86 JOHN T. HALSEY 



Plummer (personal communication quoted by Kendall, 1918) has shown 

 that in man*the maximum effects of a single intravenous dose of thyroxin 

 are reached only after ten days, and that the effects persist for eight or 

 ten days longer. 



Pliarmacodynamic Actions. Oral and intravenous administration of 

 thyroid extracts (Fawcett, Kogers, Kahe, and Beebe) or of thyroxin 

 (Kendall (a), 1914) are followed by no immediate pharmacodynamic ef- 

 fects on the blood pressure or heart rate. It is only 24 to 36 hours later 

 that the heart rate rises decidedly, this effect being accompanied by rest- 

 lessness and a slight temperature elevation. The effects ordinarily ob- 

 tained after a time from administration to normal animals of sufficient 

 amounts of thyroid substance are a striking increase in the rate of metab- 

 olism, accompanied by a rise in temperature, diarrhea, loss of weight, 

 tachycardia and nervousness. In man, thyroid feeding produces similar 

 effects so that a symptom complex may develop which in many par- 

 ticulars resembles that of Graves' disease, while in individuals already 

 suffering from this disease thyroid administration almost invariably aggra- 

 vates the condition. In thyroidectomized animals its administration is 

 able to completely overcome (for the time) the effects of the removal of 

 the gland, and comparable results can be produced in cretins and myx- 

 edematous patients. 



The effect on the metabolism, which is one of the most striking and 

 constant of the effects produced by feeding, has been most extensively 

 studied. Almost without exception, these studies have shown that, no 

 matter how administered, thyroid substance invariably brings about an 

 increase in the total metabolism (proteid, fat, and carbohydrates). There 

 is often an especially marked effect on proteid metabolism leading as a 

 rule to a negative nitrogen balance. 2 While, particularly with large doses, 

 the combustion of proteid is especially augmented, a negative nitrogen 

 balance may bo avoided by a diet containing a sufficiently large number 

 of calories, an extra quantity of carbohydrates being especially efficacious 

 in this respect. The effects on metabolism manifest themselves most strik- 

 i naly in thyroidectomized animals and in human cases of hypothyroid- 

 isni. 



Xorinal individuals show a very remarkable difference in their sus- 

 ceptibility to this drug, a fact which is of considerable clinical significance 

 and for which no entirely satisfactory explanation can be given. Small 

 doses frequently repeated are much more toxic than an equal or larger 

 amount administered at one time. 



-.lanney found that an increased nitrogen retention followed the administration 

 of very small doses in cretins and in one case of exophthalmic goiter, although in 

 normal individuals similar doses caused lessened nitrogen retention. In rats Hewitt 

 also found that very small doses of thyroid caused an Increased nitrogen retention 

 and gain in weight, which may have been due to increased appetite and greater con- 

 sumption of food. 



