11 
the first paper strictly devoted to the standardization problem and 
examine the earlier methods in vogue. We have therefore given short 
abstracts from earlier writings of such articles as bear upon the sub- 
jects before considering it in the light of more recent works, not only 
digitalis being discussed, but some other drugs belonging to the same 
group, such as strophanthus, as the same methods apply to all the 
I members of the series. 
In 1865 Fagge and Stevenson, in an address before the Royal 
Society, claimed that physiological tests would be of great medico- 
legal importance. 0 They had studied digitalin especially and said for 
this purpose frogs were better adapted than the higher animals, as the 
various organs could be examined, the animals exhibited no fear, and 
the drugs acted quickly upon them. 
In their paper published in 1866 they made a report upon the 
relative activity of several members of the digitalis group, among 
them being “antiar,” helleborus viridis, squills, digitalin, and the in- 
fusion of digitalis. The method employed was to weigh the frog, 
attach it to a piece of cork, and expose the heart, avoiding hemor- 
rhage as far as possible. It was then injected beneath the skin of the 
thighs and flanks and the time noted at which systolic standstill of 
the ventricle occurred. The length of time between the injection of 
the drug and the stoppage of the heart determined the relative tox- 
icity of the different drugs. Fagge and Stevenson considered that the 
season of the year did not alter the reaction of the frogs to the drugs. 
Ten years later Koppe 5 published the results of his investigations 
upon the relative toxicity of the active constituents of digitalis, digi- 
toxin, digitalin, and digitalein. His experiments were carried out 
upon frogs, cats, dogs, and rabbits. In his work on frogs he employed 
both Rana temporaria and R. esculenta and showed how much more 
susceptible the former were than the latter. His method was to ex- 
pose the heart in the usual manner and inject the drugs, noting the 
time when systolic standstill of the heart appeared. 
The dogs were either injected subcutaneously or the drug was ad- 
ministered by the mouth, changes in the rate of the heart and the 
strength of the beat being noticed, as well as the time when nausea 
and vomiting occurred. To cats the drug was administered both sub- 
cutaneously and by the mouth and the amount necessary to produce 
vomiting noted. Large doses produced alterations in the pulse rate. 
The drugs were given subcutaneously to rabbits and produced in them 
as the most prominent symptom a more or less complete paralysis 
associated with irregularity and slowing of the heart rate. 
°C. Hilton Fagge and Thomas Stevenson, Application of physiological tests for 
certain organic poisons, and especially digitaline. Reprinted from Guy’s Hosp. 
Reports, 1866. 
& Koppe, Arch. f. exper. Path. u. Pharmakol., Leipz., 1875, III, 274. 
