50 THE TOXICITY OF CAFFEIN. 



June 10: 9.30 a. m., reflexes much less than day before, increase slight, a few cubic 

 centimeters of urine passed since injection of caffein, looked brown and dirty, could 

 not be tested for reducing substances. 



June 13: Guinea pig alive, appetite good, condition good. 



June 14: 9 a. m., found dead. 

 Guinea pig 128. White and Hack male. Weight, 1,075 grams. Diet, hay and oats. 



June 7: 10 a. m., 13 cc 2 per cent caffein by mouth through stomach tube; 11.10 

 a. m., no symptoms, no urine passed; 1 p. m., increased reflexes, about 15 cc (esti- 

 mated) urine passed; 4 p. m., reflexes increased, still more urine passed (about 20 cc); 

 4.50 p. m., tetanus, frequent attacks, then paralysis and death at 4.58 p. m. Autopsy: 

 Lungs congested ; blood vessels of heart injected; intestines slightly congested ; fatty 

 liver. 

 Guinea pig 126. White and gray male. Weight, 980 grams. Diet, oats and hay. 



June 7: 9.40 a. m., 9.8 cc 2 per cent caffein given by mouth through stomach tube; 

 10 a. m., no symptoms; 11.10 a. m., no urine passed, reflexes increased; 1p.m., more 

 sensitive than before; 4 p. m., increase of reflexes more marked, no urine passed; 4.45 

 p. m., about 15 cc urine collected; 5 p. m., no change. 



June 8: 9 a. m., reflexes about the same as 5 p. m. previous day, no urine passed 

 since 4.45 p. m. previous day, considerable reduction of Fehling's solution, much more 

 than urine of guinea pig No. 127; 11.05 a. m., convulsions; 12 noon, still alive and 

 stretched out on abdomen; died at 1 p. m. Autopsy: Lungs badly congested; heart 

 and blood vessels injected; blood vessels of kidney and of small intestines injected; 

 liver engorged with blood; a few necrotic spots in stomach. 

 Guinea pig 127. White, black, and brown male. JPeight, 760 grams. Diet, oats and hay. 



June7: 9.50a.m., 7. 6 cc 2 per cent caffein by mouth through stomach tube; 10a.m., 

 no symptoms; 11.10 a. m., reflexes increased, no urine passed; 1 p. m., very sensitive; 

 4 p. m., sensitiveness increased, about 20 cc urine passed; 5 p. m., no change. 



June 8: 9 a. m., reflexes about the same as 5 p. m. previous day; 9.30 a. m., guinea 

 pig passed 30 cc urine since he received caffein, urine showed a moderate amount of 

 reduction; 12 noon, convulsions; died at 2.30 p. m. Autopsy: Lungs congested; 

 blood vessels of heart and of intestines injected; numerous necrotic spots in stomach; 

 other organs apparently normal. 



Examination of the protocols shows that the absorption of caffein from the gastro- 

 intestinal canal was quite rapid, symptoms having been observed as early as 20 min- 

 utes after its introduction. The duration of life, it will be remarked, varied with the 

 size of the dose. When approximately 3 decigrams per kilo were fed, all the animals 

 died in the night. They lived, therefore, less than 18 hours. Two decigrams per kilo 

 were likewise fatal, but the duration of life was longer. To decide whether or not this 

 is the smallest fatal dose, smaller amounts were fed. It seemed at first that about 150 

 mg per kilo was the smallest toxic dose, and about 200 mg per kilo the minimum fatal 

 dose. Macroscopic examination of the organs, however, threw some doubt on this 

 supposition, for well-marked lesions were noticed in all of the guinea pigs which 

 received 0.2 gram per kilo. It is quite possible, therefore, that the minimum fatal 

 dose may be somewhat higher, as we have reason to believe that, at least in some patho- 

 logic conditions, the susceptibility to caffein is increased. The presence of fatty 

 changes in the liver of No. 128 and the rapid death in this case lends especial support 

 to this view. Hence, the minimum fatal dose is probably greater than 0.2 gram per 

 kilo for the normal guinea pig. The doses employed for the tests on guinea pigs Nos. 

 129, 130, and 131 may be considered therefore the minimum fatal dose for these animals. 

 It will be also remarked that macroscopical examination of the organs of these animals 

 failed to reveal the presence of severe lesions. That the minimum toxic dose is prob- 

 ably much smaller than 0.28 gram per kilo is indicated by the experiments on guinea 

 pigs Nos. 135 and 134, in which 0.15 gram caffein per kilo induced mild symptoms 

 in from two to three hours. Both of these, however, and also No. 137 died four to six 

 days after the drug was fed. As already pointed out, caffein may be a factor in the 

 delayed death of guinea pigs which received moderate doses of it. That this suppo- 

 sition may also be true for guinea pigs Nos. 134, 135, and 137 is indeed made probable 

 by the observation that after moderate amounts of caffein symptoms may persist in 

 the guinea pig for about 24 hours, and also by the fact that the secretion of urine in 



