10 
These figures certainly show a closer relationship than has beer 
obtained by the previous workers. 
Since we have then no satisfactory chemical method of estimating 
the activity of digitalis preparations, attention has been directed 
toward the development of assay by physiological methods. Several 
have been employed in the past ten years and the results obtained by 
their aid have served to emphasize the necessity of some way of 
standardizing these drugs. In both this country and in Europe many 
writers have demonstrated by these physiological tests the great varia- 
bility of strength which exists not only in the galenical preparations 
of the drug but also in the so-called pure preparations themselves. 
Among these investigators may be mentioned Bennefeld, who in 
1881 showed that for rabbits the lethal doses of eight digitalis tine- 
tures varied about fourfold. 
Biihrer (1900) demonstrated on frogs that some of the fluid ex- 
tracts of digitalis were four times as strong as others. 
In 1902 Frankel showed that six infusions of digitalis varied from 
100 to 275 per cent, and six tinctures from 100 to 400 per cent. 
Siebert (1903) found in fifty experiments on digitalis leaves that 
the fatal doses per 100 gram frogs varied from 0.03 to 0.075 gram. 
Edmunds in 1907 showed that seventeen tinctures of digitalis pur- 
chased in the open market varied in strength as 1 to 4, while Gottlieb 
(1908) found the same ratio to exist in Heidelberg. Reed and Yan- 
derkleed (1908) found the toxic dose for guinea pigs of 240 grams 
weight varied in four tinctures from 0.6 to 1.25 c. c. 
These variations in strength depend upon several factors, among 
which may be mentioned the source of the plant ; for example, Ott a 
has pointed out that Bohemian leaves are more toxic than others. 
At the present time the English leaves are considered the best. The 
plants growing wild are preferred to the cultivated variety, and those 
growing in sunny places to those in the shade, and those grown in 
dry seasons to those gathered in rainy. However, the most important 
factor in determining the activity of the leaves is the manner of drying 
and the mode of preservation, the influence of which has been espe- 
cially studied by Focke (p. 24). 
The experiments of Bennefeld and others to determine the relative 
activities of different members of the group were carried out along 
essentially the same lines and embody the same principles as are em- 
ployed to-day in the biological standardization of these drugs. It was 
but a step from one to the other; the first writers determined the 
relative activity, while the later writers merely corrected these varia- 
tions by such means as concentration or dilution of the preparations. 
To get then any comprehensive idea of the development of modern 
physiological standardization it is necessary to go further back than 
a Ott, Yerhandl. d. Cong. f. innere Med., Wiesb., 1901, 89. 
