458  Cardiac  Stimulants  and  Depressants.  {AoctoS;  1910™' 
though  the  uncertainty  arising  from  these  factors  may  be  avoided 
by  great  care,  there  will  be  a  difference  in  different  lots  of  frogs, 
and  it  is  recommended  by  those  who  used  the  frog  method,  that 
a  standard  preparation  of  each  drug  be  kept  on  hand  and  that  each 
fresh  batch  of  frogs  be  studied  as  to  their  relation  to  the  standard 
before  they  are  used  for  the  purpose  of  testing  new  preparations. 
This  makes  the  standard  dependent  on  the  keeping  properties  of 
a  stock  galenical,  and  these  are  exceedingly  uncertain  in  many 
drugs.  Any  deterioration  will  result  in  a  lowering  of  the  standard 
for  all  subsequent  preparations.  For  these  reasons  it  seems  wiser 
to  use  some  animal  which  shows  no  such  variation,  is  always  of  the 
same  species,  can  be  easily  obtained,  and  is  large  enough  to  allow 
accurate  and  easy  calculation  and  measurement  of  doses.  The 
guinea  pig  fulfils  all  of  these  requirements,  and  has  therefore 
been  selected  by  us  for  use  in  our  experiments.  Moreover,  as 
the  guinea  pig  is  very  resistant  to  the  action  of  alcohol,  it  is 
not  necessary  to  evaporate  alcoholic  preparations  to  dryness  before 
injecting  them.  The  necessity  for  such  evaporation  when  using 
frogs  is  of  course  well  known. 
It  is  a  noteworthy  fact,  to  which  attention  has  often  been 
directed,  that  the  smaller  animals  require  doses  much  larger  in 
proportion  to  their  weight.  For  instance,  0.75  c.c.  tincture 
digitalis  which  can  be  given  safely  to  a  250  gramme  guinea  pig, 
would  correspond  to  7.2  oz.  to  a  150  pound  man,  which  would  be 
far  above  a  fatal  dose.  It  has  therefore  been  proposed  that  the 
dose  should  be  based  on  the  relative  surfaces  of  the  animals  instead 
of  on  their  weight.  This  would  be  the  2/z  power  of  the  weight,  the 
square  of  the  cube  root.  This  would  give  a  dose  of  little  more 
than  1  oz.  to  a  150  pound  man,  which  is  about  the  largest  dose 
which  can  be  given  safely.  A  series  of  experiments  on  guinea 
pigs  of  different  weight  have  shown  that  this  argument  does  not 
apply  to  them.  Comparing  pigs  of  about  225  grammes  weight  with 
others  of  500  grammes,  we  find  that  upwards  of  twice  as  much 
is  required  to  kill  the  larger  animals.  This  shows  that  for  animals 
of  the  same  species  the  dose  should  be  in  proportion  to  the  weight 
and  not  in  proportion  to  the  surface  area. 
In  doing  the  routine  work  of  standardization,  the  guinea  pigs 
are  first  weighed,  and  then  to  one  pig  is  given  hypodermically 
the  standard  minimal  lethal  dose,  to  a  second  9/10  of  this,  and  to 
a  third  11/10-     If  the  drug  is  of  proper  strength,  the  two  pigs 
