiments ,nos4 #bj1 #ch1 and #ac of series ,b with ,nos4 #fe1 #ff1 and #fi of the next series4 ,again1 further inspection and analysis of these tables show no difference in the toxicity1 although there may be considerable difference in the weight1 from which it may be concluded that the animals were of about the same age or that this plays no part in the resistance to caffein in the guinea pig4 ,diet is another factor which should be taken into consideration in this connection4 ,the recent work of ,hunt7#ci7 indicates that this may influence the resistance of animals to some poisons4 ,our experiments1 however1 fail to show any difference in the toxicity of the caffein in guinea pigs1 whether fed oats1 carrots1 or both1 for different results were obtained on the same diet1 and there seemed to be little or no difference in the toxicity of caffein when the diet was different4 ,other explanations suggest themselves to account for the results obtained4 ,seasonal changes have been assigned by a number of investigators as a cause of variation in the resistance to drugs4 ,according to ,focke17#bd7 frogs are more susceptible to digitalis in the spring than in the summer1 while ,moschkowitsch7#fa7 and ,edmunds7#ba7 reported the very opposite results4 ,schmiedeberg's7#hj7 observations on strophantin in frogs were in harmony with those of ,edmunds7#ba7 and ,moschkowitsch47#fa7 ,similar results were reported with guinea pigs4 ,harrington's7#cd7 experiments indicate that stimulation of the vagus is less effective from ,october to ,january than from ,february to ,april1 when they are also much more susceptible to operative procedure4 ,hunt found that the resistance of guinea pigs to aceto nitril is about twice as great in the summer months as it is in ,january and ,february4 ,race might also be thought of as an important factor in this connection4 ,since the guinea pigs used at different seasons of the year were of several varieties1 there is no reason to suppose1 however1 that the varieties experimented upon in the summer were more resistant than those used in the winter and spring4 ,it is highly probable1 therefore1 that the greater resistance to caffein of the guinea pigs of series ,c than those of series ,b was due to seasonal variation4 ,doses of #j4bj to #j4bd gram caffein per kilo weight1 therefore1 may be regarded as the minimum fatal dose for the guinea pig1 depending upon the season4 ,since #j4b gram per kilo proved to be rapidly fatal in series ,b1 this quantity was perhaps not the minimum fatal dose for the guinea pig at the season during which the experiments were made4 ,additional tests with smaller doses were therefore carried out during ,february and ,march4 ,the results are shown in series ,d4 ,,series ,d4 ,guinea pig #di4 ,male4 ,weight1 #eaj grams4 ,diet1 oats for #a month previous to experiment4 ,march #ag3 #c p4 m41 #d cc #b per cent caffein 7#j4af gram per kilo7 were injected subcutaneously2 #d4dj p4 m41 reflexes increased2 #e4dj p4 m41 no symptoms4 ,march #ah3 #i a4 m41 found dead1 died in less than #ah hours4 ,autopsy3 ,hemorrhage into abdominal cavity2 liver and spleen unduly congested2 intestines injected2 hemorrhagic area at point of injection4 ,guinea pig #dj4 ,male4 ,weight1 #fcj grams4 ,diet1 oats and carrots one week previous to injection4 ,february #ab3 #aa a4 m41 #e cc #b per cent caffein 7#j4aeh gram per kilo7 injected subcutaneously into back4 ,february #ac3 #a p4 m41 still alive4 ,february #ad3 #i a4 m41 found dead4 ,guinea pig #de4 ,female4 ,weight1 #dce grams4 ,diet1 oats for about one month previous to injection4 ,march #ag3 #c p4 m41 #c4e cc of #b per cent caffein injected subcutaneously in the back 7#j4afj gram per kilo72 #d4ce p4 m41 no symptoms2 #e4dj p4 m41 no symptoms4 ,guinea pig #ci4 ,male4 ,weight1 #hbj grams4 ,diet1 oats and carrots4 ,february #ab3 #aa a4 m41 #f cc 7#j4ae gram per kilo7 #b per cent caffein injected subcutaneously in back4 ,february #ad3 #i a4 m41 alive2 seemed to be in good condition2 found dead at #a p4 m4 ,guinea pig #da4 ,weight1 #ffj grams4 ,diet1 oats and carrots one week previous to injection4 ,february #ab3 #aa a4 m41 #e cc 7#j4ae gram per kilo7 #b per cent caffein injected subcutaneously4 ,february #ad3 #b p4 m41 pig alive2 apparently normal4 ,february #ah3 ,guinea pig still alive and apparently in good condition4 ,guinea pig #df4 ,female4 ,weight1 #dgj grams4 ,diet1 oats about one month previous to experiment4 ,march #ag3 #c4ae p4 m41 #d cc 7#j4agj gram per kilo7 #b per cent caffein injected into back subcutaneously2 #d4ce p4 m41 reflexes increased1 tremors on handling marked2 #e4dj p4 m41 no change1 symptoms about as before4 ,march #ah3 #b4cj p4 m41 no symptoms4 ,the experiments of this series 7,d7 likewise showed a considerable difference in the resistance of the individual guinea pigs4 ,nos4 #da1 #de1 and #df survived2 the rest of the pigs died within #ah hours to #b days after the administration of caffein4 ,since an autopsy was held on one only1 it is impossible to assign a cause for the variation in the toxicity of caffein in these guinea gigs1 as the diet and the other conditions under which the experiments were conducted were the same4 ,it was found in the experiments on cats and rabbits that the presence of morbid processes tends to increase the toxicity of caffein4 ,the observations of ,ophls7#ff7 are of interest in this connection4 ,he found spontaneous lesions of the kidney and liver in a large proportion of guinea pigs examined4 ,the greater susceptibility to caffein of guinea pigs ,nos4 #ci1 #dj1 #di1 is probably due therefore to some pathological change which increased its toxicity4 ,about #j4b to #j4bd gram per kilo may therefore be regarded as the minimum lethal dose for the normal guinea pig when caffein is introduced subcutaneously1 the minimum toxic dose being about #aej-afj mg per kilo4 ,experiments were also conducted to determine the largest dose which does not produce any visible effects4 ,in a number of tests with from #ajj to #abj mg caffein per kilo 7series ,e1 see ,table #f1 p4 #ea7 no manifestation of nervous or muscular disturbance nor any departure from the normal in respiratory activity was observed4 ,such quantities may be regarded as the largest doses which are surely safe for these animals4 ,it is quite possible1 therefore1 that the greater variation in the toxicity of caffein observed in these experiments is due to morbid conditions4 ,moreover1 there is some evidence that caffein increases the toxicity of certain poisons1 as shown by ,hale7#cc7 for acetanilid4 ,is it not possible that caffein may similarly be affected by poisons circulating within the body8 ,indeed the recent work of ,loeb7#bc7 makes this supposition highly probable4 ,this investigator found that caffein and adrenalin injected together produce myocarditis in the rabbit4 ,it is conceivable that the combined action of caffein and some preexisting poison may cause changes which terminate in the death of the animal4 ,the delayed death of guinea pigs after the administration of caffein observed in this and other series may probably be accounted for in this way4 ,experiment #eg lends some support to this view4 ,the condition of the kidneys and the presence of a severe gastro-enteritis are sufficient to account for the death of this case4 ,again the frequent association of gastro-enteritis and congestion of the organs in caffein intoxication found in different animals makes it highly probable that these lesions were caused by caffein4 ,,injection ,,into ,,the ,,peritoneal ,,cavity4 ,the experiments were carried out with different doses4 ,all the guinea pigs in this series were kept on a uniform diet1 consisting of oats4 ,most of them were of average size and there were no wide variations in their weights4 ,the experiments of series ,a with the smallest doses were conducted in ,march and ,april2 all the other experiments it will be noticed were made in ,october4 ,,series ,a4 ,guinea pig #da4 ,weight1 #gjj grams4 ,diet1 oats4 ,april #a3 #c4cj p4 m41 #d4e cc #b per cent caffein 7#acj mg per kilo7 injected into peritoneal cavity4 #e4ce p4 m41 symptoms present but no tetanus4 ,april #b3 ,found dead about #b p4 m41 duration of life about #bb hours4 ,autopsy3 ,subcutaneous hemorrhage at the point of inoculation2 serious exudate on visceral and parietal peritoneum with marked inflammation of peritoneum2 portions of intestines showed slight enteritis4 ,guinea pig #di4 ,male4 ,weight1 #cgj grams4 ,diet1 oats4 ,april #a3 #c4ae p4 m41 #b4e cc #b per cent caffein 7#ace mg per kilo7 injected into the peritoneal cavity2 #e4cj p4 m41 symptoms present2 reflexes increased1 but no tetanus4 ,guinea pig survived4 ,guinea pig #dg4 ,female4 ,weight1 #eej grams4 ,diet1 oats since about ,february #d4 ,march #ag3 #c4cj p4 m41 #c4e cc #b per cent caffein 7#abg mg per kilo7 injected into peritoneal cavity2 #d4ce p4 m41 increased irritability present1 but not marked2 #e4dj p4 m41 symptoms about the same as before4 ,march #ah3 #b4cj p4 m41 condition good2 no symptoms4 ,survived4 ,guinea pig #ej4 ,female4 ,weight1 #bij grams4 ,diet1 oats4 ,april #a3 #c4cj p4 m41 #b cc #b per cent caffein 7#ach mg per kilo7 injected into peritoneal cavity2 #e4ce p4 m41 symptoms present2 reflexes much increased1 but no tetanus4 ,survived4 ,,series ,b4 ,guinea pig #ea4 ,yellow female4 ,weight1 #dae grams4 ,october #a3 #i4ej a4 m41 #c cc 7#add mg per kilo7 #b per cent caffein injected into peritoneal cavity2 #d4cj p4 m41 no symptoms1 although under observation all day4 ,october #c3 #b p4 m41 alive4 ,guinea pig #eb4 ,white male4 ,weight1 #dej grams4 ,october #a3 #i4de a4 m41 #c4e cc1 #b per cent caffein 7#aee mg per kilo71 injected into peritoneal cavity2 #d4cj p4 m41 no symptoms developed since injection4 ,october #c3 #b p4 m41 alive4 ,guinea pig #eh4 ,brown and white male4 ,weight1 #dij grams4 ,october #a3 #i4de a4 m41 #d cc1 #b per cent caffein 7#afc mg per kilo71 injected into peritoneal cavity2 #d4cj p4 m41 no symptoms developed since injection4 ,october #c3 #b p4 m41 alive4 ,october #h3 ,found dead4 ,autopsy3 ,congestion of lungs1 spleen1 liver1 kidneys1 and small intestines4 ,,series ,c4 ,guinea pig #ei4 ,gray and white4 ,weight1 #cge grams4 ,diet1 oats4 ,october #c3 #b p4 m41 #c4ge cc 7#j4b gram per kilo7 injected into peritoneal cavity2 #b4ae p4 m41 reflexes increased but not markedly2 #d p4 m41 reflexes still more increased2 no other symptoms2 #e4cj p4 m41 no symptoms4 ,october #d3 #h4ej a4 m41 guinea pig alive and active4 ,guinea pig #eh4 ,brown and white4 ,weight1 #chj grams4 ,diet1 oats4 ,october #c3 #b p4 m41 #c4h cc caffein 7#j4b gram per kilo71 #b per cent solution1 injected into peritoneal cavity2 #b4aj p4 m41 hind legs extended1 then tetanus2 attack lasted a few seconds1 after which pig raised himself on his legs1 but reflexes remained much exaggerated2 #d p4 m4 to #e4cj p4 m41 no symptoms of caffein intoxication4 ,october #d3 #h4ej a4 m41 guinea pig alive and active4 ,guinea pig #ef4 ,gray and white male4 ,weight1 #ddj grams4 ,diet1 oats4 ,october #a3 #aa4cj a4 m41 received #d4f cc of #b per cent caffein solution 7#j4b gram per kilo7 into abdominal cavity2 #aa4de a4 m41 stiffness and rigidity of posterior extremities1 reflexes increased2 #ab4cj p4 m41 hind legs paralyzed1 reflexes increased2 #d4ce p4 m41 no symptoms1 guinea pig in good condition4 ,october #c3 ,still alive in good condition4 ,october #ad3 ,died4 ,autopsy3 ,anterior lobe of right lung hepatized4 ,small portion of small intestine edematous4 ,other organs normal4 ,guinea pig #ee4 ,white and yellow male4 ,weight1 #fij grams4 ,diet1 oats4 ,october #a3 #aa4cj a4 m41 received #f4e cc of #b per cent solution caffein 7#ahh mg per kilo7 into peritoneal cavity2 #aa4dj a4 m41 stiffness in all extremities1 reflexes markedly increased2 #ab4cj p4 m41 reflexes increased1 anterior and posterior extremities paralyzed2 #c p4 m41 found dead4 ,,series ,d4 ,guinea pig #fg4 ,gray and yellow male4 ,weight1 #ccj grams4 ,diet1 oats4 ,october #e3 #aa4be a4 m41 #d cc of #b per cent caffein injected into peritoneal cavity 7#bdj mg per kilo72 #aa4cj a4 m41 tetanus--survived1 convulsions off and on4 ,death at #b4ee p4 m4 ,autopsy3 ,severe gastroenteritis2 kidney petechiated2 congestion of lungs and liver4 ,guinea pig #fc4 ,gray and white male4 ,weight1 #cdj grams4 ,diet1 oats4 ,october #e3 #aa4bj a4 m41 #d cc of #b per cent caffein 7#bce mg per kilo7 injected into peritoneal cavity4 ,october #ad3 ,alive and in good condition4 ,guinea pig #fd4 ,brown and black female4 ,weight1 #cje grams4 ,october #e3 #aa4ce a4 m41 #c4h cc #b per cent solution caffein 7#bej mg per kilo7 injected into peritoneal cavity2 #aa4dj a4 m41 tetanus--survived1 convulsions off and on1 died at #d4ae p4 m4 ,autopsy3 ,findings exactly the same as in ,no4 #fg4 ,examination of the results of the experiments by intraperitoneal injections showed that #j4b gram caffein per kilo was toxic in two guinea pigs 7,nos4 #ei and #eh74 ,severe symptoms were observed within #ae minutes in ,no4 #ef and within one hour in ,no4 #ee after the administration of approximately the same dose of caffein4 ,one of these died within three and one-half hours2 the other1 ,no4 #ef1 made a good recovery from the acute effects4 ,this amount of caffein may be regarded1 therefore1 as the minimum toxic dose for the guinea pig when injected into the peritoneal cavity4 ,this is corroborated by the experiments of series ,b in which smaller doses failed to show any muscular1 nervous1 or respiratory symptoms1 nor were there any after effects noticed1 as all of them survived and were kept under observation for some time4 ,the guinea pigs of series ,a1 however1 seem to contradict these results4 ,it will be remarked that appreciably smaller doses induced symptoms in all of them1 and one case terminated fatally4 ,the seasonal variation1 as already pointed out1 is in all probability likewise responsible for the difference in the resistance between the guinea pigs of series ,a and ,b4 ,tests were made also to determine the minimum fatal dose4 ,for this purpose the experiments of series ,d were performed4 ,the resistance of ,no4 #fc in this series is quite striking4 ,we are unable to explain such a discrepancy in the results obtained under practically uniform conditions4 ,the minimum fatal dose of caffein1 when injected into the peritoneal cavity1 is therefore about #bdj to #bej milligrams per kilo4 ,these amounts1 it will be observed1 were rapidly fatal1 in striking contrast to the results obtained when such doses were injected subcutaneously4 ,this is probably due to a better absorption from the peritoneal cavity than from the subcutaneous tissues4 ,,administration ,,by ,,mouth4 ,all the guinea pigs in these experiments were kept on a diet of hay and oats and were of large size4 ,the tests were made with different doses of caffein in order to determine the limits of toxicity when the drug was administered by mouth4 ,guinea pig #abi4 ,white and black male4 ,weight1 #hee grams4 ,diet1 oats and hay4 ,june #f3 #b4bj p4 m41 #ab cc of #b per cent caffein 7#j4bh gram per kilo7 by mouth2 #c p4 m41 reflexes increased2 #e p4 m41 reflexes still more increased2 no other symptoms4 ,june #g3 #i a4 m41 found dead2 guinea pig passed #ge cc urine1 which was almost colorless4 ,autopsy3 ,heart and blood vessels injected2 lungs congested2 small intestines congested2 other organs apparently normal4 ,guinea pig #acj4 ,black and brown male4 ,weight1 #hjj grams4 ,diet1 oats and hay4 ,june #f3 #b4cj p4 m41 #ab cc of #b per cent caffein 7#j4c gram per kilo7 administered by mouth2 #c p4 m41 reflexes increased2 #e p4 m41 increase of reflexes greater than at #c p4 m4 ,june #g3 #i a4 m41 found dead2 only a few cubic centimeters of urine passed since #d p4 m4 ,autopsy3 ,heart and blood vessels injected2 lungs congested2 small intestines congested slightly4 ,guinea pig #aha4 ,white and yellow male4 ,weight1 #hfj grams4 ,diet1 oats and hay4 ,june #f3 #b4dj p4 m41 #ab cc #b per cent caffein administered by mouth2 #c p4 m41 reflexes increased2 #e p4 m41 reflexes still more marked4 ,june #g3 #i a4 m41 found dead1 pig passed about #e cc urine since #d p4 m4 of previous day4 ,autopsy3 ,same as in ,no4 #acj4 ,guinea pig #acf4 ,white and black male4 ,weight1 #a1jjj grams4 ,diet1 oats and hay4 ,june #i3 #d p4 m41 #g4e cc #b per cent caffein solution injected subcutaneously into the back2 #d4ej p4 m41 reflexes increased4 ,june #aj3 #i4cj a4 m41 more sensitive than normal guinea pigs1 but reflexes not quite so marked as at #e p4 m4 previous day1 about #ae cc urine passed since caffein was injected1 reduction of ,fehling's solution considerable1 no albumin4 ,june #ac3 ,alive and in good condition4 ,appetite good4 7,,note4--,parallel test with urine from two guinea pigs which did not receive caffein failed to show reduction of ,fehling's solution47 ,guinea pig #acg4 ,white and brown male4 ,weight1 #ibe grams4 ,diet1 oats and hay4 ,june #i3 #d p4 m41 #g cc #b per cent solution caffein injected subcutaneously2 #d4ej p4 m41 reflexes increased4 ,june #aj3 ,reflexes less marked than at #e p4 m4 previous day1 but is more sensitive than normal guinea pig1 about #aj cc urine passed since injection of caffein1 moderate amount of reduction of ,fehling's solution4 ,june #ac3 ,guinea pig alive1 appetite good1 condition good4 ,june #af3 #i a4 m41 found dead4 ,guinea pig #ace4 ,white and black male4 ,weight1 #iee grams4 ,diet1 hay and oats4 ,june #i3 #c p4 m41 #g4e cc #b per cent caffein solution given by mouth through stomach tube2 #d4ej p4 m41 reflexes increased4 ,june #aj3 ,reflexes less than on previous day and less marked than in ,no4 #acf1 a few cubic centimeters dirty brown urine collected but could not be tested for reduction4 ,june #ac3 ,condition good1 appetite good4 ,june #af3 #i a4 m41 found dead4 ,guinea pig #acd4 ,white and brown male4 ,weight1 #gdj grams4 ,diet1 hay and oats4 ,june #i3 #b4ee p4 m41 #f cc warm #b per cent caffein solution given by mouth through stomach tube2 #d4ej p4 m41 reflexes increased4 ,june #aj3 #i4cj a4 m41 reflexes much less than day before1 increase slight1 a few cubic centimeters of urine passed since injection of caffein1 looked brown and dirty1 could not be tested for reducing substances4 ,june #ac3 ,guinea pig alive1 appetite good1 condition good4 ,june #ad3 #i a4 m41 found dead4 ,guinea pig #abh4 ,white and black male4 ,weight1 #a1jge grams4 ,diet1 hay and oats4 ,june #g3 #aj a4 m41 #aa cc #b per cent caffein by mouth through stomach tube2 #aa4aj a4 m41 no symptoms1 no urine passed2 #a p4 m41 increased reflexes1 about #ae cc 7estimated7 urine passed2 #d p4 m41 reflexes increased1 still more urine passed 7about #bj cc72 #d4ej p4 m41 tetanus1 frequent attacks1 then paralysis and death at #d4eh p4 m4 ,autopsy3 ,lungs congested2 blood vessels of heart injected2 intestines slightly congested2 fatty liver4 ,guinea pig #abf4 ,white and gray male4 ,weight1 #ihj grams4 ,diet1 oats and hay4 ,june #g3 #i4dj a4 m41 #i4h cc #b per cent caffein given by mouth through stomach tube2 #aj a4 m41 no symptoms2 #aa4aj a4 m41 no urine passed1 reflexes increased2 #a p4 m41 more sensitive than before2 #d p4 m41 increase of reflexes more marked1 no urine passed2 #d4de p4 m41 about #ae cc urine collected2 #e p4 m41 no change4 ,june #h3 #i a4 m41 reflexes about the same as #e p4 m4 previous day1 no urine passed since #d4de p4 m4 previous day1 considerable reduction of ,fehling's solution1 much more than urine of guinea pig ,no4 #abg2 #aa4je a4 m41 convulsions2 #ab noon1 still alive and stretched out on abdomen2 died at #a p4 m4 ,autopsy3 ,lungs badly congested2 heart and blood vessels injected2 blood vessels of kidney and of small intestines injected2 liver engorged with blood2 a few necrotic spots in stomach4 ,guinea pig #abg4 ,white1 black1 and brown male4 ,weight1 #gfj grams4 ,diet1 oats and hay4 ,june #g3 #i4ej a4 m41 #g4f cc #b per cent caffein by mouth through stomach tube2 #aj a4 m41 no symptoms2 #aa4aj a4 m41 reflexes increased1 no urine passed2 #a p4 m41 very sensitive2 #d p4 m41 sensitiveness increased1 about #bj cc urine passed2 #e p4 m41 no change4 ,june #h3 #i a4 m41 reflexes about the same as #e p4 m4 previous day2 #i4cj a4 m41 guinea pig passed #cj cc urine since he received caffein1 urine showed a moderate amount of reduction2 #ab noon1 convulsions2 died at #b4cj p4 m4 ,autopsy3 ,lungs congested2 blood vessels of heart and of intestines injected2 numerous necrotic spots in stomach2 other organs apparently normal4 ,examination of the protocols shows that the absorption of caffein from the gastro-intestinal canal was quite rapid1 symptoms having been observed as early as #bj minutes after its introduction4 ,the duration of life1 it will be remarked1 varied with the size of the dose4 ,when approximately #c decigrams per kilo were fed1 all the animals died in the night4 ,they lived1 therefore1 less than #ah hours4 ,two decigrams per kilo were likewise fatal1 but the duration of life was longer4 ,to decide whether or not this is the smallest fatal dose1 smaller amounts were fed4 ,it seemed at first that about #aej mg per kilo was the smallest toxic dose1 and about #bjj mg per kilo the minimum fatal dose4 ,macroscopic examination of the organs1 however1 threw some doubt on this supposition1 for well-marked lesions were noticed in all of the guinea pigs which received #j4b gram per kilo4 ,it is quite possible1 therefore1 that the minimum fatal dose may be somewhat higher1 as we have reason to believe that1 at least in some pathologic conditions1 the susceptibility to caffein is increased4 ,the presence of fatty changes in the liver of ,no4 #abh and the rapid death in this case lends especial support to this view4 ,hence1 the minimum fatal dose is probably greater than #j4b gram per kilo for the normal guinea pig4 ,the doses employed for the tests on guinea pigs ,nos4 #abi1 #acj1 and #aca may be considered therefore the minimum fatal dose for these animals4 ,it will be also remarked that macroscopical examination of the organs of these animals failed to reveal the presence of severe lesions4 ,that the minimum toxic dose is probably much smaller than #j4bh gram per kilo is indicated by the experiments on guinea pigs ,nos4 #ace and #acd1 in which #j4ae gram caffein per kilo induced mild symptoms in from two to three hours4 ,both of these1 however1 and also ,no4 #acg