August 14, 1913] 



MATURE 



62 1 



all other institutes of this kind, was created under 

 the direction of Sir Patrick Manson. Through Ross's 

 excellent work, Laveran's discovery of the causes of 

 malaria was so far advanced that entirely new lines 

 were opened up for the hygienic struggle against 

 tropical and subtropical diseases. 



The proof by Castellani that a trypanosome is the 

 cause of sleeping sickness, the classical w'ork by Bruce 

 on illnesses caused through trypanosomes, the specific 

 cause of kala-azar |(Dum-dum sickness) as proved by 

 Leishman, are all well known to us. The therapeutic 

 influence of atoxyl in the cases of trypanosome diseases 

 was first established in the Liverpool Tropical Institute 

 by Thomas and Breinl, and quite recently Plimmer 

 h'as brought forward the use of tartar emetic as an 

 ■iin ii\, weapon against protozoal diseases. 



The life-work of Almroth Wright is also known to 

 all "I us, i.e. his work on opsonins and on the pro- 

 phylactic treatment of typhoid fever, which has been 

 i [1 I out in a practical and most excellent manner. 

 Evn these few names, to which I might add many 

 others, show what a high and leading position Eng- 

 land has taken and still holds in the fight against 

 infectious diseases. To prevent the spread of and to 

 heal infectious diseases was at all times the highest 

 aim of medical aspirations ; however, a systematic 

 pursuit of this purpose has only been possible in recent 

 times, as through the labours of all civilised nations 

 we have got an insight into the nature of infections, 

 the cause of diseases, and the means by which they 

 are transmitted. Through these methods it has been 

 possible to infect animals artificially and so obtain 

 material on which to test the drugs in a systematic, 

 and rational manner. From the very first beginnings 

 of therapeutics, chemio-therapy has indeed been in 

 existence, as all the remedies which we employ are 

 chemicals ; on the other hand, experimental chemio- 

 therapy could only develop in modern times in a fruit- 

 ful manner as a result of all this pioneer work. But 

 here also it has been proved that the four most 

 important factors are : patience, skill, luck, and, last 

 but not least, money. 



Now, gentlemen, I may perhaps take the liberty 

 of giving you an insight into the workshop of the 

 chemio-therapeutic work. The whole area is governed 

 by a simple, I might even say natural, principle. If 

 the law is true in chemistry that "Corpora non agunt 

 nisi liquida," then for chemio-therapy the principle 

 is true that "Corpora non agunt nisi fixata." When 

 applied to the special case in point this means that 

 parasites are only killed by those materials to which 

 they have a certain relationship, by means of which 

 they are fixed by them. I call such substances 

 "parasitotropic." But I should like immediately to 

 add that there are evident exceptions to this law. So, 

 for instance, we are acquainted with a small series 

 of cases in which the apparent therapeutic results are 

 obtained, although the allied substances in question 

 do not possess parasite-destroying qualities. That is 

 the case in the infiltration of the subcutaneous tissues 

 which is caused by a kind of yeast (sporotrichosis). 

 Here Block proved that the clinically highly thera- 

 peutic iodide of potassium first of all dissolves the 

 cells of the infiltration, whilst the parasites, as such, 

 are not in the first instance attacked. 



But, in any case, it is safest and best for the 

 development of chemio-therapv not to build on the 

 basis of exceptional work, but it is better to start with 

 such substances as produce the destruction of the 

 parasites by fixation. 



Now it has been assumed in different quarters 

 that some of the more modern remedies are incor- 

 rectly regarded as parasiticides, but in reality thev 

 are not such. Thus, for example, salvarsan or mer- 

 cury salts are not intended to act directly on the 

 NO. 2285, VOL. 91] 



parasites but indirectly, owing to the fact that thej 

 excite the organism to the formation of specific anti- 

 substances. This view is based mainly upon the fact 

 that if one mixes the substances in question, such 

 as, for instance, neosalvarsan, with certain pathogenic 

 agents, e.g. spiroi hales, in test-tubes, one cannot 

 perceive any reduction in their mobility after observ- 

 ing them for hours together. From this fact, which 

 was first discovered by Prof. Hata, the conclusion has 

 been drawn that salvarsan or neosalvarsan, as such, 

 did not in any way directly influence the spirochaetes. 

 Now it can very easily be shown that this conclusion is 

 quite incorrect. If, for instance, following Castelli, 

 one suspends the spirochaetes of relapsing fever in 

 indifferent mixtures of serum which do not injure their 

 vitality, and if one fills two small tubes therewith and 

 adds to one of the tubes a very small quantity of 

 salvarsan or neosalvarsan, and if one then centri- 

 fugalises and then draws off the liquid ; if one washes 

 the remaining spirochaetes again in a mixture of 

 serum and again centrifugalises it; then one obtains 

 in both tubes a deposit of spirochaetes which on micro- 

 scopic examination shows the same properties, i.e. 

 equally good mobility of the spirochaetes. If, however, 

 the spirochaetes obtained in this manner are injected 

 into test mice, then one can very soon convince one- 

 self that the spirilla treated with salvarsan do not 

 give any infection to the animal, whilst the mice 

 vaccinated with the contents of the control tube 

 promptly shows signs of infection. This proves that 

 salvarsan or neosalvarsan, as the case may be, is 

 absorbed by the spirochaetes, and must have damaged 

 them, and that this trace of salvarsan, which is so 

 exceedingly minute that it can scarcely be weighed, 

 was sufficient to prevent the increase of the parasites 

 in the animal body. Therefore, by this very simple 

 and easily intelligible experiment, the direct effect of 

 salvarsan and neosalvarsan on the spirochaetes, and 

 thereby the principle of fixation, is absolutely proved ; 

 the objection of the indirect effect based upon anti- 

 substances therefore falls to the ground. 



It was necessary, however, to penetrate more deeply 

 into the mechanism of this fixation of remedies, and it 

 is only after long-continued efforts that success has 

 been attained in obtaining a clear conception. In 

 order to make practical progress it appeared to be 

 necessary not to be satisfied with the primordial idea, 

 but to see in what manner the drugs are fixed by 

 the parasites, or, as the case may be, by the cells. 

 Only by taking a very roundabout way has it been 

 possible to obtain clearness with respect to these com- 

 plicated relations, and in this connection it was 

 especially the studies on trypanosomes and especially 

 the investigations of "drug-fast" strains of germs, 

 which led to quite definite representations with regard 

 to the process of fixation. There was no difficulty by 

 continued treatment of the experimental mice with 

 certain definite remedies, e.g. fuchsin, in finally 

 obtaining a race of trypanosomes which had become 

 immune against these remedies, i.e. "drug-fast." in 

 the case mentioned above immune to fuchsin. There 

 were especially three classes of different remedies 

 which were very suited to this purpose : — 



(1) The class of the arsenic compounds, in the fol- 

 lowing historical order : arsenious acid, arsenilic acid 

 (atoxvl), arsenophenylglycine (salvarsan and neo- 

 salvarsan). 



(2) The class of the so-called azo-dyes (the trvpan 

 red, manufactured by Weinberg, with which Shiga 

 and I made experiments, and the trypan blue of 

 Mesnil). 



(3) Certain basic triphenylmethane dyes (fuchsin, 

 methyl violet, &c). 



When a race of trypanosomes has been rendered 



