194 Colchicine 



Considerable changes oi blood-clotting time have also been re- 

 ported in rabbits injected with large doses of colchicine. This mav be 

 five times too long.-**^ It will be mentioned elsewhere that hemorrhage 

 has been considered an important factor in the action of the drug on 

 neoplastic growth.^ One author has found that the direct action of 

 colchicine, added /// 7'itr<j to oxalated blood plasma containing 

 thrombin, was to decrease the clotting time from 20 to 15 seconds. 



Much remains to be learned about what happens when a complex 

 organism is imder the influence of such a poisonous chemical. It is 

 e\ident that much of the re\iewecl work is incomplete, that even the 

 exact chemical structure of the "colchicine" that is injected is not al- 

 ways known, and that we are confronted with a puzzle in which speci- 

 fic effects of colchicine are intermingled with general toxic reactions 

 involving hormonal stinudation and metal^olic changes. The im- 

 portance of all these ajjparently innelated facts emerges when one 

 considers colchicine's action in gout, which will be discussed later. It 

 is first necessary to ha\e some idea of the metabolic changes, if any, of 

 colchicine within the body. The study of this problem has recently 

 received some new light- 



7.6: Metabolism of Colchicine 



Forensic medicine demonstrated long ago that colchicine could Ijc 

 detected, apparently unchanged, in the bodies of patients who had 

 died of an overdose.-" Experiments on cold-blooded animals, which 

 can withstand considerable amounts of the alkaloid (Table 7.2) , dem- 

 onstrated that this remained unchanged. They also brought atten- 

 tion to the considerable \ariations in toxicity depending on body 

 temperatiue.-"- "^' ''^ For instance, a frog is able to withstand an in- 

 jection of 50 mg. of colchicine. For several days the chemical may be 

 detected unchanged in the urine. If such an animal, two to three 

 weeks after the injection, is warmed to 32°C., a temperature in itself 

 harmless, death super\enes in a few days. Progressive nervous paraly- 

 sis is evident, a typical manifestation of colchicine poisoning. Similar 

 facts are to be found in hibernating bats, which do not appear to be 

 affected by colchicine.''^ Once the animals are warmed and awake, 

 the characteristic nervous poisoning becomes \'isible.''^ 



After injection in dogs and cats, colchicine is chemically detected 

 in the feces and urine. Similarly in man, it is excreted unchanged in 

 the urine. However, only a fraction of the initial dose can be re- 

 covered.-^ This suggested to early workers that the alkaloid was 

 modified and metabolized in the animal and human bod\. The 

 striking effect of temperatme suggested that some of these changes 

 may only be possible in warm-blooded animals, or in artificially 

 warmed amphibians. Table 7.2 shows that the toxicity of colchicine is 