died four to six days after the drug was fed4 ,as already pointed out1 caffein may be a factor in the delayed death of guinea pigs which received moderate doses of it4 ,that this supposition may also be true for guinea pigs ,nos4 #acd1 #ace1 and #acg is indeed made probable by the observation that after moderate amounts of caffein symptoms may persist in the guinea pig for about #bd hours1 and also by the fact that the secretion of urine in these animals was very scanty1 as shown in the preceding record of the experiments2 this means slow elimination of caffein and its products of decomposition4 ,it is conceivable that the presence of toxic amounts of caffein in the body for a considerable length of time would induce changes that ultimately lead to the death of the animal or that morbid processes are set up by the combined action of caffein and some preexisting poison4 ,since some guinea pigs1 however1 survived the doses indicated1 it is more probable that such changes would be brought about by caffein in the presence of a preexisting poison4 ,the death of these pigs1 and also of ,no4 #acg several days later1 is difficult to account for on any other theory than the one suggested4 ,were it not for the fact that controls1 that is1 animals of the same lot which had not received caffein survived all of the experimental animals1 changed conditions of environment or accident might be considered the cause of death in the guinea pigs of the last series4 ,,table #f4--,subcutaneous injection of guinea pigs4 ,,series ,a4 ---------------------------------------- ----------------------- ,number ,caffein,appearance ,duration of pig,weight4 per of of ,diet4 ,month4,remarks4 kilo4 symptoms4 life ---------------------------------------- ----------------------- ,grams4,gram4 #ah #ejj #j4cjj #b minutes #b hours ,carrots ,march ,female4 #dj minutes #ae #edh 4#bij #cj minutes ,oats do4 ,do4 #ad #ddb #cfj #ae minutes do4 do4 do4 ,do4 ---------------------------------------- ----------------------- ,,series ,b4 ---------------------------------------- ----------------------- #bj #dig #j4bjj #b hours #c hours ,oats ,april ,female4 #bj minutes#cj minutes #ch #egj 4#baj #be minutes#b hours ,carrots,febru ,male4 #ae minutes -ary #cg #hbj 4#bjj #a hour ,less than ,carrots do4 ,do4 #be minutes #ah hours and oats #ac #fah 4#aid #be hours ,oats ,march ,female4 #cf #hej 4#bjj #a hour #ah hours ,carrots ,febru ,male4 #cj minutes and oats -ary ---------------------------------------- ----------------------- ,,series ,c4 ---------------------------------------- ----------------------- #ff #eaj #j4bjj ,none #e days ,oats ,october,male4 #fe #eaj 4#bjj do4 ,survived do4 do4 ,do4 #fj #cbj 4#bai #a hour ,within do4 do4 ,female4 #ae minutes #ah hours #eg #cej 4#bjj do4 ,about do4 do4 ,do4 #b-ab days #fh #ghe 4#bjj #be minutes,less than do4 do4 ,male4 #bb hours #fi #ehe 4#bjj #bj minutes#i days do4 do4 ,do4 #fa #ccj 4#bdj #a hour ,less than do4 do4 ,female4 #cj minutes #bd hours #fb #cce 4#bch #a hour do4 do4 do4 ,do4 #gj #ede 4#bch #ej minutes,about #b do4 do4 ,male4 days #ga #edj 4#bdj #de minutes do4 do4 do4 ,do4 #gb #efj 4#bcb #ce minutes,about #c do4 do4 ,do4 days ---------------------------------------- ----------------------- ,,series ,d4 ---------------------------------------- ----------------------- #di #eaj #j4afj #a hour ,less than ,oats ,march ,male4 #dj minutes #ah hours #dj #fcj 4#aeh ,less than ,oats and,febru ,do4 #b days carrots4 -ary #de #dce 4#afj ,none ,survived ,oats ,march ,female4 #ci #hbj 4#aej #b days ,oats and,february,male4 carrots4 #da #ffj 4#aej ,survived do4 do4 #df #dgj 4#agj #a hour do4 ,oats 787,march ,female4 #bj minutes ---------------------------------------- ----------------------- ,,series ,e4 ---------------------------------------- ----------------------- #ai #eef #j4ajj ,survived ,oats ,april #db #dij 4#abj ,none do4 do4 ,february #dc #dcj 4#aaf do4 do4 do4 do4 #dd #ece 4#aab do4 do4 do4 do4 #ig #ccj 4#ajj do4 do4 do4 ,november #ih #ebj 4#ajj do4 ,about #c days,carrots do4 ---------------------------------------- ----------------------- ,,table #g4--;,injection into peritoneal cavity2 guinea pigs4 ,,series ,a4 ---------------------------------------- ----------------------- ,number ,caffein,appearance ,duration of pig,weight4 per of of ,diet4 ,month4,remarks4 kilo4 symptoms4 life ---------------------------------------- ----------------------- ,grams4,gram4 #da #gjj #j4acj #b hours #bb hours ,oats ,april ,male4 #di #cgj 4#ace #b hours ,survived do4 do4 ,do4 #ae minutes #dg #eej 4#abg #a hour do4 do4 ,march ,female4 #ej #bij 4#ach #b hours do4 do4 ,april ,do4 ---------------------------------------- ----------------------- ,,series ,b4 ---------------------------------------- ---------------------- #ea #dae #j4add ,none ,survived ,oats ,october,female4 #eb #dej 4#aee do4 do4 do4 do4 ,male4 #ec #dij 4#afc do4 do4 do4 do4 ,do4 ---------------------------------------- ---------------------- ,,series ,c4 ---------------------------------------- ----------------------- #ei #cge #j4bjj #ae minutes,survived ,oats ,october,gray and white4 #eh #chj 4#bjj #aj minutes do4 do4 do4 #ef #ddj 4#bjj #ae minutes#ad days do4 do4 ,male4 #ee #fij 4#ahh #a hour #c hours do4 do4 ,do4 #cj minutes ---------------------------------------- ----------------------- ,,series ,d4 ---------------------------------------- ----------------------- #fg #ccj #j4bdj #e minutes #cj minutes,oats ,october,male4 #fc #cdj 4#bce ,survived do4 do4 ,do4 #fd #cje 4#bej #be minutes#d hours do4 do4 ,female4 #dj minutes ---------------------------------------- ----------------------- ,,table #h4--;,caffein by mouth2 guinea pigs4 ,,series ,j4 ---------------------------------------- ----------------------- ,number ,caffein,appearance ,duration of pig,weight4 per of of ,diet4 ,month4,remarks4 kilo4 symptoms4 life ---------------------------------------- ----------------------- ,grams4,gram4 #abi #hee #j4bhj #dj minutes,less than ,hay and,june ,male4 #h hours oats #acj #hjj 4#cjj #cj minutes,less than do4 do4 ,do4 #ah hours #aca #hfj 4#bhj #bj minutes do4 do4 do4 ,do4 #ace #iee 4#aej #a hour #ej #f days do4 do4 ,do4 minutes #acd #gdj 4#afj #c hours #d days do4 do4 ,do4 7#a7acg #ibe 4#aej #ej minutes#f days do4 do4 ,do4 7#a7acf #a1jjj 4#aej do4 ,survived do4 do4 ,do4 #abf #ihj 4#bjj #bj minutes#bg hours do4 do4 ,do4 #abg #gfj 4#bjj #a hour #bh hours do4 do4 ,do4 #abh #a1jge 4#bjj #c hours #g hours do4 do4 ,do4 ---------------------------------------- ----------------------- 7#a7 ,subcutaneous injection for comparison4 ,,summary4 ,a survey of the results obtained in experiments on guinea pigs shows that the mode of introduction of caffein exerts but little influence on its toxicity4 ,on careful analysis it will be observed that the rate of absorption after the administration of caffein by mouth1 subcutaneously1 or intraperitoneally is about the same for the time of appearance of symptoms4 ,the persistence of the symptoms of caffein intoxication observed in these experiments for #bd hours after administration points to slow elimination1 which may be expected1 owing to the fact that the guinea pigs passed but little urine and caffein is not diuretic for these animals4 ,the prolonged presence of caffein in the body probably exerts a harmful influence or after effect1 which may account for the delayed death of some animals many days after a single dose of caffein was given4 ,among the factors which undoubtedly influence toxicity1 season should be considered1 while the presence of a diseased condition undoubtedly tends to decrease the resistance of the guinea pig to caffein4 ,diet was without any influence on the toxicity of the single dose of caffein4 ,,experiments ,,on ,,cats4 ,these experiments were performed on well-fed animals which were kept under observation for several days before the tests with caffein were made4 ,the diet consisted of meat exclusively4 ,in some cases the urine was examined for albumin and sugar before caffein was given4 ,no tests with caffein were made if large amounts of albumin were found4 ,it may be remarked that sugar was never found in cats before the administration of caffein1 but that considerable amounts of it were found in some cases after it was given4 ,studies by various modes of administration were made1 by subcutaneous injection1 intraperitoneally1 or by mouth4 ,attention was also directed to the resistance to caffein in young cats1 several experiments on kittens being made with this object in view4 ,,subcutaneous ,,injection4 ,rost stated that caffein is eliminated in the urine unchanged after its introduction into the body and that the amounts found varied with different species of animals4 ,in the rabbit the amount eliminated was about #ba per cent2 in the dog about #h per cent2 and in the cat somewhat less than #b4e per cent4 ,it would appear1 therefore1 that the cat decomposes caffein more readily than the rabbit or dog2 its resistance consequently ought to be greater than that of the other animals4 ,moderately large doses were accordingly employed in the preliminary experiments 7series ,a71 but the results obtained1 as shown in the protocols1 indicated that caffein is fully as toxic for the cat as for the rabbit or dog4 ,the doses were then decreased and experiments were performed in order to ascertain the smallest toxic as well as the smallest fatal dose4 ,,series ,a4 ,three decigrams of caffein per kilo were administered in these experiments4 ,the results are shown in the following protocols3 ,cat #d4 ,black and white4 ,weight1 #a1ddj grams4 ,may #bf3 #aj4je a4 m41 #bb cc #b per cent caffein 7#j4c gram per kilo7 injected subcutaneously2 #aa4aj a4 m41 copious salivation1 cat irritable1 muscular stiffness present1 but no tetanus2 #aa4de a4 m41 cat restless1 convulsions1 attacks of short duration1 no paralysis observed after the convulsions1 pupils dilated2 #d4de p4 m41 cat quiet1 slight paralysis present4 ,may #bg3 ,cat exhausted4 ,may #bh3 ,found dead4 ,cat #e4 ,black and white male4 ,weight1 #a1cif grams4 ,june #c3 #aj a4 m4 #ba cc of #b per cent caffein 7#j4c gram per kilo7 injected subcutaneously2 #ab noon1 found dead4 ,although there was considerable difference in the duration of life following the injection of the same dose of caffein per kilo1 the final outcome was the same1 as both cats died from the effects of the drug4 ,one died within #b hours and the other lived more than #cj hours after its administration4 ,three decigrams of caffein per kilo is1 therefore1 surely fatal to these animals4 ,tests made with smaller doses are shown in the following experiments3 ,,series ,b4 ,in these experiments the doses employed ranged between #j4bj and #j4be gram caffein per kilo4 ,cat #c4 ,black and white female4 ,weight1 #b1hed grams4 ,well fed4 ,june #d3 #aj4cj a4 m41 #ce cc #b per cent caffein 7#j4be gram per kilo7 injected subcutaneously2 #aa a4 m41 found dead4 ,cat #f4 ,black and white4 ,weight1 #a1fde grams4 ,june #c3 #bj cc #b per cent caffein 7#j4bdc gram per kilo7 injected subcutaneously at #c p4 m41 cat grew very irritable in a few minutes2 about #d4 p4 m4 reflexes decidedly increased2 #e p4 m41 cat paralyzed4 ,june #d3 ,cat found dead4 ,cat #h4 ,weight1 #a1gce grams4 ,october #g3 #d p4 m41 #bb cc #b per cent caffein 7#j4be gram per kilo7 injected subcutaneously in the back2 #d4cj p4 m41 cat irritable1 salivation profuse1 convulsions2 died at #e4cj p4 m42 no urine passed after caffein was given4 ,cat #i4 ,weight1 #a1ifj grams4 ,october #g3 #c4de p4 m41 #be cc #b per cent caffein 7#j4be gram per kilo7 injected subcutaneously in the back2 #d4de p4 m41 cat very irritable1 repeated attacks of convulsions1 salivation copious2 died at #e4cj p4 m42 cat did not urinate after injection of caffein4 ,cat #ab4 ,striped kitten4 ,weight1 #a1ahe grams4 ,october #i3 ,urine examined1 no albumin1 no sugar2 #a4de p4 m41 #ab cc #b per cent caffein administered2 #e p4 m41 cat alive1 no symptoms except salivation and general irritability4 ,october #aj3 #aj4cj a4 m41 found dead4 ,about #ae cc urine collected1 but no examination made4 ,cat #ad4 ,black4 ,weight1 #a1hee grams4 ,october #h3 #a4dj p4 m41 #ah4e cc #b per cent caffein 7#j4b gram per kilo72 #c p4 m41 cat became restless about #aj minutes after caffein was injected2 cried persistently and moved about in cage1 no convulsions1 cat urinated about #ae cc1 cat defecated4 ,october #i3 #i a4 m41 cat found dead in cage4 ,urine gave very heavy reduction of ,fehling's solution 7much more than was obtained from urine of rabbits72 #bj cc urine analyzed contained #d4fe per cent sugar4 ,autopsy3 ,lungs deeply congested2 liver marked fatty infiltration and degeneration2 spleen normal2 kidneys pale and anemic2 intestines normal2 stomach normal4 ,cat #ae4 ,striped4 ,weight1 #b1ade grams4 ,october #h3 #b p4 m41 #bb cc 7#j4b gram per kilo7 #b per cent caffein injected subcutaneously2 #b4cj p4 m41 cat irritable1 restless1 trying to get out of cage1 crying persistently2 #b4dj1 convulsions lasting about two minutes1 then cat raised itself and made attempts to get out of cage1 no salivation1 cat urinated about #aj cc and defecated4 ,october #i3 #i a4 m41 cat found dead in cage1 about #aj cc of urine contained enormous quantities of sugar4 ,autopsy3 ,lungs severely congested2 liver showed marked fatty degeneration2 spleen normal2 kidneys slightly pale and anemic2 intestines mildly congested2 stomach normal4 ,cat #ai4 ,white4 ,weight1 #a1ajj grams4 ,october #bj3 #ac cc of #b per cent caffein 7#j4bcf gram per kilo74 ,about #ae minutes later cat became irritable1 reflexes increased1 persistent crying1 stiffness of extremities1 diarrhea present2 #d4cj p4 m41 stiffness of muscles1 coordination much disturbed1 walked with great difficulty2 #d4cj p4 m41 no new symptoms1 persistent crying continued4 ,october #ba3 ,found dead4 ,cat #bj4 ,white kitten4 ,weight1 #gij grams4 ,october #bj3 #aa4ce a4 m41 #aj cc #b per cent caffein 7#j4be gram per kilo7 given subcutaneously2 #ab noon1 convulsions followed by paralysis2 #a4cj p4 m41 still breathing1 apparently in comatose condition1 lay on its side1 dyspnoea1 profuse salivation2 #d p4 m41 convulsions and death4 ,the results of the experiments of series ,b show that a dose of even #j4b caffein per kilo is very toxic for the cat4 ,symptoms appeared in one animal #dj minutes after the injection of caffein4 ,some of them were found dead #ah hours after injection1 which means that the duration of life was probably a great deal less since there was evidence that they had been dead for some time4 ,death occurred quite soon after larger doses were injected4 ,cat ,no4 #c died #cj minutes after it received caffein4 ,the amounts employed in these experiments can not be considered therefore as the minimum fatal doses4 ,smaller doses were then tried1 as shown in the experiments of the next series4 ,,series ,c4 ,experiments were performed on five cats which received from #adj to #aee mg per kilo1 as follows3 ,cat #bd4 ,striped4 ,weight1 #a1cjj grams4 ,october #be3 #aj a4 m41 #ej cc urine1 albumin moderate amount--no sugar2 #aj cc caffein injected subcutaneously at #ab noon2 #ab4cj1 irritable1 cried persistently1 no appetite2 #d p4 m41 no convulsions1 but persistent crying4 ,october #bg3 ,cat was still alive4 ,cat #ag4 ,weight1 #b1fbj grams4 ,october #ab3 #i4cj a4 m41 #fe cc urine collected2 more than a trace of albumin present1 no reduction of ,fehling's solution2 #c p4 m41 #bj cc #b per cent caffein 7#aej mg per kilo7 injected subcutaneously2 #c4ae p4 m41 irritable and restless4 ,october #ac3 #i a4 m41 about #ae cc urine collected1 reduction of ,fehling's solution marked2 osazone test also positive4 ,cat #bc4 ,black and white4 ,weight1 #a1fde grams4 ,october #be3 #aj a4 m41 #adj cc urine collected 7since ,october #bc71 small amount of albumin present1 no sugar4 ,october #bg3 #i a4 m41 no albumin2 no sugar in urine2 #aa4ej a4 m41 #ab4e cc caffein injected subcutaneously 7#j4ae gram per kilo72 #a p4 m41 convulsions and death4 ,cat #g4 ,striped kitten4 ,weight1 #a1bhe grams4 ,october #aa3 ,urine collected1 no albumin1 no sugar2 #i4ej a4 m41 #aj cc #b per cent caffein injected subcutaneously in the back2 #aj4aj1 violent convulsions lasting about #cj seconds2 #aj4bj1 convulsions of shorter duration2 #aj4cj convulsions2 #aj4ce1 convulsions lasting a few seconds2 urine passed about #aj4bj1 contained a moderate amount of albumin1 but there was no reduction of ,fehling's solution2 #aj4de1 profuse salivation and paralysis2 died about #aj4ej4 ,cat #ci4 ,yellow4 ,weight1 #b1bhe grams4 ,april #ac3 #b4dj p4 m41 #af cc #b per cent caffein 7#j4ad gram per kilo7 injected subcutaneously in the back2 #c4de p4 m41 cat died4 ,of the five experiments of this series three died after doses of #adj1 #aej1 and #aee mg per kilo4 ,the other two showed symptoms of toxicity1 but survived a dose of #aej mg per kilo which indicated that the minimum fatal dose was probably reached4 ,to test this supposition smaller doses were administered1 as shown in the following experiments4 ,,series ,d4 ,ten cats were used for this series of experiments1 and the doses administered varied between #ajc and #aci mg per kilo4 ,the results shown in the appended table 7p4#eh7 indicate that about #abj to #adj mg of caffein per kilo may induce mild symptoms in some cases4 ,the conclusion may be safely drawn therefore that #aej mg per kilo is approximately the minimum fatal dose for the cat when the drug is given subcutaneously4 ,that smaller doses are1 however1 by no means to be regarded as always safe is shown in the following experiments4 ,,series ,e4 ,cat #dc4 ,weight1 #c1bbe grams4,d ,d ,cat probably old2 had been in the laboratory for several weeks before the experiment4 ,gained in weight #age grams4 ,september #ad3 #aj4bj a4 m41 #bj cc #b per cent caffein 7#j4abd gram per kilo7 injected into the back2 #aa a4 m41 tetanus and death4 ,autopsy3 ,lungs congested2 liver congested and showed hemorrhagic spots in capsules and fatty degeneration2 kidneys slightly congested2 other organs normal4 ,cat #dh4 ,black female4 ,weight1 #c1jej grams4 ,september #ad3 #ah cc #b per cent caffein 7#j4aah gram per kilo7 injected subcutaneously in the back2 #aj4cj a4 m41 violent convulsions and death4 ,autopsy3 ,lungs congested in spots showing numerous petechia2 liver congested2 spleen congested2 other organs normal4 ,the diminished resistance to caffein of cats ,nos4 #dc and #dh might be due to the pathologic changes found on autopsy1 for evidence is not wanting that the toxicity of drugs might be greatly altered under pathological conditions4 ,hunt7#dj7 has shown that resistance to acetonitril is considerably diminished in chronic alcoholism4 ,this seems to be true also of other drugs under abnormal conditions4 ,smaller doses of atropin7#gh7 are required in lead poisoning than under normal conditions to produce the same results4 ,the following experiment is of interest in this connection1 for in this case a much smaller dose than was given in experiments ,nos4 #dc and #dh produced the typical symptoms of caffein poisoning and proved to be fatal4 ,cat #dg1 black and white male4 ,weight1 #d1bbj grams4 ,september #ae3 ,received subcutaneously #ah cc #b per cent caffein 7#j4jhd gram per kilo72 no symptoms observed for about six hours4 ,september #af3 ,no symptoms4 ,september #ag3 ,weight1 #d1bej grams2 injected #ah cc #b per cent caffein 7#j4jhd gram per kilo72 tetanus and death after two hours4 ,autopsy3 ,severe hemorrhagic pneumonia2 kidneys pale1 other organs normal4 ,since two controls survived the same dose in proportion to the body weight of the animal without showing any symptoms1 the assumption is justified that the lower resistance to caffein was due to the presence of pneumonia1 thus affording additional support to the view that the toxicity of caffein may be increased in disease4 ,,injection ,,into ,,the ,,peritoneal ,,cavity4 ,these experiments were carried out on full-grown and on young subjects4 ,as in previous experiments1 doses of different sizes were employed4 ,a dose of #j4b gram per kilo was tried first and then reduced gradually to #j4a gram per kilo4 ,cat #aj4 ,female4 ,weight1 #b1igj grams4 ,october #i1 #aiji3 #a4cj p4 m41 #cj cc #b per cent caffein 7#j4b gram per kilo7 injected into the peritoneal cavity2 urine examined for albumin and sugar1 negative2 cat found dead at #b4cj p4 m4 ,no urine in the bladder4 ,cat #af4 ,black female4 ,weight1 #b1dbj grams4 ,october #i1 #aiaj3 ,urine examined for albumin and sugar1 negative2 #b4cj p4 m41 #bb cc #b per cent caffein 7#j4ahc gram per kilo7 injected into the peritoneal cavity2 found dead at #c p4 m4 ,cat #ii4 ,well-fed gray female4 ,weight1 #c kilos4 ,june #bb1 #aiaa3 #c4dj p4 m41 #ae cc #b per cent caffein injected into peritoneal cavity2 salivation and marked irritability within one hour after injection4 ,june #bd3 ,alive1 appetite good4 ,cat #ih4 ,well-fed black male4 ,weight1 #d1ajj grams4 ,june #bb3 #c4de p4 m41 #bj4e cc #b per cent caffein 7#j4a gram per kilo7 injected into peritoneal cavity2 very irritable a few minutes after injection1 no other symptoms4 ,june #bd3 ,no symptoms1 appetite good4 ,cat #ic4 ,black and white4 ,weight1 #a1dej grams4 ,june #bb3 #c p4 m41 #cj cc #b per cent caffein 7#j4acg gram per kilo7 injected into peritoneal cavity2 salivation1 no other symptoms2 under observation until #f p4 m4 ,june #bc3 #i a4 m41 no urine1 cat showed no symptoms4 ,june #bd3 #i a4 m41 no symptoms1 took nourishment as usual4 ,cat #hg4 ,well-fed white female4 ,weight1 #b1fae grams4 ,june #bc3 #b4de p4 m41 #ai cc #b per cent caffein 7#j4ade gram per kilo7 injected into peritoneal cavity2 became irritable and restless4 ,june #bd3 #i a4 m41 no symptoms1 took nourishment as usual4 ,cat #ig4 ,gray4 ,age1 #c months4 ,weight1 #ejj grams4 ,diet1 meat4 ,june #bd3 #b4be p4 m41 #e cc #b per cent caffein 7#j4b gram per kilo7 injected into peritoneal cavity2 #d p4 m41 no symptoms4 ,june #bi3 ,died4 ,cat #if4 ,gray and white4 ,age1 #c months4 ,weight1 #ege grams4 ,diet1 meat4 ,june #bd3 #b4bj p4 m41 #d cc #b per cent caffein 7#j4aci gram per kilo7 injected into peritoneal cavity2 #c4ee p4 m41 no symptoms4 ,june #cj3 ,died4 ,cat #ie4 ,black4 ,age1 about #c months4 ,weight1 #hfj grams4 ,diet1 meat4 ,june #bd3 #aj4ae a4 m41 #h4f cc #b per cent caffein injected into peritoneal cavity1 salivation immediately