DISCUSSION 



that as large amounts as possible of cysteamine injected in dogs do not decrease the 

 O2 saturation of mixed venous blood taken in the right heart^. 



If as demonstrated by Patt, anoxia decreases the protective effect of cysteine, it 

 is, in our interpretation, because cysteine competes for those free radicals (mainly 

 HO2) which are formed only in the presence of oxygen. 



So far as the practical aspect is concerned, it seems that, at the present time, the 

 best compromise between toxicity, oral activity and cost is cystamine^. This 

 molecule (CH2 — CHj — 8)3 has over cysteamine the advantage of chemical stability 

 and oral activity. It protects 20 g mice even against 1,100 r [Figure 1) when irradia- 

 tion begins 30 minutes after ingestion of 7 mg. The protective action is already 

 marked 15 minutes after ingestion, reaches a maximum at 30 minutes and slowly 

 declines ; it has not completely disappeared 4 hours after ingestion. It is well 

 tolerated by man (500 mg). 



Harvey M. Patt : The data of Charlier, to which Bacq has referred, do not 

 exclude a possible role of oxygen in the protection by p-mercaptoethylamine. In 

 the first place, the dosage employed in the dog was considerably below the dosage 

 requirement for a protective effect in mice. It is not known whether this dose will, 

 in fact, protect dogs against acute radiation lethality. Secondly, it should be noted 

 that the oxygen content of mixed venous blood is a gross over-all index and does not 

 necessarily reflect the situation in various loci. In this connection, it is important to 

 recall the rather selective distribution of [i-mercaptoethylamine reported by Eldjarn. 

 Z. M. BAcqto Patt : On a weight basis dogs are much more sensitive to cysteamine 

 than are mice ; this behaviour is not exceptional ; all big mammals are on weight 

 basis more sensitive to drugs than small ones. Charlier was satisfied to confirm 

 when taking blood on the right heart, that high doses of cysteine decrease markedly 

 the oxygen content of venous blood while equiprotective doses of cysteamine (about 

 the maximal tolerated dose) have no such effect. Admittedly we assume that the 

 protective power of cysteamine compared to that of cysteine is the same in the dog 

 as in the rat or mouse. 



The introduction of cysteamine in blood in presence of Oj does not change its 

 colour, does not alter the O^ content of red cells in vitro, but protects the reticulocytes 

 against X-rays. 



H. Betz to Bacq : Bacq has shown us that the injection of cysteamine produces 

 a decrease of the ascorbic acid content of the adrenal cortex. I wonder whether 

 there is a simultaneous drop of the cholesterol content. We have shown, with Van 

 Cauwenberge^" that in the case of the injection of sodium salicylate, the drop of 

 cholesterol is a more sensitive test than the drop of ascorbic acid. If the injection 

 of cysteamine produces a kind of alarm reaction, one would expect a decrease of 

 both ascorbic acid and cholesterol. A drop of the vitamin C alone would rather 

 suggest that cysteamine acts on the metabolism of the ascorbic acid. 



Z. M. BAcq to Betz : We have observed^ that cysteamine increases the cholesterol 

 content of the suprarenals and does not change the number of circulating eosino- 

 philes. Thus, we consider that cysteamine does not produce an alarm reaction but 

 acts on the distribution of ascorbic acid in the body. 



P. Mandel : A la suite des travaux du Bacq et suivant ses indications concernant 

 les doses et conditions d'injections de la cysteamine, nous avons etudie^^ I'effet 

 protecteur de ce compose contre une irradiation de I'animal entier de 700 r [C.R. 

 Soc. Biol. 1953, 236 2010). Nous avons constate que la reduction de I'acide ribo et 

 desoxyribonucleique de la moelle osseuse et de la rate est beaucoup plus attenuee 

 chez les animaux ayant regu avant I'irradiation de la cysteamine. 



MouTON : Suite a la remarque de Bacq que le pouvoir protecteur des derives 

 genre B'ecaptan disparait lorsque le pouvoir de chelation disparait, peut-on dire de 

 fa9on generale que la protection consiste en une chelation des ions metalliques bivalents 

 (p. ex. ; Cu^ + ) du milieu irradie ? 



117 



