320 



Prof. G. Dreyer and Dr. E. W. A. Walker. 



the alimentary canal. This, in his opinion, offered a valid explanation of the 

 fact that it is often difficult or impossible to administer effective doses of 

 these drugs to large animals, since these animals do not tolerate the doses 

 which would be required to produce the same concentration in their blood 

 as is needed for successful therapeutic action in small animals. 



The observations on agglutinins had already led us to the conclusion that 

 the concentration of inoculated drugs and other foreign substances dis- 

 tributed in the blood plasma would necessarily be proportional to the 

 surface of the animal, since it was shown that the blood volume was always 

 proportional to the body surface. And this fact would equally apply within 

 any given species to an internal surface such as that of the alimentary canal. 



The blood volume formula had, however, immediately and seriously been 

 called in question (5, 6). Accordingly, it was necessary to turn aside from 

 the problems in hand until the criticisms offered had been carefully 

 examined, and the relationship of blood volume to the surface area had been 

 adequately confirmed. This, so far as we are able to judge, has now been 

 done (7). 



Accordingly, we now proceed on the assumption that the blood volume of 

 warm-blooded animals is a function of their body surface, and is given by the 

 formula B = W n /Jc, where n is approximately 072, and k is a constant to 

 be ascertained for each particular species of animal. 



Using this assumption, we find that the minimal lethal dose of a long- 

 series of substances of widely different origin and composition can satis- 

 factorily be expressed as a function of the body surface. The series of 

 substances which have been found to follow this law includes not only 

 organic bodies both of animal and vegetable origin, but also a number of 

 inorganic compounds. 



It follows that we are entirely in accord with the main conclusion reached 

 by Moore in his very suggestive discussion of the subject, namely, that 

 dosage must be proportional to body surface (in warm-blooded animals). 

 But, in view of the results which follow from the application of the blood 

 volume formula, we are unfortunately not in a position to agree with the 

 line of argument by which he deduces this conclusion from a consideration 

 of the area of the alimentary tract. Moreover, we are quite unable to admit 

 as satisfactory the explanation which he offers of the fact that drugs which 

 are successful in the treatment of various species of small animals are not 

 successful in the case of species of large size in any dose which can be used 

 with safety. For reasons which will be given below, the explanation of 

 these facts appears to us to be dependent on a specific tolerance or 

 intolerance, as the case may be, in different species of animal, and not upon 