after injection2 #aj4be1 convulsions and paralysis2 died #aj4de a4 m4 ,autopsy3 ,macroscopical examination of the organs1 negative4 ,cat #id4 ,black and white4 ,weight1 #gij grams4 ,age1 about #c months4 ,diet1 meat4 ,june #bd3 #aj a4 m41 #h cc #b per cent caffein injected into peritoneal cavity2 #d p4 m4 under continual observation since injection1 cat very irritable1 respiration more rapid than normal1 diarrhea present4 ,examination of the above protocols show that a dose of #b decigrams per kilo was fatal within one hour to one cat and that a somewhat smaller dose killed another individual in #cj minutes4 ,amounts under #j4ae gram per kilo were just sufficient to induce mild symptoms1 such as increased irritability and salivation1 which disappeared within a few hours4 ,in no case were the effects noticeable on the following day4 ,the experiments on young kittens are especially interesting1 as they proved1 contrary to expectation1 to be distinctly more resistant than full grown individuals4 ,the death of ,nos4 #ig and #if within five and six days1 respectively1 can not be ascribed to caffein1 since some of the controls also died4 ,moreover1 it will be remarked in this connection that no symptoms appeared in three of the four young kittens after the administration of a dose which was rapidly fatal to adult cats4 ,the rapid death of ,no4 #ie after the same dose forms an exception which can not be accounted for1 as macroscopical examination at autopsy proved negative4 ,,administration ,,by ,,mouth4 ,two decigrams per kilo were given at first1 but it was found that this amount was surely fatal4 ,the dose was therefore reduced to #j4abe gram per kilo4 ,in all of these experiments caffein was given by means of a soft rubber catheter slipped over the stem of a funnel which served as a stomach tube4 ,a #b per cent aqueous solution was used throughout these tests except in one case in which caffein was given mixed with the food4 ,cat #ib4 ,black and white female4 ,weight1 #a1gej grams4 ,june #aj3 #ab4je p4 m41 #ad cc #b per cent caffein 7#j4af gram per kilo7 given by mouth2 cat was quiet when tied on holder1 struggled only a little when tube was put into stomach2 #ab4cj p4 m41 cat vomited1 no other symptoms4 ,june #ac3 ,condition good1 appetite good4 ,cat #hg4 ,white female4 ,weight1 #b1fbj grams4 ,diet1 meat4 ,june #e3 #b4ae p4 m41 #bj cc #b per cent caffein 7#j4ae gram per kilo7 solution administered by mouth through stomach tube2 #b4cj p4 m41 cat irritable1 but no other symptoms2 #e p4 m41 condition about the same1 except that it was more irritable and showed some stiffness of the extremities4 ,june #ac3 ,alive and in good condition1 appetite good1 not irritable4 ,cat #ia4 ,white female4 ,weight1 #c1jej grams4 ,june #aj3 #ab noon1 #bc cc 7#j4ae gram per kilo7 of #b per cent caffein administered by mouth1 cat struggled violently2 #a4cj1 salivation2 #a4dj p4 m41 convulsions2 died at #b p4 m4 ,autopsy3 ,congestion of lungs1 liver1 and spleen2 heart vessels injected2 other organs normal4 ,cat #hh4 ,black and white female4 ,weight1 #c1bfj grams4 ,diet1 meat4 ,june #e3 #b4bj p4 m41 #be cc of #b per cent caffein 7#j4ae gram per kilo7 given by mouth2 #b4de p4 m41 cat irritable1 no other symptoms 7cat did not vomit after the administration of caffein72 #d p4 m41 cat found dead4 ,autopsy3 ,liver very much congested2 heart contracted2 body was still warm at the time of autopsy4 ,cat #ij4 ,white and yellow female4 ,weight1 #b1fhe grams4 ,diet1 meat4 ,june #e3 #c4ae p4 m41 #bg cc of #b per cent caffein 7#j4b gram per kilo7 given by mouth through stomach tube1 about half an hour later cat became irritable and began to salivate2 at #d4cj p4 m4 salivation became more marked1 dyspnoea was well developed1 and the cat was quite restless and had tremors2 #e p4 m41 short spasms of posterior extremities1 but lay quietly in the cage most of the time2 #e4bj p4 m41 convulsions of short duration and death1 muscular relaxation followed immediately after convulsions1 no vomiting1 diarrhea observed after administration of caffein1 and cat passed about #aj cc of urine4 ,june #f3 #i a4 m41 found dead4 ,cat #hi4 ,white and black female4 ,weight1 #b1hfj grams4 ,diet1 meat4 ,june #e3 #c4ae p4 m41 #bh4f cc 7#j4b gram per kilo7 of #b per cent caffein given by mouth through stomach tube1 no vomiting observed1 nor any other symptoms2 #c4cj1 found dead4 ,autopsy3 ,organs normal2 liver congested4 ,cat #hb4 ,gray female4 ,march #c1 weight #b1dej grams2 ,june #f1 weight #b1gej grams4 ,diet1 #aej grams of meat daily4 ,june #g3 ,given #j4dabe gram of caffein in #aej grams of meat1 did not eat4 ,june #h3 ,given #j4dabe gram of caffein in #aej grams of meat1 refused to eat4 ,june #i3 ,given #aej grams of meat without caffein1 ate all of it4 ,june #aj3 ,no food given4 ,june #aa3 ,no food given4 ,june #ab3 ,given #j4dabe gram caffein in #aej grams of meat 7#aej mg per kilo71 ate all of it4 ,june #ac3 ,found dead4 ,autopsy3 ,lungs congested1 liver congested2 other organs apparently normal4 ,cat #ajj4 ,gray female4 ,weight1 #b1gdj grams4 ,diet1 meat4 ,july #ag3 #c p4 m41 #ag cc of #b per cent caffein 7#abd mg per kilo7 given by mouth through stomach tube at #c4bj p4 m42 #e p4 m41 very irritable1 but no other symptoms4 ,july #ah3 ,under observation all day1 no symptoms4 ,cat #ic4 ,black and white female4 ,weight1 #a1fdj grams4 ,july #ag3 #c4cj p4 m41 #aj cc 7#j4abe gram per kilo7 of #b per cent caffein given by mouth through stomach tube4 ,july #ah3 ,under observation all day1 no symptoms4 ,from the results of the experiments of this series it appears that #j4ae gram caffein per kilo may be fatal within a few hours after its administration1 even if the drug is mixed with a moderate amount of meat4 ,experiments #hg and #ib show1 however1 that this amount may be borne by some individuals without any serious consequences1 as the cats were under observation for some time after they received caffein1 and no untoward symptoms were noticed in either of them during this time4 ,it may be remarked that cat ,no4 #ib vomited shortly after it received caffein4 ,it is practically certain1 therefore1 that this amount of caffein in proportion to the weight of the animal will in the great majority of cases prove fatal1 and perhaps in a smaller percentage of individuals it is surely toxic if it does not escape absorption4 ,smaller doses may cause irritability in some individuals1 but symptoms referable to nervous symptoms of muscles were absent1 as in experiments ,nos4 #ic and #ajj4 ,the minimum fatal dose of caffein for the cat when given by mouth is1 therefore1 #j4ae gram per kilo4 ,,table #i4--,subcutaneous injection2 cats4 ,,series ,a4 ---------------------------------------- -------------------------- ,number4 ,weight4 ,caffein ,symptoms4 ,duration of life4 per kilo4 ---------------------------------------- -------------------------- ,grams4 ,gram4 #d #a1ddj #j4cj #fe minutes ,over #bi hours4 #e #a1cif 4#cj ,about #b hours4 ---------------------------------------- -------------------------- ,,series ,b4 ---------------------------------------- -------------------------- #c #b1hed #j4be #cj minutes4 #f #a1fde 4#bdc ,few minutes #a hour #cj minutes4 #h #a1gce 4#be #cj minutes4 #a hour4 #i #a1ifj 4#be #a hour #a hour #de minutes4 #ab #a1ahe 4#bj #c hours ,less than #ah hours4 #ad #a1hee 4#bj #a hour #bj minutes ,do4 #ae #b1ade 4#bj #dj minutes4 ,do4 #ai #a1ajj 4#bcf #ae minutes ,do4 #bj #gij 4#be #d hours #cj minutes4 ---------------------------------------- --------------------------- ,,series ,c4 ---------------------------------------- -------------------------- #bd #a1cjj #j4aec #a hour ,survived4 #ag #b1fbj 4#ae #ae minutes ,do4 #bc #a1fde 4#ae #a hour #aj minutes4 #g #a1bhe 4#aee #bj minutes #a hour4 #i #b1bhe 4#ad #fe minutes4 ---------------------------------------- -------------------------- ,,series ,d4 ---------------------------------------- -------------------------- ,number4,weight4 ,caffein ,symptoms4 ,duration of life4 per kilo4 ---------------------------------------- -------------------------- ,grams4 ,gram4 #ac #gcj #j4aci ,restlessness #ba #a1afe 4#ach ,none #be #ife 4#ajc do4 #bf #a1fje 4#abe do4 #bg #a1fbe 4#abe do4 #bh #b1cce 4#abh do4 ,received #b doses3 survived4 #dj #b1gaj 4#abi do4 ,do4 #da #a1ghe 4#abc do4 ,do4 #db #b1cae 4#aab do4 ,do4 #ch #b1cbe 4#abj ,mild ,died after second dose4 ---------------------------------------- -------------------------- ,,series ,e47#a7 ---------------------------------------- -------------------------- #dc #c1bbe #j4abd #dj minutes4 #dh #c1jej 4#aah ,died soon after4 #dg #d1bbj 4#jhd ,survived4 7#b7dg #d1bej 4#jhd #b hours4 ---------------------------------------- -------------------------- 7#a7 ,pathological conditions4 7#b7 ,two days after first injection4 ,,table #aj4--;,injections into peritoneal cavity2 cats4 ---------------------------------------- -------------------------- ,number4,weight4 ,caffein ,symptoms4 ,duration of life4 per kilo4 ---------------------------------------- -------------------------- ,grams4 ,gram4 #ii #c1jjj #j4ajj ,mild ,survived4 #ih #d1ajj 4#ajj do47#a7 ,do4 #ic #a1dej 4#acg ,very mild ,do4 #hg #b1fae 4#ade do4 ,do4 #ig #eje 4#bjj ,none #e days4 #if #ege 4#aci do4 #f days4 #ie #hfj 4#bjj #ae minutes #cj minutes4 #id #gij 4#bjj ,diarrhea ,survived4 #aj #b1igj 4#bjj #a hour4 #af #b1dbj 4#ahc #cj minutes4 ---------------------------------------- -------------------------- 7#a7 ,in few minutes4 ,,table #aa4--;,administration of caffein by mouth2 cats4 ---------------------------------------- -------------------------- ,number4,weight4 ,caffein ,symptoms4 ,duration of life4 per kilo4 ---------------------------------------- -------------------------- ,grams4 ,gram4 #ia #c1jej #j4ae #a hour #dj minutes #b hours4 #hh #c1bfj 4#ae #a hour #dj minutes4 #ib #a1gej 4#af #be minutes ,survived4 #hg #b1fbj 4#ae #c hours ,do4 #ij #b1fhe 4#bj #a hour #ae minutes ,less than #ah hours4 #hi #b1hfj 4#bj #ge minutes4 #hb #b1dej 4#ae ,less than #bd hours4 #ajj #b1gdj 4#abd #a hour #dj minutes ,survived4 #ic #a1fdj 4#abe ,do4 ---------------------------------------- -------------------------- ,,summary4 ,the toxicity of caffein in cats is shown to be the same when given by mouth as when injected subcutaneously1 the minimum fatal doses in both cases being #j4ae gram per kilo4 ,when introduced by the intraperitoneal route1 caffein is1 on the contrary1 distinctly less toxic4 ,after the administration of #j4acg and #j4ade gram caffein per kilo 7,nos4 #ic and #hg7 salivation in one cat 7,no4 #ic7 and irritability and muscular stiffness in the other were the only effects noticed4 ,these symptoms were no longer observed the next day and the cats appeared to be perfectly normal4 ,experiments with larger doses indicate that the minimum fatal dose by this method of administration is about #j4b gram per kilo4 ,,experiments ,,on ,,dogs4 ,the experiments were carried out on well-fed adult dogs and on puppies1 kept under observation for some time before the drug was administered4 ,only those manifesting no signs of abnormality were used for these tests4 ,caffein was given by mouth mixed with #aj to #bj grams of meat1 or subcutaneously in #b per cent aqueous solution4 ,the young animals received caffein dissolved in milk4 ,the determination of the minimum toxic or fatal doses when the drug was fed presented considerable difficulty1 as in many instances the ingestion of the drug was closely followed by vomiting4 ,,administration ,,by ,,mouth4 ,,series ,a4 ,the effective dose in these experiments showed considerable variation4 ,one dog 7,no4 #ch7 died after a dose of #j4ab gram caffein per kilo1 while some subjects survived doses of #j4b and #j4bc gram per kilo4 ,in the #ab experiments given in ,table #ab1 page #fb1 it will be noticed that from #j4ab to #j4aeb gram per kilo proved fatal to three dogs1 while three others survived the same amounts in proportion to the body weight4 ,the results were the same with larger doses4 ,it may be observed in this connection that in the case of the five dogs in which vomiting was noticed some time during the #bd hours following the administration of caffein1 four survived1 ,no4 #ch being the exception4 ,the greater toxicity of caffein in this case is in all probability due to some morbid process1 the presence of which was indicated by the high temperature of this subject4 ,that vomiting may avert a fatal issue after larger doses of caffein is made further probable by experiment on dog ,no4 #dh1 for which1 in the absence of vomiting1 a dose of #j4b gram of caffein per kilo proved fatal4 ,on this supposition the discrepancy in the results obtained in this series may be readily explained4 ,the smallest doses which proved fatal in these experiments were #j4ade and #j4aeb gram per kilo4 ,no4 #ch1 which died from a dose of #j4ab gram per kilo1 may be considered as an exception1 as this subject was not normal4 ,experiments with caffein on dogs were made at various other times in this laboratory but failed to show that smaller doses of caffein1 even when vomiting did not occur after its administration1 were fatal1 although toxic effects were observed4 ,the conclusion is therefore justified that the minimum fatal dose of caffein for the normal dog is about #j4ae gram per kilo when given by mouth4 ,,subcutaneous ,,injection4 ,,series ,b4 ,to determine the toxicity of caffein more accurately1 especially for comparison with animals of other species1 the subcutaneous method of administration was also used4 ,the injections were made with a syringe of #bj cc capacity1 the contents of which were introduced into contiguous areas4 ,the results of experiments on six dogs indicate that approximately #aej to #afj mg per kilo is the minimum fatal dose1 since such doses proved fatal to two out of the three animals receiving this amount1 while three others which received doses of from #adc to #afj mg per kilo survived4 ,,experiments ,,on ,,puppies4 ,,series ,c4 ,in these experiments the resistance of young growing puppies to caffein was studied4 ,caffein was given by mouth to all the subjects except one1 to which it was administered subcutaneously4 ,the protocols1 only a few of which are given1 and the tabulated data of the experiments 7p4 #fb7 show that the age of the animal has a decided influence on the toxicity of caffein4 ,dog #aa4 ,weight1 #a1bfj grams4 ,august #b3 ,at #aj a4 m4 given #ab4e cc of #b per cent of caffein through stomach tube2 #b p4 m41 had convulsions1 diarrhea1 salivation1 and stiffness of limbs4 ,august #c3 ,found dead #i a4 m4 ,autopsy3 ,thoracic viscera apparently normal2 stomach immensely distended and filled with a white1 cheesy mass and some fluid2 round worms plentiful in stomach and small intestine2 mucosa of entire intestine congested2 contents of lower intestine congested2 liver pale2 spleen flabby2 kidney congested4 ,dog #aj4 ,weight1 #a1fej grams4 ,july #bf3 #i4cj a4 m41 #bi cc of #b per cent caffein added to #fj cc of milk offered1 but refused1 and was therefore fed by mouth through stomach tube2 #aj4be a4 m41 no symptoms2 #aa4cj a4 m41 restlessness1 extremities stiff1 post4 extremities spread apart1 dog shows well-marked symptoms of caffein poisoning2 #ab4aj p4 m41 symptoms more severe1 extremities extended and spread out1 is lying flat on belly so that nose touches floor of the cage2 #ab4dj p4 m41 found dead2 was alive at #ab4aj p4 m4 ,autopsy3 ,lungs showed hemorrhagic foci in all lobes2 heart apparently normal2 liver fatty2 stomach and intestines filled with round worms2 spleen and kidney apparently normal4 ,dog #i4 ,weight1 #c1jjj grams4 ,july #be3 #cej mg caffein per kilo2 #e p4 m41 lying down most of the time1 occasionally walks about in stall2 restlessness present1 but not marked2 #e4cj p4 m41 vomit which looked frothy and mucilaginous noticed on the floor of the stall2 no meat particles noticed in vomit1 though searched for2 whines occasionally4 ,july #bf3 #i a4 m41 looks well2 no signs of the effect of caffein given the day previous4 ,dog #h4 ,yellow female4 ,weight1 #c1ajj grams4 ,july #bb3 #aj4ej a4 m41 received #a4a grams of caffein in #aj grams of meat 7#ced mg caffein per kilo72 #c p4 m41 vomited mucus2 gait clumsy2 refused to eat2 continually drinking water2 very restless2 #d p4 m41 convulsions set in at #c4ee p4 m42 tonic rigidity of the posterior extremities2 profuse salivation2 convulsions were both tonic and clonic in character1 and resembled those seen in rabbits in caffein intoxication2 a striking feature was the duration of the spasm1 which began at #c4ee p4 m4 and kept up for more than two hours4 ,july #bc3 ,found dead at #i a4 m4 ,the data recorded in the table and in the protocols of the experiments of series ,c show that four out of the seven animals experimented upon died in less than #bd hours after caffein was fed2 three of these received #cjj to #ced mg caffein per kilo1 and one received #bjj mg caffein per kilo4 ,no4 #h vomited four hours after caffein was given4 ,no vomiting was observed in the other three dogs4 ,from #j4cjj to #j4cej gram of caffein per kilo may be regarded1 therefore1 as surely fatal to young growing puppies4 ,that this is in all probability the minimum lethal dose appears from the following experiments3 ,no4 #i1 which received #cej mg per kilo1 vomited one hour after and survived1 which indicates that some of it was probably not absorbed4 ,the amount which entered the circulation was therefore less than #cej mg per kilo4 ,since ,no4 #ae1 which received #bej mg caffein subcutaneously1 likewise survived1 the probabilities are that #cjj to #cej mg per kilo were the minimum fatal doses for these animals4 ,moreover1 ,no4 #ab1 which received #bjj mg caffein per kilo1 survived1 no vomiting having been observed4 ,the case of ,no4 #aa1 in which the same amount of caffein in proportion to body weight proved fatal1 may be explained perhaps by the findings of the autopsy4 ,the results obtained in these experiments justify the conclusion that young growing dogs can stand larger doses of caffein than full-grown and older dogs4 ,attention may also be called here to the difference in the symptoms produced by caffein in very young and in adult dogs4 ,it was often noticed in these experiments that the symptoms in older subjects when given toxic doses of caffein set in rather abruptly and ended in instantaneous death4 ,we failed to observe this phenomenon after the administration of large amounts of caffein to very young dogs1 in which tonic and clonic convulsions alternating with paresis were observed4 ,these symptoms set in rather gradually and lasted several hours 7see experiment ,no4 #h71 resembling the rabbit in this regard4 ,,summary4 ,the toxicity of caffein for adult dogs is about the same1 whether given by mouth or injected subcutaneously4 ,the resistance of puppies to caffein is much greater than that of adults4 ,,table #ab4--;,administration by mouth2 dogs4 7,series ,a47 ---------------------------------------- -------------------------- ,caffein ,no4 ,weight4 per ,results4 ,remarks4 kilo4 ---------------------------------------- -------------------------- ,kilos4,gram4 #dg #ac4fj #j4add ,survived ,vomiting observed4 #ee #ab4ge 4#bjj do4 ,stiffness of muscles2 no other symptoms4 #ef #g4ie 4#bjj ,found dead next day #eb #ac4fj 4#adg ,survived #eg #f4ej 4#bcj do4 ,vomited after #a hour2 convulsions after #a hour and #de minutes4 #ci #bc4aj 4#abj do4 ,increased frequency of respiration1 thirst1 loss of appetite1 vomited rest of day when he drank water1 salivation1 restlessness1 passed feces frequently4 #dh #aa4ej 4#agd do4 ,vomiting observed4 #dh #ab4jj 4#bjj ,found dead ,no vomiting observed4 ,second dose next day was given #h days after first4 #ed #ac4dj 4#bjj ,survived ,vomiting observed4 #di #ac4ae 4#aeb ,found dead next day #ch #ad4ej 4#abj do4 ,symptoms after #a hours3 ,dog had a temperature of #ajd ,f4 before caffein was given2 vomited #c hours after caffein was fed4 #ah #aj4hj 4#ade do4 ---------------------------------------- -------------------------- ,,table #ac4--,subcutaneous injection2 dogs4 7,series ,b47 ---------------------------------------- -------------------------- ,caffein ,no4 ,weight4 per ,results4 ,remarks4 kilo4 ---------------------------------------- -------------------------- ,kilos4,gram4 #fb #i4cj #j4afa ,survived ,restlessness and vomiting one-half hour after injection4 #fa;,a #ad4jj 4#afj ,found dead next day #fc #ab4jj 4#aej ,survived ,restlessness #a hour after injection4 #fd #ad4jj 4#aej do4 ,restlessness and thirst #de minutes after injection4 #ei #g4bj 4#afj ,died #a hour,marked restlessness1 but no and #bj convulsion4 minutes after injection46 #fa #ad4fj 4#adc ,survived ,symptoms observed in #a hours4 ---------------------------------------- -------------------------- ,,table #ad4--;,administration by mouth to puppies4 7,series ,c47 ---------------------------------------- -------------------------- ,caffein ,no4 ,weight4 per ,results4 ,remarks4 kilo4 ---------------------------------------- -------------------------- ,kilos4,gram4 #h #c4aj #j4ced ,found dead ,vomited in #d hours after feeding2 next day restlessness1 loss of appetite1 thirst1 incoordination of muscles1 convulsions4 #i #c4ae 4#cej ,survived ,muscular incoordination and stiffness1 restlessness1 vomited #a hour after caffein was given4 #aj #a4fj 4#cej ,died in ,convulsion2 no vomiting4 #c hours #aa #a4bf 4#bjj ,found dead ,salivation2 convulsions4 next day #ab #a4bh 4#bjj ,survived ,no symptoms4 #ae #a4bj 4#bej do4 ,subcutaneous injection4 #af #c4ej 4#cjj ,died in ,convulsions #de minutes after caffein #a hour was fed4 ---------------------------------------- -------------------------- ,,chronic ,,caffein ,,intoxication4 ,the object of this study was to ascertain the effect of repeated dosage when caffein was given daily or at longer intervals4 ,the experiments were tried on rabbits and on dogs4 ,as in the experiments on acute intoxication1 the animals were under observation for some time in the laboratory before the administration of caffein was begun in order to ascertain the presence or absence of abnormality4 ,the relation of diet to toxicity received some attention1 but the question was not studied exhaustively in the present investigation4 ,,experiments ,,on ,,rabbits4 ,full-grown adult as well as young rabbits were employed4 ,the diet consisted either of carrots or of oats2 water was given ad libitum4 ,the rabbits were kept in metal cages in a well-lighted and well-ventilated room4 ,unnecessary handling or any other procedure tending to fatigue or to cause discomfort to the animals was very carefully avoided1 since we had found that such treatment was likely to decrease the resistance of the rabbit to caffein4 ,the caffein was administered by feeding by mouth and through a stomach tube1 or by the subcutaneous method4 ,in a good many cases it was given daily1 in some at longer intervals4 ,,series ,a4 ,the experiments of this series formed a preliminary study for the purpose of testing the effect of moderate doses4 ,one decigram of caffein per kilo was given daily for several days2 when administered at longer intervals the dose was increased to #aej to #bjj mg per kilo4 ,it was found that the smaller doses did not produce any symptoms2 even the weights of the animals were not influenced4 ,doses of medium size given on two successive days were likewise without any noticeable effect 7,nos4 #ahb1 #ahc1 #abc1 #aja74 ,when a third dose of this size was given within #dh or #bd hours it proved fatal 7,nos4 #abc1 #ahb1 and #ahc74 ,exceptionally1 however1 moderately large doses 7for rabbits7 may be given for three consecutive days without fatal issue1 as in rabbit ,no4 #aja4 ,when given at intervals of two to three days1 larger doses1 as may be seen from the protocols1 can be administered without causing acute death 7,nos4 #agc1 #aha1 #bja74 ,the results of the tests of this series point to the absence of any accumulation and to the possible elimination of moderate doses of caffein and its products of decomposition within #bd hours or thereabouts4 ,when the doses are larger the time of its elimination is apparently longer1 as shown by the fact that repetitions of the dose the next day may be fatal1 but when a longer interval is allowed it may be given without causing death4 ,it will be observed that only one rabbit of this series survived1 but it was extremely emaciated4 ,this condition has been observed in a number of cases after caffein had been given for several days4 ,even when the drug was withdrawn the animals continued to lose weight4 ,this may be explained by the condition of the gastro-intestinal canal as found at autopsy4 ,the presence of inflammation of the mucous membrane of the stomach and intestines1 with ulceration of the mucous membrane of the pylorus in one of the rabbits 7,no4 #agc7 of the series1 in all probability caused diminution or loss of appetite1 which of itself would tend to cause loss of flesh and strength and finally death4 ,protocols of the experiments follow4 ,rabbit #agc4 ,carrots were fed from ,october #a to #ah and oats for the remainder of the experiment4 --------------------------- ,date4 ,weight4 ,caffein per kilo4 --------------------------- ,grams4 ,gram4 ,oct4 #i #a1ihj #j4ada ,oct4 #aa #a1ije 4#aij ,oct4 #ac #a1icj 4#bjg ,oct4 #af #b1jje #j4bbj ,oct4 #ah #a1hde ,oct4 #bj #a1gdj 4#bcj -------------------------- ,october #ba3 ,paralysis of posterior extremities4 ,october #bb3 #i a4 m41 found dead4 ,the urine was examined before and after the administration of caffein4 ,no symptoms were observed after the administration of caffein 7#e doses in #aa days71 nor was albumen or sugar found in the urine after any of the experiments on this rabbit4 ,autopsy3 ,pyloric mucosa exhibited several ulcers2 small intestines showed slight inflammation2 liver deeply congested2 kidneys showed marked inflammation of cortex2 other organs practically normal4 ,rabbit #aha4 ,diet1 carrots ,september #bi-,october #ag1 then oats4 ---------------------------- ,date4 ,weight4 ,caffein per kilo4 ---------------------------- ,grams4 ,gram4 ,oct4 #d #a1dbe #j4aje ,oct4 #e #a1dej 4#ajj ,oct4 #f #a1bgj 4#ajj ,oct4 #g #a1baj 4#ajj ,oct4 #h #a1cge 4#acj ,oct4 #i #a1cje 4#aec ,oct4 #aa #a1cgj #j4age ,oct4 #ac #a1che 4#ahj ,oct4 #af #a1cde 4#bjj ,oct4 #ag #a1jcj ,oct4 #ah #a1bcj ,oct4 #bj #a1bae ---------------------------- ,rabbit was markedly emaciated and weak4 ,no albumen or sugar found in the urine as a result of caffein feeding4 ,rabbit #ahb4 ,diet of carrots from ,september #bi4 ,received caffein subcutaneously as follows3 ----------------------------- ,date4 ,weight4 ,caffein per kilo4 ----------------------------- ,grams4 ,gram4 ,oct4 #d #a1gfe #j4ajj ,oct4 #e #a1hhj 4#ajj ,oct4 #f #a1gej 4#ajj ,oct4 #g #a1gaj 4#ajj ,oct4 #h #a1fhe 4#ace ,oct4 #i 4#aej ,oct4 #aa #a1fje 4#agd ---------------------------- ,october #ab3 #aa a4 m41 #bc hours after caffein was given1 convulsions with recovery2 rabbit died at #a4cj p4 m4 ,no sugar was found in the urine at any time after the administration of caffein4 ,albumen was present only in one specimen4 ,rabbit #ahc4 ,diet of carrots from ,september #bi4 ,received caffein subcutaneously as follows3 ---------------------------- ,date4 ,weight4 ,caffein per kilo4 ---------------------------- ,grams4 ,gram4 ,oct4 #d #a1che #j4ajj ,oct4 #e #a1dfj 4#ajj ,oct4 #f #a1che 4#ajj ,oct4 #g #a1bdj 4#abb ,oct4 #h #a1caj #j4aec ,oct4 #i #a1cij 4#adb ,oct4 #aa #a1cij 4#ahg --------------------------- ,october #ab3 #i a4 m41 found dead4 ,no albumen was found in the urine4 ,only one sample contained sugar4 ,rabbit #abc4 ,white1 female4 ,diet1 oats4 ,received caffein subcutaneously as follows3 --------------------------- ,date4 ,weight4 ,caffein per kilo4 --------------------------- ,grams4 ,grams4 ,apr4 #ad #b1cej #db ,apr4 #af #b1bej #ij ,apr4 #ag #b1cbe #hf ,apr4 #bj #b1abf #ada ,apr4 #ba #a1ife #aeb ,apr4 #bb #a1hgf #afj --------------------------- ,rabbit died #cj minutes after last injection of caffein4 ,autopsy3 ,stomach exhibited marked inflammation of mucosa4 ,slight enteritis4 ,liver and kidneys were deeply congested and dark colored4 ,rabbit ,no4 #aja1 white male4 ,diet1 oats4 ,received caffein subcutaneously as follows3 --------------------------- ,date4 ,weight4 ,caffein per kilo4 --------------------------- ,grams4 ,grams4 ,mar4 #ah #b1jbe #j4ajj ,mar4 #ai #a1igj 4#ajj ,mar4 #bj #b1jji 4#ajj ,mar4 #bb #a1hee 4#ajj ,mar4 #bc #a1gch 4#aad ,mar4 #bd #a1hae 4#aff ,mar4 #be #a1hcj 4#ahe ,mar4 #bf #a1gaj 4#agf ,mar4 #bi #a1gcd 4#bai ,apr4 #a #a1fjf 4#bbd --------------------------- ,april #e3 ,found dead4 ,autopsy3 ,marked inflammation of gastric mucosa4 ,considerable enteritis affecting the whole extent of the intestines2 liver congested and friable2 kidneys deeply congested in cortical and medullary portions2 spleen congested1 but of normal size2 lungs and heart normal4 ,four days1 #j4a per kilo2 #aj doses in #ad days4 ,rabbit #bja4 ,diet of carrots begun ,october #a2 ,october #ai1 oats4 ,subcutaneous injections as follows3 --------------------------- ,date4 ,weight4 ,caffein per kilo4 --------------------------- ,grams4 ,grams4 ,oct4 #i #a1jjj #j4aej ,oct4 #aa #a1jae 4#ahj ,oct4 #ac #a1jfe 4#ahg ,oct4 #af #a1jfe 4#bbe ,oct4 #ah #hej ,oct4 #bj #hij 4#aaa --------------------------- ,under observation six hours ,october #bj2 no symptoms4 ,october #bc3 ,died2 was much emaciated but did not show any symptoms2 emaciation set in when caffein was withdrawn2 urine never contained sugar or albumen2 symptoms observed after second dose only4 ,,series ,b4 ,the question whether caffein is cumulative in the rabbit1 suggested in the preceding experiments1 was the subject of further investigation in ,series ,b4 ,caffein was given by mouth or subcutaneously4 ,carrots formed the exclusive diet1 a measured amount being given4 ,the rabbits were kept under observation for two weeks1 except ,nos4 #cgj and #cgc1 records of which were made only for four days before the administration of caffein was begun4 ,caffein was given by mouth in experiments of ,groups ,i and ,,iii4 ,rabbits #bib1 #bic1 and #bie received daily #bj cc water by mouth for four days previous to the administration of caffein1 while in the rabbits of ,group ,,ii the caffein treatment was preceded by the injection of #j4h per cent salt solution subcutaneously4 ,the object in both cases was to ascertain whether or not the method of the administration of caffein has any influence on the animal1 but observation made from day to day failed to show any effect of such treatment4 ,about #a decigram of caffein per kilo was administered daily1 with occasional intermissions4 ,later in the course of the experiment the doses were increased1 #j4ae gram per kilo being the maximum dose given4 ,rabbit #bic died after the third dose with symptoms of typical caffein poisoning4 ,the administration of the same dose of caffein was continued #aj days longer in ,nos4 #bib and #bie4 ,it was omitted on the seventh1 fourteenth1 and fifteenth days of the experiment4 ,on the eighteenth day of the experiment the dose was increased to #aej mg per kilo and was repeated #b days later4 ,no4 #bie was found dead the next day4 ,no4 #bib survived4 ,rabbits #cac and #cae may be considered together1 as they were treated alike in every respect4 ,the initial dose of #ajj mg caffein per kilo was finally increased to #abb mg4 ,after the twelfth dose the emaciation was well marked and the rabbits were very weak4 ,no4 #cac was found dead #b days1 and ,no4 #cae #c days1 after the last dose of caffein was given4 ,it should be remarked in this connection that symptoms of caffein poisoning were never observed in these rabbits4 ,death was not due1 therefore1 primarily to caffein1 but the rapid loss of flesh and strength observed during the last few days suggests that it was due to malnutrition apparently brought about by caffein4 ,the results obtained by subcutaneous injection of caffein are given in the table as ,group ,,ii4 ,the initial dose of #ajj mg per kilo was injected daily4 ,no4 #bih died after the second dose4 ,nos4 #bbc and #bif received this amount daily for #f days4 ,an intermission of #b days followed1 at the end of which the same dose was given again4 ,the next day it was increased to #aej mg per kilo1 but no effect was observed2 #dh hours later this dose was repeated4 ,no4 #bbc was found dead1 but its mate survived4 ,symptoms of acute caffein intoxication were not observed in any of these rabbits4 ,it would seem1 therefore1 that caffein is not cumulative4 ,this supposition1 however1 appears somewhat contradictory in view of the fact that out of the eight rabbits of this series six died1 nor could any cause of death be ascribed other than caffein4 ,also the first results of ,experiments #bic1 #cgj1 and #cgc might be considered as indicating that cumulation1 though to a moderate extent1 does take place1 since in these cases reflexes developed after the drug was given for some time4 ,but this view is contradicted by the results of ,experiment #cga1 in which #aej mg per kilo given #e days after the daily dosage of caffein was suspended likewise caused increased reflexes4 ,cumulation1 therefore1 does not account for the effects noted in the other rabbit4 ,it will be observed that rabbit ,no4 #cgj1 as well as ,nos4 #cga and #cgc1 had diarrhea for several days4 ,it is quite possible that the weakened condition rendered the rabbits more sensitive to the action of the drug4 ,this is made highly probable by the observations recorded in the experiments on acute intoxication with caffein in which death occurred after small doses4 ,in such cases some pathological condition was often disclosed by the autopsy4 ,the results of this series corroborate1 therefore1 those of ,series ,a1 and indicate again the absence of cumulative action4 ,the results obtained are in all probability due to malnutrition and other conditions brought about by congestion of the viscera and consequent injury to the gastro-intestinal canal4 ,,table #af4--;,chronic caffein intoxication of rabbits2 ,series ,b on cumulation4 ---------------------------------------- --------------------------- ,group ,i4 ,group ,,ii4 ,group ,,iii4 ,data4 ---------------------------------------- -------- ,no4 ,no4 ,no4 ,no4 ,no4 ,no4 ,no4 ,no4 #bib4 #bic4 #bie4 #bif4 #bbc4 #bih4 #cae4 #cac4 ---------------------------------------- ---------------------- ,diet 7grams carrots in #b days7 #a1jjj #a1jjj #ige #icj #ije #hhj #cee #cjj ,caffein administered 7cc7 and weight 7grams73 ,mar4 #e #a1daj #a1dgj #a1jde #a1jdj #a1jgj #iee #ggj #ggj ,mar4 #g #a1dae #a1cfj #a1adj #a1jij #a1jie #a1jjj #gae #fij ,mar4 #i #a1cej #a1bgj #a1jgj #a1jjj #a1jee #a1jje #fee #ffe ,mar4 #aa #a1eje #a1dfe #a1aij #a1bcj #a1bhe #a1bej #gee #gfj ,mar4 #af #a1ehj #a1dfj #a1bcj #a1afe #a1agj #a1ade #gcj #gde ,mar4 #ag #a1eae #a1dae #a1jhj #a1jdj #a1aae #a1aje #gbj #fhe ,mar4 #ai #a1efe #a1egj #a1bhj #a1aie #a1bce #a1bbj #gaj #gce ,mar4 #ba #g #g #f #d #d #a1ehe #a1ecj #a1bfe #a1aej #a1bae #a1bfj #gee #gjj ,mar4 #bb #g #g #f 7#a7 7#a7 7#a7 #d #d #a1ddj #a1cae #a1age #a1ajj #a1jde #a1aej #fge #fce ,mar4 #bc #g #g #f 7#a7 7#a7 7#a7 #d #d #a1cce #a1adj #a1aaj #a1ade #a1aij #a1bcj #gae #gjj ,mar4 #bd #g #f 7#a7 7#a7 7#a7 #d #d #a1caj 7#b7 #a1jij #a1aae #a1agj #a1bej #fhj #fej ,mar4 #be #g #f 7#a7 7#a7 7#a7 #d #d #a1cge #a1jce #a1abe #a1bae #a1bae #fie #fhe ,mar4 #bf #g #f #d #a1bee #a1jie #a1aje #a1aee #a1aej #fge #fie ,mar4 #bg ,mar4 #bh #g #f #e4e #f #f #d #d #a1cee #a1aae #a1abj #a1afj #a1aee #eie #fhe ,mar4 #bi #g #f #f #f #e #d #d #a1che #a1aej #a1aee #a1afe #iee #fie #fge ,mar4 #cj #g #f #f #f #d #d #a1ccj #a1jge #a1jce #a1jie ,dead4 #fcj #faj ,mar4 #ca #g #f #f #f #d #d #a1cbe #a1agj #a1aaj #a1adj #fij #fje ,apr4 #a #g #f #f #f #d #d #a1cce #a1jej #a1jej #a1abj #fbe #fbj ,apr4 #b #g #f #f #f #d #d #a1cij #a1abe #a1jij #a1aee #fie #fbe ,apr4 #c #bjj ,apr4 #d #a1cjj #a1jje #a1aje #a1jhj #ehe #ehj ,apr4 #e #g #f #f #f #d #d #a1che #a1jij #a1acj #a1jij #fee #fcj ,apr4 #f #i #g4e #g4e #h #a1bfj #a1jaj #a1jej #a1aaj #efj #ecj ,apr4 #g 7#c7 ,apr4 #h #i #g4e #g4e #h #a1bfj #a1jjj #a4jij #a4ife ,dead4 ,apr4 #i ,survived4 ,dead4,surv4 ,dead4 ,dead4 ---------------------------------------- ----------------------- 7#a7 ,on these days #e cc of salt solution was administered subcutaneously4 7#b7 ,dead ,mar4 #bc4 7#c7 ,found dead #i a4 m4 ,,table #ag4--;,chronic intoxication of rabbits1 series ,b1 ,group ,,iv1 on cumulation4 ,,rabbit1 #cgj4 ---------------------------------------- ------------------------ ,caffein ,date4 ,weight4 ,carrots4 ,water4 ,urine4 by ,symptoms4 stomach4 ---------------------------------------- ------------------------ ,mg per ,grams4 ,grams4 cc4 kilo4 ,aug4 #g #b1aee #dej #ej #bhj ,aug4 #h #b1jcj #dej #be #ahe ,aug4 #i #b1aje #bij #j #bge ,aug4 #aj #b1jie #dej #cj #cce ,aug4 #aa #b1aje #dej #fe #cfj #ej ,aug4 #ab #b1abe #dej #fe #bbj #ej ,aug4 #ac #b1abj #cej #be #bfe #ej ,aug4 #ad #b1agj #dej #ce #bge #ge ,aug4 #ae #b1age #cej 787 #bjj #ge ,aug4 #af #b1agj #cfj #fe #bej #ge ,aug4 #ag #b1age #caj #ce #agj #ajj ,aug4 #ah #b1jie #ahj #dj #bhe #ajj ,severe diarrhea4 ,aug4 #ai #b1abj #djj 787 #bhe #abe ,do4 ,aug4 #bj #b1abj #djj 787 #caj #abe ,better4 ,aug4 #ba #b1abj #djj #gj #bej #abe ,do4 ,aug4 #bb #b1jdj #djj #de #bfe #aej ,diarrhea bad4 ,aug4 #bc #b1jcj #cgj #ce #bbj #aej ,diarrhea better4 ,aug4 #bd #a1iej #bae #dj #abj #aej ,do4 ,aug4 #be #a1hhe #aie #ce #fj #bjj ,reflexes4 ,aug4 #bf ,found dead at #i4 ---------------------------------------- ------------------------ ,,rabbit1 #cgc4 ---------------------------------------- ------------------------ ,aug4 #g #b1bdj #dej #ej #bcj ,aug4 #h #b1aej #aej #cj #cjj ,aug4 #i #b1abj #bje #j #aej ,aug4 #aj #b1aej #dej #ae #bde ,aug4 #aa #b1aie #dej #e #bhe #ej ,aug4 #ab #b1afj #dej #fe #cbe #ej ,aug4 #ac #b1abj #cjj #de #aij #ej ,aug4 #ad #b1aie #dej #dj #bfe #ge ,aug4 #ae #b1bae #cej #ce #bjj #ge ,aug4 #af #b1bje #caj #de #bbe #ge ,aug4 #ag #b1bdj #djj #dj #bfe #ajj ,aug4 #ah #b1bee #cej #cj #cbj #ajj ,aug4 #ai #b1aae #ahe 787 #agj #abe ,severe diarrhea4 ,aug4 #bj #b1aae #bhj #ce #aie #abe ,diarrhea4 better ,aug4 #ba #b1jej #age #ge #aae #abe ,slight diarrhea4 ,aug4 #bb #b1jfj #ahj #ge #acj #aej ,aug4 #bc #b1jje #bjj #ge #abe #aej ,reflexes4 ,aug4 #bd #a1iij #bjj #ge #aej #aej ,slight diarrhea4 ,aug4 #be #a1iej #bee #ee #acb #age ,severe diarrhea4 ,aug4 #bf #a1hgj #bje #hj #adj ,none ,do4 ,aug4 #bg #a1hcj #bjj #ej #adj do4 ,do4 ,aug4 #bh #a1iej #djj #be #bfe do4 ,slight diarrhea4 ,aug4 #bi #a1hbe #djj #j #cae do4 ,very weak and in poor condition ,aug4 #cj #a1hej #aj #adj do4 ,aug4 #ca #a1hce ---------------------------------------- ------------------------ ,,rabbit1 #cga4 ---------------------------------------- ------------------------ ,aug4 #g #b1bdj #dej #ej #cjj ,aug4 #h #b1bfj #dej #ej #bbe ,aug4 #i #b1caj #dcj 787 #cjj ,aug4 #aj #b1bie #dej #ej #cje ,aug4 #aa #b1cbj #dej #ej #cce #ej ,aug4 #ab #b1bhj #dej #gj #djj #ej ,aug4 #ac #b1cjj #cej #gj #bee #ej ,aug4 #ad #b1bfe #dbe #ee #aed #ge ,aug4 #ae #b1bfj #bej #dj #abe #ge ,aug4 #af #b1bie #aee #gj ,lost #ge ,aug4 #ag #b1ahj #aje #gj #abj #ajj ,severe diarrhea4 ,aug4 #ah #b1aej #abe #gj #ajj #ajj ,diarrhea better4 ,aug4 #ai #b1jge #baj 787 #aib #ajj ,diarrhea severe4 ,aug4 #bj #b1jge #bhj #gj #ahj #ajj ,do4 ,aug4 #ba #b1afe #bfj #ej #bbe ,none ,diarrhea better4 ,aug4 #bb #b1aje #djj #ej #bge do4 ,aug4 #bc #b1jhj #cjj #j #ade do4 ,diarrhea severe4 ,aug4 #bd #b1aje #bej #ae #bde do4 ,do4 ,aug4 #be #b1jee #cbj #aj #agf #aej ,reflexes4 ,aug4 #bf #b1jdj #aij #ge #bej #aej ,died at #a p4 m41 without having showed any symptoms other than reflexes4 ---------------------------------------- ------------------------ ,,series ,c4 ,the subjects used in these experiments were rabbits of medium size and were apparently young or at any rate were not very old4 ,the series was planned for the study of the possible effect of diet on the toxicity of caffein when given for some time1 and therefore oats were substituted for carrots1 which had been fed in the previous work1 as already stated4 ,caffein was given by mouth in the usual way1 in #a per cent solution1 #ajj mg4 per kilo daily4 ,fourteen rabbits were used for these tests4 ,their weights were recorded daily and observations made at frequent intervals during the day4 ,the only change noticed in all of the experiments of this series was progressive loss of weight which set in from #c to #h days after the administration of the drug was begun4 ,the duration of life varied considerably4 ,no4 #chb died after the first dose4 ,no4 #chi lived #b days1 ,no4 #chf1 #c days1 and ,no4 #che1 #e days2 ,no4 #cij lived #g days and ,no4 #djd lived #bj days after the administration of caffein was begun4 ,the duration of life in all the others was from #aa to #af days4 ,the findings at autopsy are interesting and suggestive as regards the possible explanation of the effects of repeated dosage of caffein4 ,in eight of the rabbits there was involvement of the mucous membrane of the stomach or intestines or of both4 ,since the same condition of the gastro-intestinal canal was observed in previous experiments with caffein when injected subcutaneously1 the mere passing of the tube into the stomach is obviously not the cause of this condition4 ,the fatal outcome due is therefore1 as was suggested above1 to inanition brought about by the condition of the gastro-intestinal canal4 ,moreover parallel experiments carried out on rabbits in the same way with alcohol survived this treatment much longer4 ,obviously then the passing of the soft rubber catheter is not the cause of this condition of the gastro-intestinal canal nor the diet4 ,rabbits were fed oats exclusively for several months in this laboratory and thrived4 ,the presence of pneumonia in the other rabbits of this series may be regarded as accidental1 as it is inconceivable that one or two doses of caffein1 as was the case in ,nos4 #chb and #chi1 could predispose the lungs to infection4 ,the results of these experiments therefore are in harmony with those of the preceding two series1 indicating that caffein does not accumulate in the body1 and that the toxicity of caffein1 whether of the single dose or of repeated doses is the same1 on a diet of carrots or of oats4 ,these results also show that caffein is much more toxic with repeated dosage4 ,as stated in the historical part of this bulletin the same view was held by ,gourewitch47#bh7 ,rabbit #chf4 ,belgian female4 ,given #a cc of #a per cent caffein for each #ajj grams1 through stomach tube4 -------------------------- ,date4 ,weight4,treatment4 -------------------------- ,grams4 cc4 ,aug4 #ag #a1cjj #ac4j ,aug4 #ah #a1bae #ab4j ,aug4 #ai 787 787 -------------------------- ,august #bj3 ,found dead #i a4 m4 ,autopsy3 ,lungs slightly congested2 liver engorged and friable2 gall cyst well filled4 ,rabbit #chi4 ,black male4 ,given #a cc of #a per cent caffein for each #ajj grams1 through stomach tube4 -------------------------- ,date4 ,weight4,treatment4 -------------------------- ,grams4 cc4 ,aug4 #ag #a1jgj #aj4j ,aug4 #ah #a1jbe #aj4j -------------------------- ,august #ai3 ,found dead #i a4 m4 ,autopsy3 ,lungs severely congested and partially hepatized2 liver was engorged2 other organs appeared normal4 ,rabbit #chb4 ,belgian female4 ,on ,august #ag weighed #a1jce grams2 received #a cc of #a per cent caffein for each #ajj grams2 #aj cc of #a per cent caffein given in all4 ,august #ah3 ,found dead #i a4 m4 ,autopsy3 ,lungs congested and hepatized2 liver engorged2 stomach showed numerous petechial hemorrhages on mucosa2 kidneys slightly congested2 intestines appeared normal4 ,rabbit #che4 ,belgian female4 ,given #a cc of #a per cent caffein for each #ajj grams1 through stomach tube4 -------------------------- ,date4 ,weight4,treatment4 -------------------------- ,grams4 cc4 ,aug4 #ag #ghj #h4j ,aug4 #ah #gfj #g4e ,aug4 #ai #gee #g4e ,aug4 #bj #gae #g4j ,aug4 #ba #gjj #g4j -------------------------- ,august #bb3 ,found dead #i a4 m4 ,autopsy3 ,lungs exhibited pneumonic lesions1 with inflammation of adjacent pleura2 a fibro-plastic exudate present around lung2 liver showed a coccidial infestation2 stomach distended with ingesta2 mucous membrane characterized by a catarrhal inflammation2 contents of small intestine liquid in nature and bile stained2 large intestine somewhat impacted2 liver and kidneys seemingly normal4 ,rabbit #djd4 ,white male4 ,given #a cc #a per cent caffein for each #ajj grams4 --------------------------------- ,date4 ,weight4 ,treatment4 --------------------------------- ,grams4 cc4 ,aug4 #bj #a1dfe #ad4e ,aug4 #ba #a1dge #ad4e ,aug4 #bb7a7 ,aug4 #bc #a1dge #ad4e ,aug4 #bd #a1djj #ad4j ,aug4 #be7b7 #a1dje #ad4j ,aug4 #bf #a1dae #ad4j ,aug4 #bg #a1djj #ad4j ,aug4 #bh7a7 ,aug4 #bi #a1caj #ac4j ,aug4 #cj #a1cbj #ac4j ,aug4 #ca #a1ccj #ac4e ,sept4 #a #a1cce #ac4e ,sept4 #b #a1cae #ac4j ,sept4 #c #a1cej #ac4e ,sept4 #d #a1cce #ac4e ,sept4 #e #a1cej #ac4e ,sept4 #f #a1chj #ad4j ,sept4 #g #a1cge #ad4j ,sept4 #h #a1cbe #ac4j --------------------------------- 7#a7 ,not fed4 7#b7 ,reflexes4 ,september #i3 ,found dead #i a4 m4 ,autopsy3 ,both lungs showed extensive pneumonia1 with adhesions to pleura2 pleuritis and pericarditis very marked2 large amount of fibrous exudate in pleural cavity2 pyloric end of stomach slightly congested2 liver congested2 other organs normal4 ,rabbit #cic4 ,belgian4 ,given #a cc of #a per cent caffein to each #ajj grams1 through stomach tube4 --------------------------------- ,date4 ,weight4 ,treatment4 --------------------------------- ,grams4 cc4 ,aug4 #ag #iej #i4e ,aug4 #ah #iaj #i4j ,aug4 #ai #hie #i4j ,aug4 #bj #iaj #i4j ,aug4 #ba #ije #i4j ,aug4 #bb7a7 ,aug4 #bc #hbe #h4j ,aug4 #bd #hgj #h4e ,aug4 #be #hce #h4e ,aug4 #bf #ghj #h4j ,aug4 #bg #gfe #g4e ,aug4 #bh7a7 ,aug4 #bi #gaj ,aug4 #cj7b7 ,aug4 #ca7a7 --------------------------------- 7#a7 ,not fed4 7#b7 ,condition very poor2 not fed4 ,september #a3 ,found dead4 ,autopsy3 ,lungs congested and adhering to the pleura2 extensive inflammation of pleura2 liver slightly enlarged and congested2 mucosa of stomach and small intestines slightly congested2 other organs normal4 ,rabbit #cij4 ,belgian1 male4 ,given #a cc of #a per cent caffein to each #ajj grams through stomach tube4 --------------------------------- ,date4 ,weight4 ,treatment4 --------------------------------- ,grams4 cc4 ,aug4 #ag #a1dij #ae4j ,aug4 #ah #a1cgj #ad4j ,aug4 #ai #a1cfe #ac4e ,aug4 #bj #a1cdj #ac4e ,aug4 #ba #a1bfe #ab4e ,aug4 #bb7a7 ,aug4 #bc #a1abj #aa4j --------------------------------- 7#a7 ,not fed4 ,august #bd3 ,found dead #i a4 m4 ,autopsy3 ,heart and lungs appeared normal2 abdominal viscera showed no apparent pathologic change other than coccidial infection of the liver and fullness of the blood vessels4 ,rabbit #cib4 ,maltese1 female4 ,given #a cc of #a per cent caffein to each #ajj grams through stomach tube4 -------------------------------- ,date4 ,weight4 ,treatment4 -------------------------------- ,grams4 cc4 ,aug4 #ag #a1bfe #ab4e ,aug4 #ah #a1bge #ab4e ,aug4 #ai #a1bdj #ab4e ,aug4 #bj #a1bbj #ab4j ,aug4 #ba #a1bde #ab4e ,aug4 #bb7a7 ,aug4 #bc #a1ahj #ab4j ,aug4 #bd #a1aij #ab4j ,aug4 #be #a1aee #aa4e ,aug4 #bf #a1adj #aa4e ,aug4 #bg #a1adj #aa4e ,aug4 #bh7a7 ,aug4 #bi #a1aae #aa4j ,aug4 #cj #a1jhj #aa4j ,aug4 #ca #a1jbj #aj4j ,sept4 #a #iie #aj4j ,sept4 #b #icj #i4j -------------------------------- 7#a7 ,not fed4 ,died at #c p4 m4 ,september #b4 ,autopsy3 ,the stomach and small intestines showed numerous small hemorrhagic spots2 a thick coating of mucus surrounded the contents of the stomach2 the other organs were apparently normal4 ,rabbit #djc4 ,black4 ,given #a cc of #a per cent caffein for each #ajj grams4 -------------------------------- ,date4 ,weight4 ,treatment4 -------------------------------- ,grams4 cc4 ,aug4 #bj #a1fdj #af4e ,aug4 #ba #a1fdj #af4e ,aug4 #bb7a7 ,aug4 #bc #a1dij #ae4j ,aug4 #bd #a1eae #ae4j ,aug4 #be #a1dge #ae4j ,aug4 #bf #a1cij #ad4j ,aug4 #bg #a1ccj #ac4e ,aug4 #bh7a7 ,aug4 #bi #a1acj #aa4e ,aug4 #cj #a1jee #aj4e -------------------------------- 7#a7 ,not fed4 ,august #ca3 ,found dead at #c p4 m4 ,autopsy3 ,extensive gastroenteritis2 liver enlarged and congested2 spleen slightly congested2 peritoneum thickened and congested2 other organs normal4 ,rabbit #hhd4 ,black1 female4 ,given #a cc of #a per cent caffein for each #ajj grams through stomach tube4 -------------------------------- ,date4 ,weight4 ,treatment4 -------------------------------- ,grams4 cc4 ,aug4 #af #a1aie #ab4j ,aug4 #ag #a1bje #ab4j ,aug4 #ah #a1adj #aa4e ,aug4 #ai #a1ahj #ab4j ,aug4 #bj #a1ade #aa4e ,aug4 #ba #a1ade #aa4e ,aug4 #bb7a7 ,aug4 #bc #a1jje #aj4j ,aug4 #bd #a1jce #aj4e ,aug4 #be #iij #aj4j ,aug4 #bf #ifj #i4e ,aug4 #bg #iee #i4e ,aug4 #bh7a7 ,aug4 #bi #hgj #i4j ,aug4 #cj7b7 #hej #h4e ,aug4 #ca #haj #h4j ,sept4 #a #gdj #g4e -------------------------------- 7#a7 ,not fed4 7#b7 ,poor condition1 mucus from rectum4 ,september #b3 ,found dead at #i a4 m4 ,autopsy3 ,the mucosa of stomach showed numerous hemorrhagic spots2 the first portion of the small intestines was slightly congested2 the other organs were apparently normal in appearance4 ,rabbit #chc4 ,belgian1 female4 ,given #a cc of #a per cent caffein for each #ajj grams through stomach tube4 -------------------------------- ,date4 ,weight4 ,treatment4 -------------------------------- ,grams4 cc4 ,aug4 #af #iie #aj4j ,aug4 #ag #a1jje #aj4j ,aug4 #ah #iij #aj4j ,aug4 #ai #hie #i4j ,aug4 #bj #ide #i4e ,aug4 #ba #ife #i4e ,aug4 #bb7a7 ,aug4 #bc #hge #i4j ,aug4 #bd #hee #h4e ,aug4 #be #hej #h4e ,aug4 #bf #ghe #h4j ,aug4 #bg #gaj #g4j -------------------------------- 7#a7 ,not fed4 ,august #bh3 ,found dead at #i a4 m4 ,autopsy3 ,lungs1 heart1 and spleen apparently normal2 liver infected with coccidia2 stomach apparently normal2 walls of small intestines injected2 colon marked congestion and hemorrhagic2 kidneys hemorrhagic4 ,rabbit #chg4 ,belgian male4 ,given #a cc of #a per cent caffein for each #ajj grams through stomach tube4 -------------------------------- ,date4 ,weight4 ,treatment4 -------------------------------- ,grams4 cc4 ,aug4 #ag #a1bfj #ab4e ,aug4 #ah #a1cdj #ac4j ,aug4 #ai #a1cce #ac4j ,aug4 #bj #a1cjj #ac4j ,aug4 #ba #a1cbe #ac4j ,aug4 #bb7a7 ,aug4 #bc #a1bje #ab4j ,aug4 #bd #a1bjj #ab4j ,aug4 #be #a1bhe #ab4e ,aug4 #bf #a1ahe #ab4j ,aug4 #bg #a1bee #ab4e ,aug4 #bh7a7 ,aug4 #bi #a1aae #aa4j ,aug4 #cj #a1ace #aa4e ,aug4 #ca #a1age #ab4j ,sept4 #a #a1jej #aj4e ,sept4 #b #ijj #i4j -------------------------------- 7#a7 ,not fed4 ,september #c1 found dead4 ,autopsy3 ,stomach and small intestines showed numerous hemorrhagic spots2 thick coating of mucus surrounded the contents of the stomach2 bladder was greatly distended with urine2 the other organs were apparently normal4 ,rabbit #chh4 ,belgian male4 ,given #a cc of #a per cent caffein for each #ajj grams1 through stomach tube4 -------------------------------- ,date4 ,weight4 ,treatment4 -------------------------------- ,grams4 cc4 ,aug4 #ag #a1jhj #aj4j ,aug4 #ah #a1aae #aa4j ,aug4 #ai #a1aej #aa4e ,aug4 #bj #a1acj #aa4e ,aug4 #ba #a1abj #aa4j ,aug4 #bb7a7 ,aug4 #bc #a1jbj #aj4j ,aug4 #bd #ihe #aj4j ,aug4 #be #ifj #i4e ,aug4 #bf #ijj #i4j ,aug4 #bg #hge #i4j ,aug4 #bh7a7 -------------------------------- 7#a7 ,not fed4 ,august #bi1 found dead #i a4 m4 ,autopsy3 ,heart and lungs normal2 liver and kidneys engorged2 stomach normal2 intestines showed a catarrhal inflammation1 though not severe2 spleen normal2 walls of colon somewhat injected4 ,rabbit #cia4 ,belgian4 ,given #a cc of #a per cent caffein to each #ajj grams through stomach tube4 ------------------------------ ,date4 ,weight4,treatment4 ------------------------------ ,grams4 cc4 ,aug4 #ag #idj #i4e ,aug4 #ah #iej #i4e ,aug4 #ai #iee #i4e ,aug4 #bj #ice #i4e ,aug4 #ba #ide #i4e ,aug4 #bb7a7 ,aug4 #bc #hce #h4e ,aug4 #bd #hje #h4j ,aug4 #be #hjj #h4j ,aug4 #bf #gfe #g4e ,aug4 #bg7b7 #fij #g4j ,aug4 #bh7a7 ,aug4 #bi #efe #e4e ------------------------------ 7#a7 ,not fed4 7#b7 ,poor condition4 ,august #cj1 found dead #i a4 m4 ,autopsy3 ,heart injected2 lungs normal2 liver affected slightly with coccidiidea2 stomach normal in appearance2 small intestines normal1 but colon considerably inflamed2 kidneys slightly engorged2 other organs normal4 ,rabbit #djb4 ,black female4 ,given #a cc of #a per cent caffein to each #ajj grams4 ------------------------------ ,date4 ,weight4,treatment4 ------------------------------ ,grams4 cc4 ,aug4 #bj #b1jcj #bj4j ,aug4 #ba #a1iej #ai4e ,aug4 #bb7a7 ,aug4 #bc #a1iee #ai4e ,aug4 #bd #a1ije #ai4j ,aug4 #be #a1hij #ai4j ,aug4 #bf #a1ghj #ah4j ,aug4 #bg #a1gfe #ag4e ,aug4 #bh7a7 ,aug4 #bi #a1fcj #af4e ,aug4 #cj #a1edj #ae4e ,aug4 #ca #a1eaj #ae4j ,sept4 #a #a1dbe #ad4j ------------------------------ 7#a7 ,not fed4 ,september #b1 found dead #i a4 m4 ,autopsy3 ,the lungs were badly congested1 the posterior lobe of the right lung showing hepatization2 the liver was considerably enlarged and congested2 the mucous membrane of the stomach and small intestines was congested and showed numerous hemorrhagic spots2 the kidneys showed slight congestion2 all other organs normal4 ,,series ,d4 ,the evidence brought forth in the preceding pages regarding cumulation of caffein naturally suggests the question whether or not the body acquires a tolerance for it4 ,this question has already been answered in the affirmative by ,gourewitch17#bh7 but owing to the method he used for the identification of caffein and the few experiments made his results are not conclusive4 ,the experiments of series ,a1 ,b1 and ,c might be regarded as indicating that tolerance for caffein is not acquired by the rabbit4 ,it was noticed1 however1 that the rabbit apparently does tolerate increasingly larger doses under certain conditions1 as the following experiments show3 ,rabbit #bbc4 ,belgian hare1 male4 ,october #bb3 ,weight1 #a1ebj grams2 #ae cc #b per cent caffein injected subcutaneously at #b p4 m4 ,november #a3 #aj4cj a4 m41 weight1 #a1eaj grams2 #ag cc #b per cent caffein injected subcutaneously 7#bbe mg per kilo71 reflexes observed1 but no tetanus4 ,november #d3 #aj4cj a4 m41 weight #a1ece grams2 #ai cc #b per cent caffein injected subcutaneously at #b4dj p4 m42 #d4dj p4 m41 no symptoms4 ,november #h3 ,weight1 #a1dbe grams2 #bj cc #b per cent caffein 7#bhe mg per kilo7 injected at #aa4de p4 m42 #e p4 m41 no symptoms4 ,november #ag3 ,weight1 #a1cbe grams2 #bb cc #b per cent caffein injected at #b4ee p4 m4 7#cbi mg per kilo71 no symptoms4 ,november #ah3 ,rabbit in good condition4 ,rabbit #bbd4 ,belgian hare1 female4 ,diet1 carrots4 ,october #ah3 ,weight1 #a1ice grams2 #aa4bj a4 m41 #ae cc #b per cent caffein 7#aee mg per kilo7 injected4 ,november #a3 ,weight1 #a1ghj grams2 #bj cc #b per cent caffein 7#bbd mg per kilo7 injected subcutaneously1 reflexes increased1 muscle tremors present1 but no other symptoms4 ,november #d3 ,weight1 #a1gaj grams2 #ba4e cc #b per cent caffein 7#beb mg per kilo7 injected4 ,november #h3 ,weight1 #a1dce grams2 #bb4e cc #b per cent caffein or #cad mg per kilo injected at #aa4dj p4 m42 #e a4 m41 no symptoms4 ,november #ag3 ,weight1 #a1cdj grams2 #bd cc #b per cent caffein 7#ceh mg per kilo7 injected subcutaneously4 ,november #ah3 #i a4 m41 rabbit died4 ,rabbit #bbf4 ,gray male4 ,diet1 carrots4 ,october #bh3 ,weight1 #a1jde grams2 #aj cc #b per cent caffein injected subcutaneously at #a4ej p4 m42 #d4cj p4 m41 tremors observed1 but no other symptoms4 ,october #bi3 ,rabbit in good condition4 ,november #a3 ,weight1 #iej grams2 #aj4ee a4 m41 #aa cc #b per cent caffein injected subcutaneously 7#bca mg per kilo74 ,november #d3 ,weight1 #icj grams2 #b4ej p4 m41 #ab cc #b per cent caffein injected subcutaneously 7#beh mg caffein per kilo74 ,november #f3 ,weight1 #ide grams2 #aa4de a4 m41 #ae cc #b per cent caffein 7#cac mg per kilo7 injected subcutaneously4 ,november #ag3 ,rabbit still alive2 weight1 #hij grams4 ,the results of these experiments indicate that when sufficient time is allowed between two successive injections1 susceptibility to caffein is not increased4 ,the rabbit1 on the contrary1 seems to acquire a tolerance for the drug1 for the fourth dose was #ae per cent larger than the minimum fatal dose of caffein4 ,this is in all probability due to the better elimination of caffein and its products of decomposition and to recovery from the deleterious effects of each dose1 made possible by long intervals between injections4 ,the results of these experiments may be briefly summed up by stating that subminimum doses of caffein given to the rabbit daily or at intervals 7not too long7 do not produce any symptoms such as were observed in acute caffein intoxication1 namely1 increased reflexes and convulsions1 or increased rate of respiration1 thus showing that it is not cumulative4 ,but evidence of undoubted summation of effect was adduced to show that if the administration of subminimum doses of caffein be continued daily for a period of #aa to #ah days the result is fatal4 ,tolerance1 however1 may be acquired1 although to a limited extent only1 provided sufficiently long intervals between injections are allowed to give time for repair of the injury done by the drug and to develop a mechanism for its better decomposition and elimination4 ,furthermore1 the evidence just given indicates that the elimination of subminimum doses of caffein and its products of decomposition is probably accomplished within #bd hours or thereabouts4 ,that the elimination of larger doses is not accomplished in this interval is made probable by the following experiment3 ,gray rabbit #dee4 ,female4 ,diet1 oats4 ,october #ab3 ,weight1 #a1ahe grams2 #c4cj p4 m41 #aa4e cc #b of per cent caffein injected into the lumbar muscles2 #c p4 m41 reflexes increased4 ,october #ac3 #aj a4 m41 rabbit weighed #a1jgj grams2 no symptoms of caffein poisoning1 reflexes normal2 #aj4cj a4 m41 #aj cc #b per cent caffein injected into the lumbar muscles2 #aa4cj a4 m41 rabbit jumped off the table1 had convulsions1 and died4 ,,experiments ,,on ,,dogs4 ,having gained some information respecting the effects of repeated doses of caffein on rabbits1 it was of interest to find out how carnivora reacted to the drug when similarly administered4 ,a number of dogs were used for the purpose4 ,considerable variation in the mode of experimentation1 as will appear later1 was allowed4 ,since the condition of the animal1 its age1 environment1 or diet might be factors influencing toxicity1 tests were made on full-grown and on young growing dogs whose food was varied4 ,the subjects of the experiment were kept under observation for a few days to several weeks before the administration of caffein was begun1 in order to determine whether or not any morbid condition existed1 as well as to ascertain whether the new environment had any effect on these animals4 ,caffein was given chiefly by mouth1 but the subcutaneous method was also employed during a portion of the experimental period in some dogs4 ,the initial dose1 which varied for different individuals1 was maintained for a variable length of time4 ,it was then progressively increased1 in most cases until the death of the animal4 ,with larger doses the intervals between successive injections were also increased4 ,,series ,a4 ,six dogs were used in this series4 ,caffein was administered by mouth for periods of six days to five weeks4 ,it was given daily or at intervals of two1 and sometimes of three1 days4 ,in a few instances the drug was withheld for four or even for seven days1 and its administration was resumed at the end of this time4 ,the initial dose in these experiments varied approximately between #dj and #adj mg per kilo4 ,the doses were then increased gradually1 and thus the maximum resistance of the subject to caffein was tested4 ,the diet consisted either exclusively of meat or largely of carbohydrates with a minimum amount of meat to give flavor to the food4 ,dog #aa4 ,female4 ,diet consisted of rice1 #bej grams2 cane sugar1 #bej grams2 meat1 #ej grams2 cracker meal1 about #ajj grams4 ,caffein was given by mouth daily or at intervals of one day1 when the dose did not exceed #a4e grams4 ,before the dose was increased to #b grams1 or approximately #j4bac gram caffein per kilo1 an interval of two days was allowed4 ,symptoms were noticed the next day4 ,an interval of two days was therefore allowed again at the end of which the same dose was repeated4 ,it will be remarked that there were no symptoms this time1 and the general condition of the dog seemed to be good4 ,two grams of caffein were1 therefore1 given daily during the next two days without any untoward effects2 the dose was then increased to #b4e grams4 ,even after this enormous quantity no symptoms were observed except slight tremors4 ,when this dose was repeated #bf hours later1 it proved fatal4 ,no albumin or sugar was found in the urine1 although the dog was fed on a very liberal carbohydrate diet4 ,the following is a complete record of the experiment4 ,april #bj3 ,urine acid1 no albumin1 no sugar4 ,april #ba3 ,urine free from sugar4 ,april #bb3 ,urine free from sugar4 #a gram caffein given in the afternoon4 ,april #bc3 #i a4 m41 dog was very thirsty1 drank a large quantity of water1 urine did not reduce ,fehling's solution4 ,april #bd3 #b4cj p4 m41 #a gram caffein1 no sugar in urine4 ,april #be3 #a gram caffein administered4 ,april #bf3 ,weight1 #aj4f kilos1 urine collected in the morning1 no sugar2 #d4aj p4 m41 #a4e grams caffein4 ,april #bg3 #a4e grams caffein2 #a4cj p4 m41 diet as before1 no sugar in urine4 ,april #bh3 ,weight1 #aj4b kilos1 no caffein1 no sugar in urine4 ,april #cj3 ,weight1 #aj4d kilos1 no sugar in urine2 #d4bj p4 m41 #b grams caffein4 ,may #a3 ,urine examined1 sugar absent1 weight #aj kilos1 vomited1 sick1 tremors observed1 drank #ejj cc water at one time1 appetite poor4 ,may #b3 ,no caffein1 drank #aej cc water4 ,may #c3 ,urine1 no sugar1 moderate quantity of albumen present2 #ab noon1 #b grams caffein given by mouth1 weight #aj4c kilos2 #b p4 m41 urine1 sugar negative1 condition of dog good1 no symptoms of caffein intoxication4 ,may #d3 #aj a4 m41 about #aj cc thick1 dark-colored mucilaginous urine found in collecting bottle2 albumin a little more than a trace1 decidedly less than on ,may #c1 no sugar1 condition of dog pretty good except for slight muscular tremors2 #d p4 m41 #b grams caffein by mouth 7as usual74 ,may #e3 ,urine not examined1 no symptoms2 #d p4 m41 #b grams caffein4 ,may #f3 ,urine not examined2 #b4cj p4 m41 #b4e grams caffein given by mouth2 #d p4 m41 slight tremor1 no other symptoms4 ,may #g3 ,no examination of urine1 no symptoms observed2 #d p4 m41 #b4e grams caffein4 ,may #h3 #i a4 m41 found dead1 urine collected since last dose of caffein was given did not contain any sugar or albumin1 the amount of caffein fed to this dog was #ah grams in #ah days4 ,autopsy3 ,post-mortem examination showed marked enteritis with hemorrhagic spots on the mucosa2 liver and kidneys congested and dark colored2 lungs congested2 thyroid gland was greatly enlarged and congested4 ,dog #bh4 ,april #cj3 ,weight1 #f4h kilos2 the diet consisted of #bej grams rice1 #bej grams sugar1 #ajj grams cracker meal1 and #ajj grams of meat4 ,on ,may #c his weight was #g kilos4 ,he received #a gram of caffein by mouth at #ab noon4 ,at #b p4 m4 he vomited and tremors were observed4 ,the next day1 ,may #d1 tremors were still present though less pronounced4 ,examination of the urine for sugar and albumin was negative2 on ,may #d1 #a gram caffein was given again and repeated on ,may #e4 ,on this date his general condition was not good--dog had no appetite and refused to take caffein4 ,as the dog lost #aj per cent of his weight he was put on a meat diet exclusively and the dose of caffein was reduced to #j4e gram4 ,he became sick after the second dose1 and the administration of caffein was therefore discontinued4 ,it was resumed after five days and the caffein was administered in increasing amounts1 i4 e41 on ,may #ah1 #j4e gram2 ,may #ai1 #j4e2 ,may #bj1 #a2 ,may #ba1 #a gram in two doses of #j4e each1 given at intervals of one hour2 ,may #bb1 #a gram4 ,dog became irritable1 but no other symptoms were observed4 ,the administration of caffein was omitted the next day4 ,on the following day when the same dose of caffein was given there was again marked irritability and tremors4 ,the experiment was therefore discontinued4 ,dog #bb4 ,male bulldog4 ,june #bd3 ,dog weighed #ac4g kilos4 ,diet consisted of meat exclusively2 #a gram caffein was given by mouth2 diarrhea developed2 no caffein was given for three days4 ,june #bh3 ,dog weighed #ac4f kilos1 #a4e grams caffein given at #aj a4 m4 ,june #cj3 #a4ge grams caffein administered4 ,july #b3 ,dog weighed #ac4e kilos2 #b grams caffein or #j4ae gram per kilo1 caused well-marked thirst1 but did not produce any other symptoms4 ,dog #bj4 ,female4 ,may #ab3 ,weight1 #g4g kilos4 ,fed liberal carbohydrate diet1 consisting of rice1 #ajj grams2 sugar #ajj grams2 meat and cracker meal1 a sufficient quantity to flavor the food4 ,may #ad3 ,weight1 #g4g kilos4 ,examination of urine for albumin and sugar gave negative results4 ,urine was acid to litmus4 ,may #ag3 ,weight1 #g4d kilos4 ,three hours after it was fed the dog received #j4e gram caffein by mouth4 ,the test of the urine the next day for sugar was negative1 but a trace of albumin was present4 ,it will be noticed that the doses were increased gradually and that symptoms were observed only after the fourth dose of #j4a gram per kilo4 ,later meat was substituted for the carbohydrate diet and the administration of caffein was stopped for four days4 ,at the end of this period #ajj mg caffein per kilo was fed daily for five days1 and the dose was then very gradually increased4 ,diarrhea occurred twice1 but no other symptoms1 the second attack having lasted a few days4 ,the following is a complete record of the experiment3 ,may #ai3 #j4e gram caffein #aa4de a4 m4 ,may #bj3 #j4ge gram caffein #ab4de a4 m4 ,may #ba3 #j4ge gram caffein #ab noon2 no sugar1 no albumin in urine4 ,may #bb3 #j4ge gram caffein2 urine1 same condition found2 no symptoms4 ,may #bc3 ,weight1 #g4e kilos2 no caffein4 ,may #bd3 #j4ge gram caffein2 tremors very marked4 ,may #be3 ,no caffein4 ,may #bf3 #j4ge gram caffein4 ,may #bg3 #j4ge gram caffein4 ,may #bh3 #j4ge gram caffein4 ,may #bi3 #a gram caffein in two doses of #j4ge and #j4be gram4 ,may #cj3 ,no caffein4 ,may #ca3 ,no caffein2 meat diet exclusively4 ,june #a3 ,no caffein2 meat diet exclusively4 ,june #b3 ,no caffein2 no sugar1 no albumin in urine4 ,june #c3 ,weight1 #g4f kilos2 #j4ge gram caffein2 no sugar in urine4 ,june #d3 ,weight1 #g4c kilos2 #j4ge gram caffein2 no sugar in urine4 ,june #e3 ,weight1 #g4e kilos2 #j4h gram caffein2 drank #ejj cc water2 ate #bjj grams meat4 ,june #f3 ,weight1 #g4d kilos2 #j4h gram caffein2 #ejj cc urine2 drank #ejj cc water2 ate #bjj grams meat2 no symptoms4 ,june #g3 ,weight1 #g4g kilos2 #j4h gram caffein #aj a4 m42 #djj cc urine1 #ejj cc water1 #bjj grams meat4 ,june #h3 ,weight1 #g4e kilos2 #j4i gram caffein1 #dej cc urine1 #a p4 m42 #bjj grams meat1 #ejj cc water4 ,june #i3 ,weight1 #g4f kilos2 #j4i gram caffein1 #a p4 m42 #ejj cc water1 #bjj grams meat and bone dust2 diarrhea and restlessness all afternoon4 ,june #aj3 ,weight1 #g4f kilos2 #a gram caffein1 #ejj cc water1 #bjj grams meat1 #dhj cc urine4 ,june #aa3 ,weight1 #h kilos2 #a gram caffein1 #dgj cc urine1 #ejj cc water1 #bjj grams meat4 ,june #ab3 ,weight1 #g4h kilos2 #a gram caffein1 #gaj cc urine1 #ejj cc water1 #bjj grams meat4 ,june #ac3 #dej cc urine1 #ejj cc water1 #cjj grams meat4 ,june #ad3 ,weight1 #g4i kilos2 #a4b grams caffein1 #ejj cc water1 #cjj grams meat1 #dij cc urine4 ,june #ae3 ,weight #g4h kilos1 #ejj cc water1 #cjj grams meat1 #eej cc urine4 ,june #af3 ,weight #h4j kilos1 #a4b gram caffein1 #ejj cc water1 #cjj grams meat1 bone dust added to check diarrhea4 ,june #ag3 #ejj cc water1 #cjj grams meat1 #dej cc urine1 diarrhea continues1 bone dust added4 ,june #ah4 ,weight #g4h kilos1 #a4c gram caffein1 #cjj grams meat1 #ejj cc water1 #cjj cc urine4 ,june #ai3 ,dog very thirsty1 drank #a liter of water and ate #cej grams of meat2 #ifj cc urine passed during the past #bd hour4 ,june #ba3 ,weight #g4e kilos1 #a4e grams caffein given at #aj a4 m4 ,at #b p4 m4 convulsions and death4 ,this dog received a total of #ba4ae grams caffein in #be doses during a period of #ce days1 which amounts to an average of #he mg per kilo daily4 ,dog #ai4 ,female fox terrier4 ,may #ac3 ,weight #f4d kilos4 ,diet consisted of rice1 #ajj grams2 sugar1 #ajj grams2 and a sufficient quantity of meat and cracker meal to give flavor to the food4 ,examination of the urine showed a trace of albumin but no sugar4 ,the urine was acid to litmus4 ,two days later the urine was alkaline to litmus4 ,there was still a small amount of albumin but no sugar4 ,may #ag3 #j4e gram caffein was given by mouth4 ,examination of the urine collected the next day still showed the presence of albumin and the absence of reducing substances4 ,the dog had tremors4 ,caffein was1 therefore1 not administered4 ,may #ai3 #j4e gram caffein was given by mouth4 ,may #bj3 #j4ge gram caffein was fed at #ab4de p4 m4 ,the dog vomited during the night and tremors were observed the next morning4 ,the urine collected was examined for albumin and sugar1 but neither was found4 ,may #ba3 #ab noon1 #j4ge gram caffein was fed4 ,the dog weighed #f kilos1 which therefore represented a loss of #j4d kilo4 ,grew abnormally thirsty and lost appetite1 but no other symptoms of caffein poisoning were observed4 ,may #bb3 ,the dog was again given #j4ge gram caffein at #ab noon4 ,the examination of the urine for albumin and sugar gave negative results4 ,the dog died at #d4ae p4 m4 ,the fatal dose for this dog was therefore #j4abe gram caffein per kilo1 and the total amount of caffein ingested in six days amounted to #c4be grams1 or #j4ed gram per day1 which makes #ij mg per kilo4 ,dog #ba4 ,white female bull4 ,this dog was kept on a diet exclusively of meat1 and was given water ab libitum4 ,from #j4e to #j4f gram of caffein was administered daily for seven days2 the doses were then increased and were given at longer intervals4 ,no symptoms of the effects of caffein were observed until a dose of #a4e gram was fed1 when diarrhea was noticed on the next day4 ,in the following record the details of the experiment are given3 ----------------------------- ,date4 ,weight4 ,caffein4 ----------------------------- ,kilos4 ,grams4 ,june #g #ab4e #j4e ,june #h #ab4e 4#e ,june #i #ab4e 4#e ,june #aj #ab4c 4#f ,june #aa #ab4c 4#f ,june #ab #ab4c 4#f ,june #ac #ab4c 4#f ,june #ad #ab4c 4#h ,june #af #ab4g #j4h ,june #ah #ab4i #a4j ,june #ba #ac4d #a4b ,june #bd #ac4c #a4e ,june #be 7#a7 4#j ,june #bg #ac4e #a4e ,june #cj #ac4e #a4ge ----------------------------- 7#a7 ,diarrhea4 ,july #b3 #aa4cj a4 m41 #b4j gram caffein fed by mouth2 #a4cj p4 m41 tetanus1 dog died4 ,the total amount of caffein fed to dog ,no4 #ba out of the #be days of the experiment was #ad4de grams1 or an average of #egh mg per day1 which amounts to about #db to #dc mg per kilo of body weight4 ,notwithstanding the diversity in the method of experimentation1 there was a striking uniformity in some of the results obtained4 ,all the experiments of the series showed absence of cumulative action of caffein4 ,the experimental evidence presented indicates that moderately large doses may be given at intervals of about #bd hours without inducing any symptoms of nervous or any other disturbance4 ,this is illustrated in the tests on dog #aa1 which were preliminary in character4 ,in this subject #ajj to #aej mg of caffein per kilo were ingested daily for several days without showing any changes4 ,later in the course of the experiment1 after larger doses were given1 mild symptoms only1 such as tremors1 were observed4 ,additional evidence of the absence of cumulative action of caffein was furnished by the results of the following experiments3 ,dog #bc received #adb mg of caffein per kilo on three successive days4 ,his general condition indicated that these amounts of caffein were toxic1 but he survived4 ,in another series of tests1 made after he was allowed to rest a few days1 he again failed to show any cumulation of the drug1 as he survived this time a series of tests of longer duration than the first4 ,a much better illustration of the absence of cumulative action of the drug is furnished by the experiments on dog ,no4 #bj4 ,in this case #ajj to #abe mg of caffein per kilo1 given on #aj consecutive days1 did not cause any marked effects4 ,diarrhea and restlessness were the only symptoms observed4 ,these experiments therefore show that the elimination and decomposition of caffein are apparently effected by the body within twenty-four hours or thereabouts4 ,experiments on dog #ai1 however1 form an exception--the third dose of #abe mg caffein per kilo having proved fatal4 ,the very low protein content of the diet of this dog suggests itself as a possible cause of the lower resistance to caffein of this subject4 ,but it may be observed that the same diet was furnished to dog #bj1 which stood such amounts of caffein much longer4 ,the presence of a trace of albumin in the urine of dog #ai is likewise inadmissible as a cause of the difference in the toxicity of caffein in this dog1 for the urine of dog #bj likewise contained a trace of albumin4 ,the alkaline reaction of the urine1 together with the fact that the first dose of only #fj mg of caffein per kilo induced symptoms of toxicity1 suggests the presence of an abnormal condition which in all probability was the cause of the death of this subject under the conditions indicated4 ,in a large number of experiments on caffein performed in this laboratory it has been observed that symptoms due to caffein often disappeared when the administration of the same dose of the drug was continued4 ,thus dog #ai vomited when the amount of caffein was increased to #abe mg per kilo4 ,when this amount was repeated the next day there was no vomiting4 ,similar observations were made on dogs #aa and #bc1 also on other dogs4 ,no4 #bb developed diarrhea at first2 when the administration of caffein was resumed several days later1 however1 there was no diarrhea4 ,in other experiments performed in this laboratory1 symptoms of nervous irritability induced by caffein disappeared on continued treatment4 ,it was interesting1 therefore1 to inquire whether resistance to caffein would be increased by the continued administration of progressively larger amounts of the drug4 ,when doses of #aej and over were fed1 the intervals allowed were usually longer than #bd hours4 ,two and sometimes three days were permitted to elapse between two successive doses4 ,this was done in order to allow time for recovery from possible changes induced by larger doses of caffein1 and thus prevent the summation of effect4 ,in the experiments considered1 therefore1 ,nos4 #aa1 #bc1 #bj1 and #ai1 the toxicity of caffein does not seem to be greater than in the experiments on acute caffein intoxication in the dog4 ,it was thought1 however1 that the large initial doses or the quick change to large doses when the amounts used in the beginning were small1 might have something to do with failure to induce a marked degree of tolerance4 ,the experiment on dog #ba was therefore carried out by giving from #dj to #fj mg per kilo for eight days1 and then increasing the dose1 but tolerance could not be induced1 as is shown in the protocol to the experiment4 ,,series ,b4 ,according to the studies of ,chittenden17#af7 low protein diet improves the general metabolism of the body1 fatigue is diminished1 and bodily vigor1 therefore1 correspondingly increased4 ,the expectation is1 therefore1 justified that the defense of the organism against deleterious substances introduced into the body is much improved by such a diet1 thus increasing its resistance to poisons4 ,hunt's experiment on this subject1 also quoted by ,chittenden1 lends support to this view4 ,he found that mice fed on carbohydrates chiefly1 or on foods containing only a small amount of protein1 were more resistant to acetonitril4 ,it was interesting1 therefore1 to inquire whether the toxicity of caffein differs under similar conditions of diet4 ,a fixed diet of the same calorific value was provided for all dogs of this series1 but the protein content for three of the animals was approximately one-third of the amount usually fed to dogs4 ,caffein was at first administered subcutaneously1 but all the dogs on a low protein diet developed abscesses at the site of injection1 while none of those on high protein diet showed a local reaction4 ,feeding by mouth was then begun and continued throughout the experiment in each case4 ,the initial dose was #ej mg per kilo1 which was given daily for seven to nine days4 ,it was then increased progressively by #be mg per kilo2 #ge mg per kilo were administered for one to two days1 #ajj mg for two to three days1 #abe mg for one to two days1 #aej mg for one to two days1 and a single dose of #age mg4 ,it will be remarked that sometimes an interval of one day had to be allowed during which no caffein was fed4 ,dog #cj4 ,black and tan hound1 male4 ,the dog was under observation for about eight weeks before the experiment was begun and had received a high protein diet4 ,he was then given #ej mg caffein for nine consecutive days4 ,on the tenth day the dose was increased to #ge mg per kilo4 ,as no symptoms developed1 this dose was increased to #ajj mg per kilo1 and was fed one day apart4 ,it was then raised to #abe mg per kilo4 ,for the first time since the drug was fed1 symptoms appeared2 they were noticed a few hours after feeding and persisted during the next day4 ,although the appetite was good1 no caffein was given on this day4 ,on the following day this dose was repeated4 ,as the symptoms were not serious1 #aej mg per kilo were given daily for the next three days1 until #age mg per kilo was reached4 ,this dose proved fatal within six hours4 ,record of experiment follows3 ,october #i3 ,weight1 #i kilos1 on full nitrogen diet1 received daily #j4gbd gram nitrogen per kilo or #hg calories per kilo1 received #ah grams meat per kilo1 #d grams lard per kilo1 #c grams carbohydrates per kilo1 bone dust1 ad libitum4 ,november #c3 ,weight1 #i4aj kilos4 ,november #aj3 ,weight1 #i kilos4 ,november #bj3 ,weight1 #i4ee kilos4 ,november #bi3 ,weight1 #h4gj kilos4 ,december #f1 #g1 #h1 and #i3 ,received subcutaneously #bb cc #b per cent caffein4 ,condition good1 site of injection normal4 ,december #aj1 #aa1 #ab1 #ac1 and #ad3 ,received #j4dcge gram caffein by mouth equal to #j4jej gram per kilo1 no symptoms1 appetite and general condition good4 ,december #ae3 #aa4cj a4 m41 received #j4fefc gram caffein by mouth1 or #j4ge gram per kilo1 no symptoms1 appetite good1 condition excellent4 ,december #af3 #aa a4 m41 received #j4hgj gram caffein by mouth1 or #j4a gram per kilo1 weight #h4gj kilos1 no symptoms4 ,december #ag3 ,no caffein given4 ,december #ah3 ,received #j4hgj gram caffein1 or #j4a gram per kilo1 no symptoms4 ,december #bj3 #b4de p4 m41 received #a4jhge grams caffein1 or #j4abe per kilo2 #d p4 m41 ate food readily1 seemed very uncomfortable and sick4 ,december #ba3 #i a4 m41 stiffness in muscles1 but no other symptoms1 appetite good1 no caffein given4 ,december #bb3 #aa a4 m41 received #a4jhge grams caffein1 or #j4abe gram per kilo2 #c p4 m41 depressed in spirits and sick1 but no other symptoms observed4 ,december #bc3 #aa4cj a4 m41 received #a4cje grams caffein1 or #j4aej gram caffein per kilo2 #a4cj p4 m41 apparently quite sick1 but no other symptoms1 had good appetite4 ,december #bd3 #aj a4 m41 received #j4age gram caffein per kilo2 #d p4 m41 when about to be fed fell over and died2 no autopsy4 ,the total amount of caffein given dog #cj was #aa4cdeh grams1 administered for a period of eighteen days4 ,the average daily amount per kilo was therefore #gb mg4 ,the feces became offensive when the amounts of caffein were increased to #ge mg per kilo4 ,it will be observed that in this dog the appetite was uniformly good until the day of his death4 ,whether or not this is the cause of his resistance to caffein will be discussed later4 ,dog #cb4 ,white1 male1 young4 ,although he was growing rapidly this dog's weight was constant1 but he looked anemic4 ,he received a high protein diet until ,december #c1 when the rations were increased by one-third4 ,this dog was under observation from ,october #bf to ,december #f when the administration of caffein was begun4 ,he then received #ej mg caffein per kilo daily for nine days consecutively without showing any effects1 when the dose was increased to #ge mg per kilo1 then to #ajj mg per kilo4 ,this dose was further increased to #aej mg per kilo without causing symptoms1 which was repeated the next day4 ,no symptoms having been observed after such amounts of caffein1 #age mg per kilo were fed4 ,this dose1 however1 proved fatal within two hours4 ,record of experiment follows3 ,october #bf3 ,weight1 #f4ij kilos4 ,november #c3 ,weight1 #f4ij kilos4 ,november #aj3 ,weight1 #f4ij kilos4 ,november #bj3 ,weight1 #f4ij kilos4 ,november #bi3 ,weight1 #f4ee kilos4 ,december #c3 ,put into cage1 diet increased one-third4 ,december #f1 #g1 #h1 #i3 ,weight #f4cj kilos2 #ab4cj p4 m41 received #af cc #b per cent caffein by subcutaneous injection in back1 no symptoms of any kind noticed1 site of injection normal4 ,december #aj1 #ad3 #j4je gram caffein per kilo4 ,december #ae3 ,received #j4dgbe gram caffein by mouth1 no symptoms4 ,december #af3 ,received #j4fee gram caffein1 #j4ajj gram per kilo4 ,december #ag3 ,no caffein given4 ,december #ah3 ,received #j4fee gram caffein daily1 #j4ajj gram per kilo1 no symptoms4 ,december #bj3 ,received #j4hahh gram caffein1 #j4abe gram per kilo1 no symptoms1 appetite good4 ,december #ba3 ,received #j4ihbe gram caffein1 #j4aej gram per kilo1 somewhat uncomfortable1 no other symptoms4 ,december #bb3 ,received #j4ihbe gram caffein1 #j4aej gram per kilo1 no symptoms except some uneasiness4 ,december #bc3 #i a4 m41 no symptoms1 appetite good2 #aa4cj a4 m41 received #a4adf grams caffein1 #j4agei gram per kilo2 #a4cj p4 m41 died while making an effort to get out of cage1 tonic contraction of limbs observed before death4 ,the amount of caffein received during the entire experimental period was #i4bbbc grams1 or an average per day approximately of #hj mg per kilo1 and therefore #aj per cent more than dog ,no4 #cj received4 ,it will be observed that the appetite in dog ,no4 #cb was likewise uniformly good1 and that he received a very high protein diet which was also of a very high calorific value4 ,autopsy 7dog #cb74--,stomach presented a severe inflammation of the mucosa1 especially in the fundus and pyloric portions4 ,the gastritis was more marked in pyloric portion1 and the inflammatory condition extended along the whole course of small intestines1 which presented numerous hemorrhagic areas1 and a thick catarrhal exudate on the mucosa4 ,the large intestine contained quite a large number of parasites1 probably round worms4 ,the liver was enlarged and the gall cyst well filled4 ,the spleen was also considerably engorged1 kidneys appeared normal1 other organs all appeared normal4 ,dog #ca4 ,black spaniel1 male4 ,this dog had been under observation one month previous to the experiments with caffein4 ,the usual initial dose was then administered for nine days4 ,there were no signs of local irritation when the drug was given subcutaneously1 but symptoms of toxicity were present4 ,these disappeared1 however1 when the drug was administered by mouth4 ,the dose was therefore increased to #ge mg per kilo4 ,this1 as will be seen1 proved fatal within six hours4 ,high nitrogen diet1 same as ,no4 #cj4 ,november #c3 ,weight #aj4bej kilos4 ,november #aj3 ,weight1 #aj4be kilos4 ,november #bj3 ,weight1 #aj4cj kilos4 ,december #a3 ,put in cage4 ,december #f1 #g1 #h1 #i3 ,weight1 #aj4bj kilos2 received #bf cc #b per cent caffein subcutaneously1 site of injection normal4 ,december #f3 ,very restless and excited1 whined when handled as though muscles were sore1 appeared to be sick4 ,december #aj-ad3 ,condition good1 received #j4ea gram caffein by mouth daily1 no noteworthy symptoms1 appetite continues good1 somewhat restless at intervals4 ,december #ae3 #aa4cj a4 m41 received #j4gfe gram caffein per mouth 7#j4jge gram per kilo72 #b p4 m41 depressed in spirit1 seemed sick and uncomfortable2 #d4ae p4 m41 when about to feed1 animal jumped up1 then fell back dead4 ,autopsy 7dog #ca73 ,lungs congested2 heart filled with blood and contained small amount of blood-stained fluid in pericardial sac4 ,liver deeply congested1 soft and friable2 gall bladder distended with bile2 kidneys showed inflammation of cortex2 spleen pale1 normal in size and consistency2 stomach practically empty1 the mucosa of the pyloric portion exhibited severe gastritis1 with thick catarrhal exudate4 ,this catarrhal inflammation extended through the duodenum2 remaining portion of small intestine showed mild inflammation2 large intestine appeared practically normal4 ,the total amount of caffein received by dog #ca during #aj days was #e4cie mg1 or a daily average of #ec4i mg per kilo4 ,this unusually low resistance to caffein 7which was practically the only case in all the experiments on dogs presented in this research7 suggests the presence of some abnormal condition4 ,the bloody exudate in the pericardial cavity indicating pericarditis1 which is likely to induce secondary changes of cardiac muscle1 may be considered as a possible cause of the increased toxicity of caffein in this case4 ,dog #bi4 ,male fox terrier1 black4 ,this dog was kept on a low nitrogen diet for nearly five weeks before the feeding of caffein was begun4 ,the administration of #ej mg of caffein per kilo was then carried on for eight days without showing any symptoms of toxicity4 ,the usual increase of dose was then given--#ge mg per kilo--which was followed by a manifestation of symptoms4 ,further increase1 however1 to #ajj mg per kilo had no visible effect4 ,nevertheless it was considered advisable to suspend the feeding of caffein for one day4 ,the same amounts were then repeated on two consecutive days4 ,no symptoms having been observed1 #abe mg per kilo were given4 ,as symptoms of toxicity and especially loss of appetite were observed1 the dog was not given any caffein the next day4 ,since his appetite had now improved1 the experiment with larger doses was resumed4 ,death followed after the second dose of #aej mg per kilo4 ,protocol follows3 ,weight1 #i4ij kilos4 ,one-third nitrogen diet4 ,receives #j4bfi gram nitrogen per kilo 7#hh4bfi calories per kilo74 ,november #c3 ,weight1 #i4he kilos4 ,november #aj3 ,weight1 #i4ee kilos4 ,november #ab3 ,weight1 #i4dj kilos4 ,november #bi3 ,weight1 #i4he kilos4 ,december #f3 ,weight1 #i4ij kilos2 #aa4ce a4 m41 received #be cc #b per cent caffein solution by subcutaneous injection in back2 #d p4 m41 no symptoms1 appetite good4 ,december #g-i3 ,received #be cc caffein #b per cent solution--subcutaneous injection1 no symptoms1 area of injection inflamed and swollen4 ,december #aj1 #ac3 ,site of injection showed increased inflammation1 received #j4die gram caffein 7#ej mg per kilo7 in #cj grams meat daily without showing any symptoms4 ,december #ad3 #ab noon1 received #j4gdbe gram caffein by mouth 7#j4jge per kilo72 #b4cj p4 m41 restless and uneasy4 ,december #ae3 #aa4cj a4 m41 received #j4gdbe gram caffein by mouth2 #b p4 m41 depressed in spirits1 although continues to have good appetite4 ,december #af3 ,weight1 #i4ej kilos2 #c4ae p4 m41 received #j4ieji gram caffein by mouth2 #d4ej p4 m41 no symptoms4 ,december #ag3 ,animal rested4 ,december #ah3 ,received #j4iej gram caffein by mouth1 no symptoms4 ,december #ai3 ,received #j4ieji gram caffein by mouth1 no symptoms4 ,december #bj3 #b4de p4 m41 received #a4ahge grams caffein 7#j4abe gram per kilo72 #d p4 m41 restless and quite sick2 ate only a little food4 ,december #ba3 #i a4 m41 still uncomfortable1 allowed to rest1 no caffein given1 gradually recovered appetite4 ,december #bb3 #aa a4 m41 received #a4hge grams caffein2 #c p4 m41 seemed sick1 but showed no other symptoms1 appetite fair4 ,december #bc3 #i a4 m41 showed no symptoms from the day before1 ate food gradually1 seemed sick2 #aa4cj a4 m41 received #a4dbe grams caffein 7#j4aej gram per kilo72 #a4cj p4 m41 looked and behaved as if very sick1 no other symptoms2 #c4de p4 m41 in attempting to get out of box fell over on back1 had convulsions1 whined1 dyspnoea1 died within #cj seconds4 ,autopsy3 ,stomach exhibited mild inflammation2 small intestine inflamed and hemorrhagic areas on mucosa2 liver engorged and friable2 spleen normal2 kidneys slightly congested2 other organs appeared normal4 ,the total amount of caffein fed to ,dog #bi was #ab4ace grams1 which was given in #ah days4 ,the average daily amount per kilo was therefore #fg4fh mg4 ,dog #bh4 ,male fox terrier4 ,low nitrogen diet was begun about four weeks before the feeding of caffein2 #ej mg of caffein was then fed for seven consecutive days4 ,partial loss of appetite was observed after the first dose4 ,as the experiment progressed the desire for food steadily diminished1 and the feces became