8 
These experiments indicate, therefore, that caffeine increases the 
danger of acetanilide mixtures, as do also the opium alkaloids. On 
the other hand, in these experiments upon the lower animals sodium 
bicarbonate appears to be a fairly good antagonist and would pos- 
sibly be of use in acetanilide poisoning in man. 
In Part II it is shown that caffeine is not materially antagonistic 
to the circulatory depression following antipyrine, but that it pre- 
vents the slowing in the heart rate. In the experiments upon the 
intact animal the mixtures of the above drugs were invariably more 
poisonous than antipyrine alone. In contrast, and as in the acet- 
anilide experiments, sodium bicarbonate was somewhat antagonistic 
to the heart effect of antipyrine, hut when given to the intact animal 
it did not seem to lessen the toxicity of the antipyrine in any degree. 
HISTORICAL. 
The year 1884 has become notable in the history of therapeutics 
on account of the introduction of antipyrine, the first of a large series 
of drugs as agents for the reduction of excessive temperature. This 
was followed very shortly (in 1886) by the second member of the 
antipyretic group, acetanihde, and in quick succession a large number 
of similar bodies appeared, all of which possessed in a general way 
the same action. The powerful influence of these drugs upon high 
temperature made them all extremely popular, and especially so 
since up to this time the other drugs used in the relief of fever were 
not only uncertain in their action but were very much less powerful. 
Although having been preceded by antipyrine by two years, acet- 
anihde quickly outranked it in popularity, and it has never been 
supplanted to any great extent by any of the large number of anti- 
pyretics appearing later. Many cases of poisoning appeared almost 
from the first, due not only to the enormous doses that were pre- 
scribed, but also to the inherent poisonous properties of these drugs. 
This, however, did not seem to detract from its popularity, which 
seems to have been based partly upon the idea that it was less 
poisonous than antipyrine,® and certainly less poisonous than other 
drugs of the series excepting acetphenetidin and partly upon the fact 
that it was somewhat more efficient, ^ at least in the doses used, and 
thought to be necessary. The chief reason for its greater popularity, 
however, seems to have been neither its comparative smaller degree 
of toxicity nor its greater efficiency, but its comparative cheapness.'' 
The immediate popularity of this group of compounds arose from 
their decided antipyretic action, but it was quickly observed that 
they were also very efficacious in relieving various more or less 
“Barr, Pharm. Jour, and Tr., Bond., 1887, XVIII, 170. 
& Faust, Deutsch. med. Wchnschr., 1887, XIII, 575. 
c Hinzelmann, Munch, med. Wchnschr., 1887, XXXIV, 36. 
