716 6..ARSENICALS 



reduced tryparsamide in mice is 30 by subcutaneous and intraperitoneal 

 injection, and 120 by intravenous injection (Fulton and Yorke, 1943). 

 One might expect that a small fraction of the tryparsamide reduced in the 

 body would produce some typical trivalent toxicity. Tryparsamide causes 

 relatively little liver damage even when administered over long periods of 

 time to human subjects. In 34 of 66 patients studied and receiving on an 

 average 532 g tryparsamide in 193 injections over 7.4 years, only slight 

 impairment of liver function was observed, and when jaundice occurred 

 it disappeared rapidly (Kopp and Solomon, 1943). The toxic dose of carbar- 

 sone oxide is much less than for carbarsone, and furthermore the oxide 

 systemically causes acute liver damage and hemorrhagic pulmonary edema, 

 reactions not seen with carbarsone (Anderson et al., 1947). 



The pentavalent arsenicals occasionally induce optic damage and blind- 

 ness, this being the most serious reaction to tryparsamide and atoxyl, al- 

 though it does not occur with carbarsone, showing that it is not the penta- 

 valent nature alone which is responsible; no trivalent arsenicals produce 

 this. It has been known since 1905 that atoxyl causes optic damage and a 

 similar action of tryparsamide was discovered in 1915. Young and Loeven- 

 hart (1924) believed that a p-amino group is necessary for this effect, since 

 neither o- nor m-amino compounds are active, but Longley et al. (1942) 

 showed that some arsenicals without an amino group, or with a m-acetyl- 

 amino group, can bring about optic damage. We do not know the structural 

 requirements, nor do we understand the specificity of these substances 

 for the optic system. The nature of the damage is as follows: progressive 

 concentric contraction of the visual field; cloudiness of vision and an occa- 

 sional shimmering effect, but with no scotomatas and no disturbance of 

 reflexes; pallor of the optic disk and some narrowing of the retinal vessels; 

 acute degeneration of the retinal ganglion cells, leading to a marked decrease 

 in number, and of the innermost portion of the nuclear layer of the retina, 

 with some damage to rods but none to cones; and proliferation of glial 

 cells in the retina. The peripheral portions of the optic nerve are the most 

 sensitive, but the optic nerve itself may exhibit degeneration and demyelin- 

 ization; there is little evidence of central damage. Almost complete optic 

 atrophy may be induced in the most severe cases. This is not at all the same 

 optic injury produced by iodoacetate (Sorsby et al., 1957). It appears that 

 this selective action on the optic system is due to either (1) a peculiar per- 

 meability of the cells involved to these pentavalent arsenicals, the intracel- 

 lularly active form being trivalent, or (2 ) a direct action of the pentavalent 

 forms, unassociated with inactivation of SH enzymes. Most enzymes which 

 have been investigated, with the possible exception of certain lipases, are 

 quite resistant to atoxyl and tryparsamide, so that the mechanism, if 

 direct, must for the present remain obscure. 



