August 14, 19 13] 



NATURE 



factors, which chemically must be regarded as a 

 stereo-chemical facilitation, come into action. 



Examples of such stereo-chemical facilitations are 

 frequently found in chemistry, e.g. in the chemistry 

 of the ortho-condensations. And so the haptophoric 

 group of the arsenic molecule primarily brings the 

 arsenic along to the cell, and v secondarily brings about 

 its possibility of action. 



Now. it is a frequent practice of many uncivilised 

 peoples, in order to be certain of killing their enemies, 

 that they not only rub over their arrow with one kind 

 of poison but with two or three totally different 

 kinds of poison. And so it also appeared advisable 

 to imitate this procedure against the parasites, which 

 is otherwise not very praiseworthy, and to poison our 

 synthetically poisoned arrows not singly but doubly. 

 In association with Dr. Karrer I succeeded in deposit- 

 ing the reduced arsenic compound, e.g. salvarsan, 

 even on metals, and so in arriving at remedies which, 

 used experimentally on animals, show an increased 

 effect. 



In the previous remarks I have described the condi- 

 tions which are necessary in order that a certain sub- 

 stance may exert a parasiticidal effect, and indeed 

 must effect such, if it operates directly on certain 

 definite parasites in an aqueous solution, such as, for 

 instance, is the case with the ordinary disinfectants. 

 In the manner described above it is easily possible 

 to arrive at a very large number of substances which 

 will destroy bacteria and allied substances in aqueous 

 solutions. But, of course, the problem is much more 

 difficult when it is a question of internal disinfection 

 or of the destruction of living parasites within the 

 infected organism. If the problem is set before us 

 of sterilising a room, then indeed it is an easy matter 

 to do so, owing to the present advancement of science ; 

 but the task becomes more difficult when the room 

 is filled up with materials ; and when these materials 

 are of such a delicate sensitiveness as living cells, 

 then the difficulty of the problem will be manifest 

 Without any further explanation. As a matter of fact. 

 it has proved that substances which bring about a 

 colossal bactericidal effect in aqueous solutions even 

 when thev are highly diluted, are totally ineffective 

 in therapeutics properly so called. For it has turned 

 out that, generally speaking, these disinfectants are 

 more or less powerful cell poisons, and seriously 

 injure the organism ; they are, therefore, not only 

 parasitotropic but also organotropic. 



Now, it depends exclusively on the relationship be- 

 tween parasitotropic and organotropic as to whether a 

 certain disinfectant can be used as a remedy. In 

 Robert Koch's celebrated experiment, in which even 

 the largest doses of sublimate did not produce even 

 a trai e of therapeutic effect on anthrax infection, it 

 is evident that the parasitotropic effect was reduced to 

 nil by the organotropic effect. If the relationship of 

 organotropic to parasitotropic is somewhat jnore 

 favourable, then one may observe a peculiar pheno- 

 menon, consisting in the course of the infection being 

 rendered worse to an extraordinarv degree by the 

 remedy, owing to the effect that the parasites increase 

 to a much greater extent than is generallv the case. 



This phenomenon, discovered by Hata, is explained 

 by the fact that the ratio of organotropic effect to 

 parasitotropic effect is of such a nature that almost 

 the whole of the poison is absorbed by the organism, 

 but only in infinitesimal quantities by the parasites. 

 According to a biogenetic foundation principle it is 

 quite a common thing for substances which act 

 destructively in large quantities to bring about an 

 increase in the vital functions in smaller doses. Only 

 such substances, therefore, can be used as therapeutic 

 agents in which the ratio between organotropic effect 

 and parasitotropic effect is a favourable one, and that 

 NO. 2285, VOL. 91] 



can be easily ascertained by experiment by a com- 

 parison between dosis toxica and dosis tolerata. Only 

 such substances can be considered therapeutic agents 

 of which a fraction of the dosis tolerata is sufficient 

 to bring about therapeutic effects. 



The organotropic effect of drugs is, of course, to 

 be attributed, according to the views of Langley and 

 myself, to this, that there are, in the most various 

 cells of the body and its organs, quite different chemo- 

 receptors, exactly in the same manner as we have 

 postulated for the parasites. Apart from the pharma- 

 cological effect of the various remedies, this chemii al 

 difference of the organs appears clearly in the vital 

 colouring. 



I will mention here — in order only to indicate a few 

 examples — the methyl blue colouring of the nerve 

 trunks, the neutral red colouring of the cell granules, 

 and the distribution of the isamine blue in the so-called 

 pvrrol cells, so carefully and excellently investigated 

 by Edwin Goldmann. The pathologico-anatomical 

 findings point also to a chemical divergence on prin- 

 ciple. When we see that after the introduction of 

 paraphenylenediamine only the summit of the 

 diaphragm assumes a black colouring ; when we see 

 that vinylamine in the case of all kinds of animals 

 isolates and injures the renal papillae and causes them 

 to die ; when after the introduction of cyanosin, as 

 Hata and Goldmann have found, certain definite 

 regions in the hair of mice become coloured, and the 

 colouring matter becomes stored to the greatest degree 

 in the milk glands ; when a colouring material of the 

 pyronine series in the case of mice brings about a 

 general dropsy amounting to 50-60 per cent, of the 

 bodv without injuring the kidney, which doubtless is 

 onlv to be referred to an alteration of the vessels of 

 the' subcutaneous connective tissue, then all these 

 phenomena can only be explained by the fact that at 

 these particular spots definite chemical connections of 

 a specific nature must take place, which must be 

 referred to the presence of certain definite chemo- 

 receptors. 



Now, according to the above representations, all 

 these fixations are dependent on the haptophoric 

 grouping of the drugs, and, therefore, it was a matter 

 of great interest to observe how phenylarsenic acid, 

 the mother-substance of the modern arsenic com- 

 pounds, behaves when various different groups are 

 attached thereto. In this connection it has turned 

 out that when we introduce different constituent fixa- 

 tion groups, e.g. chlorine, the oxygen_ group, the 

 hydroevanic acid group, the sulphuric acid group, the 

 ammonia radical, we can manufacture, starting out 

 from one substance, a series of combinations, the 

 toxic effect of which may vary fifteen hundredfold. 

 The combinations which are to the greatest extent free 

 from poison — these are derivatives of sulphuric acid, 

 especially the sulpho-phenylarsine acid and its salts — 

 are less toxic than sodium chloride, and, on the other 

 hand, there are substances the very smallest quantity 

 of which brings about death. And in this connection 

 we can see that, according to the nature of the sub- 

 stances, very different organs of the animal's body 

 are injured. ' Sometimes it is the intestinal tract, and 

 the animals die of profuse diarrhoea ; sometimes it is 

 the liver, and the mice — a rare occurrence — become 

 jaundiced and die of serious alterations in the liver; 

 sometimes the red blood corpuscles become dissolved, 

 and the animals die of severe anaemia. Frequently 

 also the central nervous system becomes injured, and 

 in the case of mice this usually relates to the vestibular 

 nerve of the inner ear. The interference with the 

 equilibrium, produced in this way, causes the mice 

 constantly to turn in circles just like the Japanese 

 dancing mice. In the case of human beings the optic 

 nerve is the point of attack for numerous derivatives of 