fetid4 ,symptoms of intoxication manifested themselves early in the experiment1 and vomiting occurred after the fourth dose4 ,the dog was then put on a diet exclusively of meat4 ,after an intermission of #aj days #aji mg caffein per kilo were given4 ,since there were no symptoms1 the following day the amount was increased to #abe mg per kilo4 ,this dose proved fatal within #af to #bj hours4 ,this dog was stout and strong1 weight #ab4be kilos1 received daily #j4bfi gram nitrogen per kilo 7#hh4bfi calories per kilo74 ,november #c3 ,weight1 #aa4ge kilos4 ,november #aj3 ,weight1 #aa4ie kilos4 ,november #bj3 ,weight1 #aa4bj kilos4 ,all through this period had been kept in a cold1 poorly ventilated room1 put in a warm room1 with bedding and good ventilation4 ,november #bi3 ,weight1 #aa4ie kilos4 ,december #a3 ,put in a cage2 weight1 #aa4ie kilos4 ,december #f3 ,weight1 #aa4ie kilos2 #aa4de a4 m41 received #j4jej gram caffein per kilo2 then received #cj cc #b per cent caffein 7#j4f gram7 in practically one subcutaneous injection2 #d4cj p4 m41 ate only part of food4 ,december #g3 #aj4be a4 m41 received #cj cc #b per cent caffein by subcutaneous injection 7#j4f gram1 or #ej mg1 per kilo72 #a4de p4 m41 seemed sensitive to touch1 no desire for food1 depressed in spirit4 ,december #h3 #aa4dj a4 m41 received #cj cc #b per cent caffein by subcutaneous injection 7#ej mg per kilo72 #a p4 m41 depressed in spirit1 hind legs seemed somewhat stiff1 no desire for regular food1 site of injection inflamed4 ,december #i3 #aj4ej a4 m41 received #cj cc #b per cent caffein by subcutaneous injection 7#ej mg per kilo72 #b4cj p4 m41 had vomited1 no desire for regular food4 ,december #aj3 ,inflammation of site of injection1 and swelling very pronounced2 #b p4 m41 received #j4eige gram caffein1 or #ej mg per kilo1 with #cj grams of meat1 refused regular food4 ,december #aa1 #ab3 ,received #j4eige gram caffein by mouth1 no symptoms except refusal of regular food1 feces fetid4 ,december #ac-bb3 ,put on meat diet exclusively1 high temperature1 no caffein1 weight #aj kilos1 appetite good1 feces fetid4 ,december #bb3 #ab a4 m41 weight #aa kilos1 received #a4b grams caffein by mouth 7#j4aji gram per kilo72 #d p4 m41 no symptoms4 ,december #bc3 #aa4cj a4 m41 received #a4cge grams caffein 7#j4abe gram per kilo7 had vomited food of the day before1 but could notice no caffein or capsules in vomit2 #d4cj p4 m41 no symptoms1 seemed in good spirits1 appetite good1 had no meat to feed with1 so was given low nitrogen feed1 of which he ate about one-fourth4 ,december #bd3 #i a4 m41 found dead1 stiff1 and cold4 ,the most striking effect of caffein in this dog is the increased intestinal putrefaction4 ,the feces were still fetid #aj days after the administration of caffein was stopped4 ,autopsy1 dog #bh3 ,stomach partially filled with an undigested food mass2 mucosa showed severe inflammation2 small intestines presented a hemorrhagic enteritis along whole extent2 large intestine also exhibited mild inflammation2 liver was engorged2 spleen appeared normal2 kidneys slightly congested in cortical portion2 other organs appeared normal4 ,dog #bd4 ,white and tan male3 ,was put on low protein diet six weeks before experiments with caffein were begun4 ,the initial dose of #ej mg per kilo was then administered on eight consecutive days4 ,the only symptoms observed during this period of caffein administration were those of intestinal putrefaction4 ,fetid feces were noticed already after the first dose of caffein was injected4 ,when the second dose of #ge mg of caffein was repeated1 mild symptoms appeared1 but none have been observed even with increased amounts of caffein4 ,one-third nitrogen diet4 ,received daily #j4bfi gram nitrogen per kilo 7#hh4bfi calories per kilo74 ,october #bf3 ,weight #aa4ae kilos4 ,food consisted of #e grams cracker meal per kilo2 meat1 #c grams per kilo2 lard1 #b grams per kilo2 tapioca1 #aj4fi grams per kilo4 ,kept in a cold1 damp room with poor ventilation until ,november #bj4 ,november #c3 ,weight1 #aa kilos4 ,november #aj3 ,weight1 #aj4ge kilos4 ,november #bj3 ,weight1 #aj4ee kilos2 changed to a warm room1 with bedding and good ventilation4 ,november #bi3 ,weight1 #aj4he kilos4 ,december #a3 ,put into a cage4 ,december #f3 ,weight1 #aj4ij kilos2 #aa4be a4 m41 received #bh cc #b per cent caffein subcutaneously in side1 below the shoulders1 area washed with alcohol and ether1 approximately #ej mg per kilo administered1 no symptoms4 ,december #g3 #aj4ae a4 m41 received #bh cc #b per cent caffein injected subcutaneously2 feces soft and very fetid2 #a p4 m41 depressed in spirit1 eyes dull4 ,december #i3 #aj4de a4 m41 received #be cc #b per cent caffein solution subcutaneously1 feces still fetid1 site of injection inflamed and swollen1 no other symptoms4 ,december #aj3 ,inflammation of area of injection more pronounced2 #b p4 m41 given #j4eddi gram caffein and #cj grams of meat2 #d p4 m41 fed1 no symptoms1 feces fetid4 ,december #aa3 #ab a4 m41 given #j4edei gram caffein and #cj grams of meat1 no symptoms1 feces fetid4 ,december #ab1 #ac3 ,given #j4edei gram caffein daily1 without noticing any symptoms4 ,december #ad3 #ab a4 m41 received #j4hag gram caffein 7#ge mg per kilo72 #b4cj p4 m41 restless and uncomfortable1 no other symptoms4 ,december #ae3 #aa4cj a4 m41 received #j4hage gram caffein by mouth2 #b p4 m41 depressed in spirit1 acted as though sick1 no other symptoms4 ,december #af3 ,weight1 #aa kilos2 #aa a4 m41 received #j4ajj gram caffein per kilo 7#a4ajj grams7 by mouth1 no symptoms4 ,december #ag3 ,rested4 ,december #ah3 #b4cj p4 m41 received #a4ajj grams caffein by mouth2 #d p4 m41 no symptoms4 ,december #ai3 #ab noon1 received #a4ajj grams caffein by mouth2 #d4ae p4 m41 no symptoms4 ,december #bj3 #b4de p4 m41 given #a4cge grams caffein 7#j4abe gram per kilo72 #c4de p4 m41 vomited--one of the capsules being found intact1 the other broken open2 #d p4 m41 given regular diet1 containing #a4cgeg grams caffein in capsules1 ate most of this during the night1 whined at intervals1 coordination disturbed1 appeared very sick1 but exhibited no other symptoms4 ,december #ba3 #i a4 m41 found dead1 stiff1 and cold4 ,the total amount of caffein received by dog #bd was between #aj4aji and #aa4dhd grams4 ,as one of the capsules vomited was intact and the other broken open1 the amount was probably about #aj4ge grams4 ,the fatal dose in this case was undoubtedly less than #ahe mg per kilo--somewhere between #abe and #ahe mg4 ,autopsy showed heart in diastole2 posterior lobe of right lung deeply congested2 liver engorged2 gall cyst filled2 spleen appeared normal2 stomach well filled with semifluid mass2 pyloric portion of stomach exhibited a severe inflammation of mucosa2 mucosa of duodenum greatly inflamed and showed hemorrhagic areas and catarrhal exudate2 remainder of small intestine also exhibited mild inflammation2 kidneys deeply engorged1 mesentery injected4 ,a comparison of the fatal doses of caffein in the experiments on high and low protein diet does not show much difference in the resistance to caffein1 since #age mg per kilo proved fatal to ,nos4 #cj and #cb1 while ,no4 #bi died after receiving #aej mg per kilo1 and ,no4 #bd received #abe to #ahe mg per kilo4 ,moreover1 ,no4 #bh1 which was changed from low to high protein diet1 succumbed when given #abe mg per kilo4 ,observations made during the experimental period indicate1 however1 greater toxicity of caffein in the subjects on low protein diet4 ,dog #cj showed the effects of the drug when the dose was increased to #abe mg of caffein per kilo1 while in ,no4 #cb1 #aej mg per kilo were received without any manifestation of symptoms4 ,dog #ca1 which was likewise on a high protein diet1 is evidently an exception1 and its low resistance to caffein may be accounted for by the condition found at autopsy4 ,in other dogs on low protein diet symptoms of intoxication appeared early in the experiment4 ,in ,nos4 #bi and #bd it was observed as soon as the amount of caffein was increased to #ge mg per kilo4 ,in dog #bh the first dose of caffein #ej mg per kilo was toxic4 ,the symptoms of gastro-intestinal disturbance were especially marked after caffein on low protein diet4 ,this may seem to contradict the results of experiments on dogs #aa and #bj1 in which larger doses of caffein failed to induce symptoms of intoxication4 ,but it should be observed that the diet1 which consisted almost exclusively of carbohydrates1 was given only during the administration of caffein1 while in the experiments of series ,b the subjects received a low protein diet for several weeks before the administration of caffein was begun1 and it was continued through the entire caffein period4 ,it will be remarked that the absence of cumulative action in the experiments of the preceding series was also observed in dogs on high as well as on low protein diet4 ,the appearance of symptoms after smaller doses of caffein in the latter experiments might suggest cumulative action1 but since these symptoms disappeared on continued administration of the substance cumulation is clearly not indicated4 ,the gastrointestinal lesions observed on post-mortem examination were1 it will be recalled1 also found in rabbits similarly treated4 ,the explanation suggested probably applies also in the case of dogs4 ,,series ,c4 ,as already pointed out in the experiments on acute toxicity of caffein1 young growing dogs are probably more resistant to caffein than adults4 ,that this may also hold true in chronic caffein intoxication seemed indicated by the following experiments4 ,dog #cc4 ,black female puppy4 ,weight1 #d kilos4 ,had been continuously on a meat diet4 ,december #bb3 #b4cj p4 m41 received #j4fi gram of caffein 7#j4agb gram per kilo72 #c4ae p4 m41 no symptoms except that feces were fetid4 ,december #bc3 #aa4cj a4 m41 received #j4gi gram of caffein 7#j4aig gram per kilo72 #a4cj p4 m41 no symptoms4 ,december #bd3 #aa a4 m41 received #j4hg gram of caffein 7#j4bjji gram per kilo72 #d p4 m41 no symptoms4 ,it will be observed that the only effect produced in dog #cc by feeding caffein was increased intestinal putrefaction1 although #b4cg grams of caffein were given in three days4 ,additional data on the effects of the age of animals on the resistance to caffein seemed desirable4 ,the following experiments were therefore carried out4 ,six puppies of the same litter were weaned when #g to #h weeks old and put on a milk diet4 ,three of them received this diet throughout the experimental period4 ,meat was substituted in the other three a few days before the administration of caffein was begun1 and was continued until the end of the experiment4 ,caffein was given by mouth2 the initial dose1 which was administered for several days and then gradually increased1 being #afj to #bjj mg for each dog1 except one1 which received only #ajj mg per kilo for several days and then an increased amount4 ,an intermission of a few days 7during which no caffein was given7 was allowed4 ,this was done on account of some studies carried on at the same time on the effect of caffein on certain constituents of the urine4 ,,pup ,,no4 #a4 ---------------------------------------- ------------------------- ,treatment ,date4 ,weight4 ,food 7#b per cent ,symptoms4 7milk74 caffein74 ---------------------------------------- ------------------------- ,grams4 cc4 cc4 ,apr4 #ba #a1dej #cjj #aj4j ,no symptoms4 ,apr4 #bb #a1ebj #cjj #aj4j ,do4 ,apr4 #bc #a1dej #bej #aj4j ,do4 ,apr4 #bd #a1cge #bej #aj4j ,do4 ,apr4 #be #a1dbj #bej #aj4j ,do4 ,apr4 #bf #a1cij #bej ,none4 ,apr4 #bg #a1djj #bej ,none4 ,apr4 #bh #a1dje #bej ,none4 ,apr4 #bi #a1dbj #bej ,none4 ,passed worms4 ,apr4 #cj #a1dcj #bej ,none4 ,do4 ,may #a #a1dej #bej #aj4j ,no symptoms4 ,may #b #a1eae #bej #ae4j ,do4 ,may #c #a1dge #bej #ae4j ,do4 ,may #d #a1die #bej #ae4j ,do4 ,may #e #a1eae #bej #bb4j ,seems dull and whines4 ,may #f #a1ece #bej #bj4j ,whines4 ,may #g #a1ebe #bej #bj4j ,no symptoms4 ,may #h #a1ecj #bej #bj4j ,do4 ,may #i #a1ejj #bej #bc4j ,diarrhea2 passed worms2 tremor and rigidity of legs2 whines4 ,may #aj #a1dij #bej ,none4 ,completely recovered from the effects of #ith4 ,may #aa #a1ece #bej #be4j ,can not balance itself2 continually vomiting4 ,may #ab #a1dfj #cjj ,none4 ,recovered from effects4 ,may #ac #a1dge #cej ,none4 ,in good condition4 ,may #ad #a1ede #bej ,none4 ,may #ae #a1eej #bej ,none4 ,may #af #a1eee #bej ,none4 ,may #ag #a1efj #bej #be4j ,salivated in cage2 stiffness of muscles4 ,may #ah #a1dej #bej ,none4 ,weak and stiff2 diarrhea4 ,may #ai #a1ejj #bej ,none4 ,no symptoms4 ,may #bj #a1efe #bej ,none4 ,may #ba #a1ede #bej ,none4 ,may #bb 7#a7 #bej ,none4 ,may #bc #a1eie #bej #bg4j ,tremors2 gait clumsy2 in- coordination of movements4 ,may #bd #a1die #bej #bg4j ,diarrhea2 vomited2 weak and stiff2 found dead #i a4 m4 #beth4 ---------------------------------------- ------------------------- 7#a7 ,sunday4 ,autopsy3 ,marked pulmonary congestion2 liver very pale2 heart wall injected2 slight inflammation of stomach and intestines4 ,,pup ,,no4 #b4 ---------------------------------------- -------------------- ,food ,treatment ,date4 ,weight4 7milk74 7#b per cent ,symptoms4 caffein74 ---------------------------------------- -------------------- ,grams4 cc4 cc4 ,apr4 #ba #a1cej #cjj #e4j ,no symptoms4 ,apr4 #bb #a1bdj #cjj #e4j ,do4 ,apr4 #bc #a1bej #bjj #g4e ,do4 ,apr4 #bd #a1bje #bjj #g4j ,do4 ,apr4 #be #a1bbj #bjj #g4j ,do4 ,apr4 #bf #a1baj #bjj ,none4 ,apr4 #bg #a1baj #bjj ,none4 ,apr4 #bh #a1bje #bjj ,none4 ,apr4 #bi #a1bjj #bjj ,none4 ,passed worms4 ,apr4 #cj #a1baj #bjj ,none4 ,may #a #a1bbj #bjj #aj4j ,no symptoms4 ,may #b #a1bbj #bjj #aj4j ,do4 ,may #c #a1bce #bjj #aj4j ,do4 ,may #d #a1bce #bjj #aj4j ,do4 ,may #e #a1bce #bjj #ag4j ,whines4 ,may #f #a1bej #bjj #ag4j ,do4 ,may #g #a1bce #bjj #ae4j ,diarrhea and worms4 ,may #h #a1bej #bjj #ae4j ,diarrhea4 ,may #i #a1afe #bjj #ah4j ,little or no symptoms4 ,may #aj #a1bce #bjj ,none4 ,no symptoms4 ,may #aa #a1cjj #bjj #bj4j ,salivated in cage2 refused to eat2 draws up hind legs4 ,may #ab #a1bjj #bjj ,none4 ,recovered4 ,may #ac #a1bae #bjj ,none4 ,in good condition4 ,may #ad #a1bhj #bjj ,none4 ,may #ae #a1cjj #bjj ,none4 ,may #af #a1caj #bjj ,none4 ,may #ag #a1caj #bjj #bj4j ,salivated in cage2 stiff2 all symptoms4 ,may #ah #a1bej #bjj ,none4 ,weak and stiff4 ,may #ai #a1bde #bjj ,none4 ,no symptoms4 ,may #bj #a1caj #bjj ,none4 ,may #ba #a1cbe #bjj ,none4 ,may #bb #a1cbe #bjj ,none4 ,may #bc #a1cbe #bjj #bb4j ,somewhat stiff4 ,may #bd #a1cae #bjj #bb4j ,restless2 scratches eyes2 sick4 ---------------------------------------- -------------------- ,,pup ,,no4 #c4 ---------------------------------------- ----------------------- ,apr4 #ba #a1bae #cjj ,none4 ,apr4 #bb #a1bbj #cjj ,none4 ,apr4 #bc #a1bbj #bjj ,none4 ,apr4 #bd #a1bjj #bjj ,none4 ,apr4 #be #a1bje #bjj ,none4 ,apr4 #bf #a1aie #bjj ,none4 ,apr4 #bg #a1bjj #bjj 7#a7 ,apr4 #bh #a1bae #bjj ,none4 ,apr4 #bi #a1bbj #bjj ,none4 ,apr4 #cj #a1bjj #bjj ,none4 ,may #a #a1bbe #bjj #aj4j ,no symptoms4 ,may #b #a1bcj #bjj #aj4j ,do4 ,may #c #a1bce #bjj #aj4j ,coughs and whines4 ,may #d #a1bde #bjj #aj4j ,passed worms4 ,may #e #a1bgj #bjj #ag4j ,eyes appear dim and is continually scratching them4 ,may #f #a1bfj #bjj #ag4j ,appears restless and draws up hind legs when walking4 ,may #g #a1bdj #bjj #ae4j ,eyes dim2 passed worms2 diarrhea4 ,may #h #a1bfe #bjj #ae4j ,coughing continually2 very restless4 ,may #i #a1bdj #bjj #ah4j #ab noon2 salivated in cage2 passed worms2 diarrhea2 foaming at mouth2 can not balance himself2 rigidity and tremor of hind legs4 #b4ae1 found dead4 ---------------------------------------- ----------------------- 7#a7 ,urine squeezed from bladder4 ,autopsy3 ,severe pulmonary congestion2 catarrhal gastritis2 mild enteritis with small hemorrhagic areas on mucosa4 ,,pup ,,no4 #d4 ---------------------------------------- -------------------------- ,treatment ,date4 ,weight4 ,food4 7#b per cent ,symptoms4 caffein74 ---------------------------------------- -------------------------- ,grams4 ,milk cc4 7cc74 ,apr4 #bh #a1fgj #cjj ,apr4 #bi #a1fgj #cjj ,apr4 #cj #a1fgj #cjj ,may #a #a1fij #cjj ,may #b #a1fij #cjj ,may #c #cjj ,may #d #a1gbj #cjj ,may #e #a1gce #cjj ,meat 7grams74 ,may #f #a1gfj #fj ,may #g #a1gde #hj ,may #h #a1gaj #ahj ,may #i #a1gej #ahj ,may #aj #a1gej #ahj ,may #aa #a1gee #ahj #aj4j ,no symptoms4 ,may #ab #a1gcj #ahj ,none4 ,may #ac #a1ghe #ahj ,none4 ,may #ad #a1hce #aae #aj4j ,do4 ,may #ae #a1hbj #aae #aj4j ,do4 ,may #af #a1hce #aae #aj4j ,passed worms4 ,may #ag #a1hfj #aae #aj4j ,feces soft and black4 ,may #ah #a1hee #aae #ae4j ,stiff2 loss of appetite4 ,may #ai #a1ggj #aae #ae4j ,loss of appetite4 ,may #bj #a1gee #aae #ae4j ,do4 ,may #ba #a1ghj #aae #ag4j ,restless4 ,may #bb #aae #ag4j ,feces soft and black4 ,may #bc #a1ghe #aae #ag4j ,loss of appetite4 ,may #bd #a1gie #aae ,loss of appetite2 threw up worms4 ,may #be #a1fcj #aae #bj4j ,loss of appetite2 worms2 cough2 diarrhea4 ,may #bf #a1fjj #aae #bc4j ,weak2 no appetite2 diarrhea2 cough4 ,may #bg ,found dead1 #i a4 m4 ---------------------------------------- -------------------------- ,autopsy4--,lung uniformly congested2 liver deeply congested2 heart muscle pale with hemorrhagic areas2 kidneys pale with hemorrhagic spots on surface and in cortex2 slight catarrhal inflammation of stomach and the small intestines4 ,,pup ,,no4 #e4 ---------------------------------------- -------------------------- ,treatment ,date4 ,weight4 ,food4 7#b per cent ,symptoms4 caffein74 ---------------------------------------- -------------------------- ,grams4 ,milk cc4 7cc74 ,apr4 #bh #a1gde #cjj ,apr4 #bi #a1gde #cjj ,apr4 #cj #a1gej #cjj ,may #a #a1gfe #cjj ,may #b #a1gfe #cjj ,may #c #cjj ,may #d #a1dij #cjj ,may #e #a1hje #cjj ,meat 7grams74 ,may #f #a1hae #fj ,may #g #a1hbe #hj ,may #h #a1ggj #ahj ,may #i #a1gie #ahj ,may #aj #a1hje #ahj ,may #aa #a1hjj #ahj #aj4j ,no symptoms4 ,may #ab #a1gbj #ahj ,none4 ,may #ac #a1hae #ahj ,none4 ,may #ad #a1hde #aae #aj4j ,do4 ,may #ae #a1hcj #aae #aj4j ,do4 ,may #af #a1hae #aae #aj4j ,loss of weight2 no other symptoms4 ,may #ag #a1hcj #aae #ae4j ,no symptoms4 ,may #ah #a1hce #aae #ae4j ,stiffness4 ,may #ai #a1hbe #aae #ae4j ,no symptoms4 ,may #bj #a1hej #aae #ae4j ,a little stiff4 ,may #ba #a1hce #aae #ag4j ,no symptoms4 ,may #bb #aae #ag4j ,may #bc #a1hbj #aae #ag4j ,do4 ,may #bd #a1hce #aae #bj4j ,do4 ,may #be #a1hdj #aae #bj4j ,feces soft and black4 ,may #bf #a1hbj #aae #bc4j ,may #bg #a1hdj #aae #be4j ,a little stiff4 ,may #bh #a1hcj #aae #be4j ,may #bi #aae ,none4 ,may #cj #aae ,none4 ,may #ca #a1ggj #aae ,none4 ,june #a #a1gfe #aae #be4j ,diarrhea2 stiff in hind legs4 ,june #b #a1gej #aae #bg4e ,diarrhea and worms4 ,june #c #a1fce #bg4e ,paralyzed2 vomited2 died at #c p4 m4 ---------------------------------------- -------------------------- ,,pup ,,no4 #f4 ---------------------------------------- -------------------------- ,treatment ,date4 ,weight4 ,food4 7#b per cent ,symptoms4 caffein74 ---------------------------------------- -------------------------- ,grams4 ,milk cc4 7cc74 ,apr4 #bh #cjj ,apr4 #bi #a1bhj #cjj ,apr4 #cj #a1bij #cjj ,may #a #a1cae #cjj ,may #b #a1ccj #cjj ,may #c #cjj ,may #d #a1cfj #cjj ,may #e #a1cfe #cjj ,meat 7grams74 ,may #f #a1cie #fj ,may #g #a1cfe #hj ,may #h #a1cdj #ahj ,may #i #a1chj #ahj ,may #aj #a1djj #ahj ,may #aa #a1dbe #ahj #ad4e ,no symptoms4 ,may #ab #a1dgj #ahj ,none4 ,may #ac #a1dhe #ahj ,none4 ,may #ad #a1eaj #aae #ad4e ,do4 ,may #ae #a1ejj #aae #ad4e ,do4 ,may #af #a1dhe #aae #ad4e ,passed worms4 ,may #ag #a1dhj #aae #ad4e ,may #ah #a1dhe #aae #ai4e ,feces soft and black2 almost diarrhea4 ,may #ai #a1die #aae #ai4e ,may #bj #a1ejj #aae #ai4e ,scratches her eyes and chases her tail4 ,may #ba #a1ejj #aae #ag4j ,may #bb #aae #ag4j ,may #bc #a1dgj #aae #ag4j ,may #bd #a1dfe #aae #bj4j ,may #be #a1dej #aae #bj4j ,feces soft and black4 ,may #bf #a1dej #aae #bc4j ,diarrhea and worms4 ,may #bg #a1cee #aae #bc4j ,refused to eat all food4 ,may #bh #a1bgj #aae #bc4j ,threw up worms1 stiff1 and has skin over both eyes4 ,may #bi ,found dead4 ---------------------------------------- -------------------------- ,highest amount of caffein given1 #cfb mg per kilo4 ,no autopsy4 ,examination of the results obtained in the experiments of series ,c shows that young and growing dogs tolerate large amounts of caffein4 ,in four subjects of this series1 ,nos4 #a1 #b1 #c1 and #f1 no effect was observed when moderately large amounts 7#afj to #bjj mg per kilo of caffein7 were fed4 ,symptoms were noticed only when these amounts of caffein were increased from #ej to #fj per cent4 ,the other two dogs1 ,nos4 #d and #e1 of this series were less resistant1 however1 to caffein1 as #j4af gram of the drug per kilo induced well-marked symptoms4 ,since these were fed meat1 while ,nos4 #a1 #b1 and #c received milk1 the difference in toxicity may be due to the diet employed1 but ,no4 #f1 which likewise received a meat diet1 failed to show the effects of caffein when #bjj mg per kilo were fed4 ,on the other hand1 it should be noticed that ,no4 #a died after receiving #cfj mg per kilo1 ,no4 #b survived a dose of #ccd mg1 while ,no4 #c died after a dose of #cbb mg per kilo of caffein4 ,the fatal doses for ,nos4 #d1 #e1 and #f were #bhg1 #cce1 and #cjj mg per kilo1 respectively4 ,although the differences are too small to justify any definite conclusion regarding the effect of a milk diet or of a meat diet on the toxicity of caffein1 the results nevertheless suggest a reasonable possibility that caffein is more toxic to young dogs when on an exclusively meat diet than when fed milk4 ,it is perfectly evident1 however1 that the resistance to caffein in either case is very great1 almost twice that of adult subjects4 ,as shown in series ,a and ,b1 #abe to #age mg per kilo proved fatal to all but two animals in these experiments1 while symptoms of toxicity appeared after much smaller doses4 ,in other respects the behavior of young dogs toward caffein was the same as that of the adult4 ,in neither case was cumulation nor tolerance observed under the conditions of these experiments4 ,the findings at autopsy were likewise similar1 as gastro-enteritis was the chief lesion observed on macroscopic examination4 ,it might be mentioned1 however1 in this connection1 that the symptoms of caffein intoxication in young dogs often