HISTORICAL REVIEW. 15 



a dose. The toxic dose in man varies from 0.5 to 1.5 grams. Dis- 

 turbance of the circulation, such as palpitation of the heart and full- 

 ness of pulse, restlessness, and diarrhea were the symptoms he 

 observed. 



Extensive investigations on the action of caffein were carried out 

 by Leblond 50 (1883), who studied its effect on the circulation in man 

 and lower animals, and its toxicity in the lower animals alone. Five 

 to twenty centigrams of caffein and 0.06 to 0.25 gram of salicylate of 

 soda were dissolved and injected into the muscles of the thigh of 

 young guinea pigs weighing a little over 300 grams. In the three 

 experiments reported the death of the animals occurred after 23 min- 

 utes, 40 minutes, and 1 hour and 20 minutes. Symptoms appeared 

 in from 10 to 15 minutes after the injection of caffein. Incoordination 

 of movements, convulsions, both tonic and clonic, opisthotonos, 

 tremors, increased frequency of respiration, ataxia, paralysis were 

 the symptoms observed. It is worthy of note that the appearance 

 of paresis preceded the convulsions. Diminished sensation was 

 reported in one pig, but no sensory disturbances nor reflexes had been 

 observed in the other. Two rabbits, one of which received 0.5 and 

 the other about 0.3 gram of caffein per kilo with equal parts of sali- 

 cylate of soda, were injected subcutaneously into the thigh. Dimin- 

 ished sensation, paresis of the posterior extremities, hyperexcita- 

 bility, convulsions, opisthotonos, dilation of the veins of the ear were 

 observed. Death followed in 1 hour and 23 minutes in one rabbit 

 and in 3 hours and 7 minutes in the other. 



Filehne 22 (1886) experimented with caffein on Rana esculenta and 

 Rana temporaria. The subcutaneous injection of 7 mg of caffein into 

 Rana esculenta caused tetanus, while 50 mg given by mouth caused 

 tonic spasms. He further stated that the difference between Rana 

 esculenta and Rana temporaria as regards the reaction to caffein was 

 one of degree only. 



Amat 3 (1889) reported experiments on three guinea pigs, in which 

 0.4 to 0.5 gram per kilo injected subcutaneously proved fatal within 

 38 and 44 minutes. One guinea pig which received 0.1 gram of 

 caffein per kilo survived. The symptoms observed in the two fatal 

 cases were general muscular rigidity and convulsions. 



Parisot M (1890) made a study of the toxicity of caffein on different 

 species of animals. Unlike most of his predecessors, however, he 

 reported, at least in some cases, the weight of the animals on which he 

 worked. After the subcutaneous and intramuscular injections of 

 from 5 to 20 mg of caffein into Rana temporaria weighing from 14 to 16 

 grams, he noticed increased irritability at first; later, a loss of reflexes, 

 inability to use the muscles, complete muscular rigidity resembling 

 rigor mortis, and also cessation of heart action. The effect of caffein 

 produced in the green frog was analogous to that observed in 



