102  Biological  Standardization  of  Drugs.    { ^^ilSl";  i?i  l 
than  in  his  earher  experiments.  In  inexperienced  hands  the 
variation  would  probably  be  even  greater. 
These  methods  all  depend  on  the  estimation  of  the  least  fatal 
dose,  but  for  reasons  to  be  given  such  an  end  reaction  appears 
tO'  me  to  be  undesirable.  Digitalis  glucosides  act  not  only  on 
the  heart  but  also  directly  on  the  central  nervous  system  first 
stimulating  and  then  depressing  it.  In  these  general  toxic  methods 
the  drug  is  given  in  sufficient  doses  to  cause  death  without  refer- 
ence to  the  organs  chiefly  affected  and  no  one  can  say,  although 
much  theorizing  has  been  indulged  in,  whether  the  death  is  the 
result  of  an  action  on  the  heart  or  on  the  brain  or,  and  I  think  it 
extremely  likely,  a  resultant  of  the  action  on  both  brain  and  heart. 
The  method  is  usually  carried  out  using  mammals  and  while 
this  is  believed  by  some  to  be  a  step  in  the  right  direction  on 
account  of  the  closer  relation  between  the  higher  animals  when 
compared  to  cold-blooded  animals  (frogs)  and  man  certain  experi- 
mental evidence  tends  to  show  that  this  is  not  necessarily  so. 
At  least  it  is  to  be  noted  that  death  in  such  animals  in  certain 
cases  apparently  resulted  fromi  a  paralysing  action  on  the  central 
nervous  system  while  the  heart  as  recorded  by  blood  pressure 
tracings  was  still  in  good  condition.  In  other  cases  the  respiratory 
movements  were  kept  up  some  time  after  the  heart  had  stopped 
beating  and  the  blood  pressure  had  fallen  to  zero.  Further  the 
allegation  that  these  effects  on  the  central  nervous  system  are  all 
secondary  to  the  heart  action  is  contrary  to^  the  known  facts  of 
Physiology. 
In  this  connection  it  is  further  urged  that  a  digitalis  preparation 
with  a  high  percentage  of  the  saponin  like  body,  digitonin,  would 
easily  cause  death  from  the  action  of  this  poison  which  depresses 
both  the  heart  and  the  central  nervous  system.  Thus  such  a 
preparation  would  probably  show  a  high  value  by  a  general  toxic 
method  although  the  heart  tonic  principles  mig'ht  be  present  in 
relatively  small  amounts,  or  of  two  preparations  with  the  same 
proportion  of  substances  acting  on  the  heart  that  with  the  larger 
amount  of  the  saponin  like  body  would  assay  stronger.  In  the 
general  toxic  method  in  which  frogs  are  used,  as  in  Houghton's 
twelve  hour  method,"  this  objection  would  naturally  lose  some 
weight  on  account  of  the  ability  of  such  animals  to  live  a  con- 
siderable time  independently  of  the  central  nervous  system,  the 
action  of  the  drug  being  therefore  presumably  upon  the  heart. 