presented marked differences from those observed in those of more advanced age4 ,the resemblance of the effects of caffein in young puppies and in rabbits was very striking4 ,in both1 the tonic with clonic convulsions were observed after a sufficient quantity of caffein was administered4 ,in the dogs which were fully grown a large dose of caffein was usually followed by tonic convulsions and almost instantaneous death4 ,moderately large amounts of caffein fed daily to puppies for several days--in some cases as long as #aj days--induced mild symptoms only4 ,no cumulative effect was observed in any of the experiments of series ,c4 ,there seems to be tolerance of certain functions toward caffein1 but no general tolerance of the body could be obtained in these experiments4 ,caffein is apparently less toxic for adult dogs on high than on low protein diet4 ,in young and growing dogs caffein is somewhat less toxic when milk1 rather than meat1 forms the exclusive diet4 ,some pathological conditions apparently increase the toxicity of caffein also in dogs4 ,the symptoms of caffein intoxication observed in young dogs are in some respects different from those in full grown and older animals1 and resemble those noticed in rabbits4 ,,discussion ,,of ,,results4 ,it was pointed out at some length in the introduction that the toxicity of some drugs may not be the same for all forms of life4 ,this observation was also made by some investigators who experimented with caffein on different species of animals4 ,thus ,maurel7#ee7 stated that caffein is twice as toxic for the frog as for the rabbit when administered by mouth4 ,frhner's7#bf7 experiments1 on the other hand1 made on domestic animals1 failed to show great differences in the toxicity of caffein4 ,according to this observer1 horses seem to be more susceptible than cattle1 goats1 and swine1 the minimum toxic dose being the same for all of these1 while the resistance of the dog to caffein is about midway between that of the horse and the other animals mentioned4 ,it may be remarked1 however1 that ,frhner made only #ac experiments4 ,that these data are inadequate for the formation of any conclusions as to the toxicity of caffein is evident since the most striking effect of caffein observed in the work herein reported was the comparatively wide range of variation in the resistance of individuals of the same species to this drug4 ,this was found to be the case even when the conditions of experimentation were approximately uniform1 and was observed whatever the mode of administration of the drug employed4 ,the toxicity for different individuals also varied in acute as well as in chronic intoxication4 ,it is for this reason that the number of tests employed were often quite large1 for no conclusions of any value could be drawn without averaging the results of a sufficiently large number of experiments4 ,furthermore1 it is to be borne in mind that the action of a drug may differ according to the mode of its introduction into the body and that different species of animals may vary in this regard4 ,this is especially true of some substances when given by mouth1 the range in toxicity for certain species of animals being much greater when thus administered than when injected subcutaneously or intravenously4 ,maurel's7#ef7 investigations are of interest in this connection1 as his work embraces a systematic study of the toxicity of a large number of substances in the rabbit1 pigeon1 and frog when given by mouth1 subcutaneously1 intravenously1 or when injected into the muscles4 ,according to this investigator the range of variation of the toxicity of a substance is widest when given by mouth4 ,potassium sulphocyanid1 for example1 is about #b4e times as toxic for the frog as for the rabbit when given by mouth4 ,quinin hydrobromid is three times as toxic for the frog as for the pigeon1 while for the rabbit it is twice as toxic as for the pigeon4 ,when given by hypodermic injection the toxic dose per kilo weight is practically the same for all three species4 ,the difference of resistance according to the mode of administration is even more marked for spartein sulphate4 ,when given by mouth the toxicity for the rabbit is six times as great as for the frog1 but when injected subcutaneously the toxic dose is about the same for the rabbit and for the frog4 ,the relation of the mode of administration to toxicity is further shown in the following substances3 ,for the rabbit the minimum fatal dose per kilo of quinin hydrobromid is #a4e grams administered by mouth1 #j4e gram when injected subcutaneously1 and #j4jg gram by the intravenous path1 while strychnin sulphate is twice as toxic administered intravenously as subcutaneously1 and six times as toxic as when administered by mouth4 ,the mode of introduction1 however1 does not always affect the toxicity of a substance4 ,this is made evident by the action of strychnin on frogs in which1 according to ,maurel7#ef71 the toxic dose is the same whether given by mouth or injected into the subcutaneous tissues4 ,this appears to hold true also for other animals as demonstrated by the experiments of ,hatcher7#ce7 on the cat1 in which he observed that strychnin is as readily absorbed from a full stomach as from the subcutaneous tissues4 ,these findings are extremely interesting1 especially in view of ,maurel's7#eg7 work on the subject1 according to which he finds that a substance is much less toxic when given by mouth than when administered by hypodermic injection or intravenously4 ,that this generalization does not admit1 however1 of universal application is made evident by the work of various experimenters4 ,claude ,bernard7#aj7 observed that curara is as poisonous for the pigeon when given by mouth as when injected subcutaneously1 while ,zalesky7#hf7 found that samandarin is more toxic for frogs when introduced into the stomach than by injection into the lymph sacs4 ,our experiments with caffein likewise show that ,maurel's generalization does not always hold good1 since it was found in experiments with gray rabbits that the minimum fatal dose is but moderately greater by mouth than by the subcutaneous path4 ,equally interesting is the observation of the writer1 that in the guinea pig the difference in the toxicity between the subcutaneous and intraperitoneal injections is very slight1 while in the cat the toxicity of caffein is the same whether given by mouth or injected into the subcutaneous tissues1 and is markedly less when injected into the peritoneal cavity4 ,the experiments on dogs show considerable variation of effective dose when given by mouth1 but the interesting observation was made that the toxic dose by mouth may be smaller in some cases than the average dose by subcutaneous injection4 ,if the resistance to caffein by subcutaneous injection of the different species of animals experimented upon in the present research be compared1 it will be noticed that the gray rabbit or ,belgian hare1 which is more resistant than the other varieties employed1 stands more caffein in proportion to the weight of the body than the other animals4 ,although the minimum fatal dose was found to be somewhat larger for the guinea pig than for the gray rabbit when caffein was injected intraperitoneally1 it was on the contrary smaller by other paths of introduction1 and approximated quite closely the minimum fatal dose for rabbits of the other varieties4 ,cats as well as dogs were found to be distinctly less resistant to caffein than the herbivora4 ,there are a number of factors far more important than zoological differences which influence the toxicity of caffein4 ,some of these are age1 season1 and pathologic conditions4 ,as these factors have already been dwelt upon in their appropriate places1 further discussion might seem unnecessary1 but owing to their importance in determining the action of a drug1 emphasis is desirable4 ,especially is this the case with pathological conditions in relation to toxicity4 ,while no positive proof of diminished resistance to caffein in pathological conditions was obtained by subjecting the suggestion to experimental test1 it was observed in these experiments on rabbits that death occurred in some individuals after small doses which are usually not even toxic4 ,the findings at autopsy indicate the presence of pathological conditions4 ,the same was observed in some experiments on cats and dogs4 ,it is extremely probable1 therefore1 that disease modifies the reaction of the organism to caffein as well as to other drugs47#gh7 ,that the resistance to drugs may vary according to the age of the subject has been maintained by a number of pharmacologists4 ,according to ,guinard17#cj7 young dogs1 rabbits1 and guinea pigs are very susceptible to morphin1 resembling children in this regard4,e ,the minimum fatal dose for these animals is about one-third less than for the adult4 ,this is not true1 however1 for the young of other species4 ,cats under #ae days of age tolerate twice the toxic dose of morphin for the adult cat4 ,young beeves and goats are likewise more resistant to this alkaloid than adults4 ,on the other hand1 according to ,livon17#ed7 young guinea pigs are more sensitive to alkaloids than adults4 ,the toxicity of caffein1 as shown in the present investigation1 was found to be less in the young than in the adult4 ,in dogs the young subjects are in some instances almost twice as resistant as adults4 ,the difference was found to be less in cats and rabbits than in dogs1 but it was quite marked4 ,e ,a case of accidental poisoning reported recently by ,wichura 7,mnich4 ,md4 ,woch41 #aiaa1 ,no4 #cj1 p4 #afah7 throws some doubt on the accepted view that the susceptibility of young children to morphin is greater than that of adults4 ,wichura also found that the therapeutic doses of codein preparations ordinarily recommended for children in pleuritic cough are not effective in this condition4 ,the effect of season on the toxicity of drugs has been discussed in the section on the experiments on guinea pigs1 which were more resistant to caffein in the fall than in ,february and ,march4 ,the effect of season seems to vary with the animal1 but it may also differ with the substance employed4 ,in ,noe's7#fe7 studies on this subject cantharidin was found to be more toxic for the hedgehog in ,november than in ,july4 ,the effect of season was different for morphin1 as it was observed that the resistance of the hedgehog was greater at the end of the summer than earlier in the season4 ,the relation of diet to toxicity of drugs has been studied by ,hunt47#ci7 ,his experiments indicate that this is an important factor in the resistance to acetonitril4 ,the studies here reported on the effect of diet on toxicity of caffein in rabbits were confined to experiments with oats and carrots and do not show any modification of the resistance to caffein4 ,the question of diet in chronic intoxication in dogs1 however1 suggests that in these animals diet may affect the toxicity of caffein1 although the data on this subject are far from satisfactory4 ,there is nevertheless sufficient evidence to suggest that a high protein diet for the adult dog tends to greater resistance of the animal to caffein and similarly the growing dog tolerates larger quantities of caffein on a milk diet than on a diet of meat4 ,this brings us to a consideration of the behavior of caffein in chronic intoxication4 ,although in both rabbits and dogs absence of cumulation was evident1 in other respects decided differences in the resistance to caffein were observed4 ,while the rabbit tolerates more than twice the single dose of caffein per kilo for the dog1 the result is quite different in repeated dosage of the drug1 the rabbit succumbing to continued administration of much smaller doses of the drug than the dog4 ,this is probably due to lesions of the gastro-intestinal canal caused by caffein which occasions loss of appetite much more readily in the rabbit than in the dog4 ,the abundant energy reserve in the dog makes it possible for this animal to stand inanition much longer than the rabbit and other herbivora4 ,the difference in the behavior of the rabbit and dog toward caffein is interesting as showing complete reversal of resistance in acute and chronic intoxication4 ,from the statement in the introduction it is evident that the size of the single toxic or lethal dose of a substance is in no wise an index of the active degree of its toxicity4 ,the experiments with caffein here reported furnish additional evidence that this is true1 at least for the rabbit4 ,,general ,,summary ,,and ,,conclusions4 ,the toxicity of caffein in the rabbit varies with the mode of its administration1 being least when given by mouth and greatest by intravenous administration4 ,the toxicity is from #ae to #bj per cent greater by subcutaneous injections than by mouth1 but is about half of that when injected into the peritoneal cavity4 ,no difference was observed in the toxicity of caffein whether administered into gluteal or into the lumbar muscles4 ,when introduced by this route the toxicity was found to be less by one-third than when it is injected into the peritoneal cavity1 but is about #cj per cent more toxic than the subcutaneous injections4 ,white or black rabbits were found to be less resistant to caffein than gray rabbits4 ,the resistance of the guinea pig to caffein1 as of the rabbit1 is greatest when given by mouth4 ,the minimum fatal dose is less by intraperitoneal injections1 but greater than by subcutaneous injections1 thus differing from the rabbit in this regard4 ,the adult cat is less resistant than the guinea pig or rabbit to caffein4 ,the minimum lethal dose by mouth is the same as by subcutaneous1 and is less than by intraperitoneal1 injection4 ,the minimum fatal dose for dogs was found to be the same by mouth as by subcutaneous injection and is almost the same as for the cat4 ,the toxicity of caffein varies in the guinea pig according to season of the year4 ,age is likewise a factor in the toxicity of caffein1 young animals being more resistant than the full-grown and older animals2 this was shown in experiments on rabbits1 cats1 and dogs4 ,the symptoms of caffein poisoning also were different in puppies and in full-grown dogs4 ,different diets1 such as carrots and oats1 did not influence the resistance of rabbits and guinea pigs to caffein4 ,low protein diet tends to decrease resistance to caffein in dogs4 ,young growing dogs are less resistant to caffein on a meat than on a milk diet4 ,caffein is not cumulative in the rabbit or dog1 even if administered for a considerable length of time4 ,some degree of tolerance may be induced in the rabbit under certain conditions1 but not in dogs under the conditions of the experiments made in this investigation4 ,the possibility1 however1 that dogs may acquire tolerance for caffein is not excluded4 ,although the rabbit tolerates a much larger single dose of caffein than the dog1 it was found1 in experiments on chronic intoxication that the rabbit is less resistant to caffein than the dog4 ,the toxicity of caffein is probably increased under pathological conditions1 since comparatively smaller doses were fatal to rabbits1 cats1 and dogs1 when marked lesions not due to caffein were found at autopsy4 ,glycosuria was observed in rabbits1 guinea pigs1 and cats when caffein was given in sufficient amounts4 ,,table #ah4--;,acute caffein intoxication3 ,table showing average minimum toxic and minimum fatal doses for adult animals4 ,table headings3 ,,sc3 ,subcutaneously4 ,,bm3 ,by mouth4 ,,ip3 ,intraperitoneally4 ,,im3 ,intramuscular4 ,,iv3 ,intravenous4 ---------------------------------------- ---------------------------- ,effect ,dose per kilo 7grams7 ,animal4 of ---------------------------------------- ----- dose4 ,,sc ,,bm ,,ip ,,im ,,iv ---------------------------------------- ------------------------ ,rabbit1 gray ,toxic #j4ae #j4cbe #j4ajj #j4ac #j4je -#j4abe -#j4ae ,fatal 4#cj 4#cej 4#aej 4#bj #j4aj -4#af ,rabbit1 white,toxic or black ,fatal 4#bj 4#bij ,guinea pig ,toxic#j4ae- 4#af 4#aej 4#bjj ,fatal 4#bj- 4#bdj4bhj- 4#cjj 4#bdj- 4#bej ,cat ,toxic 4#ab- 4#ad 4#abe 4#abe- 4#aej ,fatal 4#ae 4#aej 4#ahj- 4#bjj ,dog ,toxic 4#ajj- 4#abj ,fatal 4#ae- 4#af 4#adj- 4#aej ---------------------------------------- ------------------------ ,,note4--,the doses given in this table are approximate4 ,,caffein ,,bibliography4 #a4 ,,abderhalden and ,,brahm4 ,zts4 ,physiol4 ,chem41 #aiji1 #fb3 #acc4 #b4 ,,albers4 ,deut4 ,klin41 #aheb1 #e3 #egg4 #c4 ,,amat4 ,diss4 ,paris1 #ahhi4 #d4 ,,amory4 ,boston ,med4 ,surg4 ,j41 #ahfh1 #a3 #bfa4 #e4 ,,von ,,anrep4 ,arch4 ,ges4 ,phys41 #ahhj1 #ba3 #ahe4 #f4 ,,aubert4 ,pflger's ,arch41 #ahgb1 #e3 #ehi4 #g4 ,,auer and ,,meltzer4 ,j4 ,pharm4 ,exper4 ,ther41 #aiaa1 #b3 #djb4 #h4 ,,baldi4 ,terapia ,moderna1 #ahia1 #e3 #fag4 #i4 ,,bennett4 ,brit4 ,med4 ,j41 #ahgd1 #b3 #fgd4 #aj4 ,,bernard1 ,,claude4 ,leons sur les substances toxiques1 ,paris1 #aheg1 p4 #bib4 #aa4 ,,binz4 ,arch4 ,exper4 ,path4 ,pharm41 #ahgh1 #i3 #ca4 #ab4 ---- ,ibid41 #ahia1 #bh3 #aig4 #ac4 ,,brill4 ,diss4 ,marburg1 #ahfa4 #ad4 ,,buchheim and ,,eisenmenger4 ,beitr4 ,anat4 ,physiol41 #ahgj1 #e3 #aae4 #ae4 ,,bunge and ,,schmiedeberg4 ,arch4 ,exper4 ,path4 ,pharm41 #ahgf1 #f3 #bcc4 #af4 ,,chittenden4 ,the ,nutrition of ,man1 #aijg4 #ag4 ,,cogswell4 ,lancet 7,london71 #aheb1 #b3 #dhh4 #ah4 ,,danilewski4 ,arch4 ,exper4 ,path4 ,pharm41 #ahid1 #ce3 #aje4 #ai4 ,,drzewina4 ,compt4 rend4 ,soc4 biol41 #aiaa1 #gj3 #ggb4 #bj4 ,,dumas and ,,pelletier4 ,ann4 chim4 phys41 #ahbc1 #bd3 #ahb4 #ba4 ,,edmunds4 ,j4 ,amer4 ,med4 ,assoc41 #aijg1 #dh3 #agdd4 #bb4 ,,filehne4 ,arch4 ,phys41 #ahhf1 p4 #gb4 #bc4 ,,fleischer and ,,loeb4 ,archives of ,internal ,medicine1 #aiji1 #c3 #gh4 #bd4 ,,focke4 ,arch4 ,pharm41 #aijc1 #bda3 #fgh4 #be4 ,,frerichs4 ,handwrterbuch ,phys41 #ahdf1 #c3 #gba4 #bf4 ,,fr,,hner4 ,monats4 prakt4 ,tierh41 #ahib1 #c3 #ebi4 #bg4 ,,gentilhomme4 ,bull4 ,soc4 ,med4 ,reims1 #ahfg1 #e3 #ic4 #bh4 ,,gourewitch4 ,arch4 ,exper4 ,path4 ,pharm41 #aijg1 #eg3 #cad4 #bi4 ,,guinard4 ,compt4 rend4 ,soc4 biol41 #aijj1 #b 7#b;d ser473 #gbg4 #cj4 ----4 ,compt4 rend41 #ahic1 #aac3 #ebj4 #ca4 ----4 ,la ,morphine et l'apomorphine1 ,paris1 #aijc4 #cb4 ,,gunn4 ,arch4 ,int4 ,pharm4 ,ther41 #aiji1 #ai3 #cai4 #cc4 ,,hale4 ,u4 ,s4 ,public ,health and ,marine-,hospital ,service4 ,hyg4 ,lab4 ,bul4 #ec1 p4 #dc4 #cd4 ,,harrington4 ,amer4 ,j4 ,phys41 #ahih1 #a3 #che4 #ce4 ,,hatcher4 ,j4 ,amer4 ,med4 ,assoc41 #aiaj1 #fj3 #gdf4 #cf4 ,,henneguy4 ,diss4 ,montpellier1 #ahge4 #cg4 ,,hofmeister4 ,arch4 ,exper4 ,path4 ,pharm41 #ahid1 #cc3 #aih4 #ch4 ,,hoppe4 cho ,md4 ,neuchtel1 #aheh4 #ci4 ,,hunt4 ,u4 ,s4 ,public ,health and ,marine-,hospital ,service4 ,hyg4 ,lab4 ,bul4 #fi1 p4 #ea4 #dj4 ----4 ,ibid41 ,bul4 #cc4 #da4 ,,igersheimer and ,,stami4 ,arch4 ,exper4 ,path4 ,pharm41 #aiji1 #fa3 #ah4 #db4 ,,jacobi and ,,golowinski4 ,arch4 ,exper4 ,path4 ,pharm41 ,supplement ,bd4 #aijh1 p4 #bhf4 #dc4 ,,jobst4 ,ann4 ,pharm41 #ahch1 #be3 #fc4 #dd4 ,,johansen4 ,diss4 ,dorpat1 #ahfi4 #de4 ,,kobert4 ,lehrbuch der ,intoxicationen1 #aijb1 #a3 #bd4 #df4 ,k,,ster4 ,arch4 ,gesamt4 ,phys41 #aiaj1 #acf3 #ag4 #dg4 ,,kr,,ger and ,,schmidt4 ,ber4 d4 chem4 ,ges41 #ahii1 #cb3 #bfgg4 #dh4 ,,kurzak4 ,zts4 ,aerzte zu ,wien1 #ahfj1 n4 f41 #c3 #fbe4 #di4 ,,lapicque4 ,compt4 rend4 ,soc4 biol41 #aiaj1 #fh3 #ajjg4 #ej4 ,,leblond4 ,diss4 ,paris1 #ahhc4 #ea4 ,,lehmann1 ,c4 ,g4 ,lehrbuch fr physiolische ,chemie1 #ahdb1 #a3 #ccf4 #eb4 ,,lehmann1 ,j4 ,ann4 chim4 pharm41 #ahec1 #hg3 #bje4 #ec4 ,,leven4 ,arch4 ,phys41 #ahfh1 #a3 #ahj4 #ed4 ,,livon4 ,compt4 rend4 ,soc4 biol41 #ahig1 #d3 #igi4 #ee4 ,,maurel4 ,compt4 rend4 ,soc4 biol41 #aijg1 #fb3 #hig4 #ef4 -----4 ,ibid41 #aiji1 #ff3 #ghb4 #eg4 -----4 ,ibid41 #aiaj1 #fi3 #e4 #eh4 ,,meltzer and ,,auer4 ,j4 ,exper4 ,med41 #aije1 #g3 #ei4 #ei4 ,,mitchell4 ,j4 ,phys41 #ahfb1 #e3 #aji4 #fj4 ,,mitscherlich4 ,diss4 ,berlin1 #ahei4 #fa4 ,,moschkowitsch4 ,arch4 ,pharm41 #aijc1 #bda3 #ceh4 #fb4 ,,mulder4 ,j4 prakt4 ,chem41 #ahch1 #ae3 #bhj4 #fc4 ----4 ,poggendorff's ,ann4 ,physik ,chem41 #ahch1 #dc3 #ahj4 #fd4 ,,neubauer4 ,arch4 ,exper4 ,path4 ,pharm41 #aija1 #df3 #acc4 #fe4 ,,noe4 ,arch4 ,int4 ,pharm4 ,ther41 #aijd1 #ab3 #afj4 #ff4 ,,oph,,ls4 ,proc4 ,soc4 exper4 biol4 med41 #aiaa1 #h3 #ge4 #fg4 ,,oudry4 ,nouvelle ,bibliothek ,mdicale1 #ahbg2 ,geiger's ,magazin ,pharm41 #ahbg1 #ai3 #di4 #fh4 ,,parisot4 ,diss4 ,paris1 #ahij4 #fi4 ,,pelletier4 ,j4 ,pharm41 #ahbf1 #ab3 #bbi2 also quoted by ,brill1 #c4 #gj4 ,,peretti4 ,diss4 ,bonn1 #ahge4 #ga4 ,,pfaff4 ,schweigger-,seidel1 #ahca1 #a3 #hg4 #gb4 ,,pfaff and ,,liebig4 ,ann4 ,pharm41 #ahcb1 #a3 #ag4 #gc4 ,,pohl4 ,arch4 ,exper4 ,path4 ,pharm41 ,suppl4 ,bd41 #aijh1 p4 #dbg4 #gd4 ,,pratt4 ,boston ,med4 ,surg4 ,j41 #ahfh1 #b3 #hb4 #ge4 ,,robiquet4 ,dict4 ,tech41 ,paris1 #ahbc1 #d3 #ei4 #gf4 ,,rost4 ,diss4 ,heidelberg1 #ahie4 #gg4 ,,runge4 ,neuste phyto-chem4 ,entdeckungen1 ,breslau1 #ahbj4 #gh4 ,,salant4 ,u4 ,s4 ,dept4 ,agr41 ,bureau of ,chemistry ,cir4 #ha4 #gi4 ,,schmiedeberg and ,,bunge4 ,arch4 ,exper4 ,path4 ,pharm41 #ahgd1 #b3 #fb4 #hj4 -----4 ,ibid41 #aiaj1 #fb3 #bif4 #ha4 ,,sollman and ,,brown4 ,j4 ,amer4 ,med4 ,assoc41 #aije1 #de3 #bbi4 #hb4 ,,strecker4 ,ann4 ,chem4 ,pharm41 #ahfa1 #aah3 #aea #hc4 ,,stuhlmann and ,,falck4 ,arch4 path4 ,anat4 ,phys41 #aheg1 #aa3 #cbd4 #hd4 ,,thierfelder and ,,von ,,mering4 ,zts4 physiol4 ,chem41 #ahhe1 #i3 #eaa4 #he4 ,,voit4 ,untersuch4 ber den ,einfluss des ,kochsalzes1 des ,kaffes ,mnchen1 #ahfj4 #hf4 ,,zalesky4 ,hoppe-,seyler ,med4 ,chem4 ,untersuch41 ,berlin1 #ahff1 #he-aaf4 99 99 99 99 99 ,transcriber's ,notes ,obvious typographical errors have been corrected1 but variations in spelling1 punctuation and hyphenation have been retained4 ,rabbit #cif4 ,the date ,august #ae has been corrected to ,august #ai4 ,the data for ,rabbit #abc is presented as printed in the original1 although it is likely that the ,caffein per kilo4 values should be preceded by a decimal point 7or that the heading should be ,mg474 ,standard footnotes are identied alphabetically thus ,a4 ,notes to the tables are placed directly under the tables and identified numerically thus 7#a74 ,numeric references within the text refer to the bibliography4 ,the headings of ,table #ah have been abbreviated for clarity on small screens4 ,italics are shown thus italic and bold thus bold4