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Title: The treatment of syphilis with salvarsan
Author: Usher, Victor F.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1912
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In the therapeutics of organismal diseases, the trend of research during recent years has been devoted almost entirely to the study of vaccine and serum therapy, but the latest discovery in therapeutic scienc: comes from another direction. Ehrlich has shown us that chemistry has its place in the treatment of these affections and the role that chemico-therapy is likely to play, opens up a still wider field for research and may even rival the discoveries in serum therapy. The results of the researches made by Ehrlich are by no means chance ones. For twenty five years he endeavored to put into practice a principle that he alone held, namely that, to get a threapeutic effect a drug can have influence only upon the tissues of the body with which it forms a chemical combination. As some drugs could act very injuriously upon the Living cells of the body, he strove to find those which act similarly upon the organisms which are the causes of the various diseases. He conceived the theory of chemico-septors and worked with substances which according to their chemical characteristics formed combinations with the tissues upon which he desired, to produce an effects. For years he conducted his experiments entirely at his own expense,and it was not until the "Speyerhaus" was built by a private donation with ample resources, that Ehrlich was enabled to obtain, all the means and opportunities, for his investigations. Working now hand in hand with some dozen coexperimenters - biologists and chemists - he endeavoured to discover the specific chemioo-septors of certain drugs and put into practice his principles of chemico - therapy. His first point was to discover those substances which act upon parasites, that is, which are parásito - tropi and from these to select those which, though parásito tropic, were not organo - tropic, having therefore no action upon the cells of the host. He divided the drugs which have a parasiticidal action into three groups. 1. Arsenic and Antimony. 2. The Azo dyes e.g. trypan red, and trypan blue. 3. The basic triphenylmethane dyes e.g. parafuchsin, methyl violet, and pyrornin. The action of these drugs was tried upon trypanosomes and the spirilla of relapsing fever and as these organisms live and multiply in the blood,investigations were easily made both in vivo and in vitro, and by these means specific chemico-septors were established between any one preparation of the above named groups and the organism in question. The products of the two dye groups he found, though, actively parasito-tropic, were also organo-tropic and thereby produced severe toxic effects upon the host. Arsenic, though usually pentavalent and toxic to the cells of tne host, if used in its trivalent form was found by Ehrlich to establish arseno-septore with the trypanosomes and the spirilla of relapsing fever and to be innocuous to the cells of the host. Consolely sequently attention was directed^to the arsenic group. He sought for a preparation that was trivalent and readily soluable and could produce"by the one fell swoop and in twenty four hours a therapia magna sterilizans" with perfect safety to the host. Beginning with the synthetic arsenical compound, Atoxyl - which had already been introduced as a treatment for trypanosomiasis - the ultimate product of his researches is the substance now known as "Salvarsan or 606" with which he hoped to revolutionise the treatment in protozoal diseases. At first his object- was to confine his investigations to trypanosomes and the spirilla of relapsing fever but they were extended later on to syphilis as well. The starting point in the discovery of salvarsan was the finding of the correct constitution of atoxyl. This drug was discovered in 1865 by a French Chemist named Be/champ, who considered the substance to be a very loose combination of analin and arsenic acid. Ehrlich working with Bertheim however, discovered atoxyl to be the sodium salt of para-amidophenÿl arsenic acid, a stable and active chemical substance capable of forming numerous compounds. Atoxyl was first brought into clinical importance by Thomas of Liverpool - in treating trypanosomiasis - but was soon abandoned on account of its extremely toxic effects, especially upon the kidneys and the optic nerves. The reason for this was shown by Ehrlich when he reconstituted its chemical formula. He proved that the arsenic was present in the pentavalent form, and that in the body atoxyl was split up into two arsenic components, in one of which the arsenic was trivalent, and in the other probably pentavalent. The former was capable of fixation with the parasites, but the latter being incapable of fixati at all, accumulated in the body as the result of continu medication and caused toxic effects in persons with a natural sensitiveness to arsenic. Starting then with atoxyl,Ehrlich found that the reduction products he made from it out side the body were more active in the body, proportionally to the amount of their reduction. Arsacetin was the next step along the line but clinically it unfortunately possesses the same dangerous sequelae to its use • By further reduction arsenophenylglycin - designated as 418 - was the next trivalent a.rsenical compound discovered, but biologically, though acting strongly upon trypanosomiasis, it was shown to have very little action upon the spirilla of recurrent fever and therefore not an ideal preparation. Experimenting further, greater success was obtained wit arsenophenal which killed the spirilla of relapsing fever after two injections. Later, greater success at was obtained with dichlorphenalarsenious acid which would do the same after one injection. With this drug the goal had been reached, the "therapia magna sterilisans" which Ehrlich had been searching for; but the substance could never be used clinically on account of the extremely toxic effects which it produced upon animals, TTith one single injection mice suffered for two weeks with progressive nervous symptoms, beginning with shaking of the head and travelling over the body until the nice became dancing mice. Further investigation revealed the drug called dioxydiamido-arsenobenzol or 592, but as this salt was insoluble its dihydrochloride was searched for. The action of both however is identical. The dihydrochloride of the dioxydianido-arsenobenzol therefore is the substance "606" or"salvarsan" now upon the market as Ehrlich's preparation for the treatment of spirillary diseases. "306" then is the 306th derivative of atoxyl, which is an ami do derivative of phenyl arsenious acid and though it can be prepared from atoxyl by a complicated process, it bears no direct relationship to it. The dioxydiamido-arsenobenzol is a yellow powder, readily oxidized, insoluble in water, but dissolves easily on the addition of sodium hydrate. The dihydrochloride is also a yellow powder, dtasily oxidize into poisonous compounds end accordingly preserved in sealed tubes in vacuo or containing inert gases.- It is soluble in water and readily soluble in warm normal saline; this solution is strongly acid in reaction. If the acidity of this solution is neutralised by the addition gradually of sodium hydrate the free base, dioxydiamido-arsencbenzol,is liberated and thrown down is a precipitate. Then if further sodium hydrate is added to the precipitate, the hydrogen atoms of the phenol hydroxyls become replaced by soda to form the soluble sodium salt (the phenalate of the base) and the compound goes into solution as the disodium salt of dioxydiamido-arsenobenzol. Ehrlich emphasises in the constitution of salvarsan two important facts. Firstly, that it is trivalenjt - seen by the formula, and secondly, the para-pcsition of the hydroxyl groups. This position is correlated with marked spirillicidal properties. 'Pith this second compound of arsenic then, we have radicals introduced which (a) reduce the toxicity of the compound, (b) increase spirillicidal properties ,(c) render the compound more stable 'Jerking on the chemical properties of salvarsan Pucliner and Hilpert estimated the amount of arsenic in that compound. Taking an ordinary market specimen they found, after careful weighing, the tube to be .6510 grm., the extra '. 'eight of .0510 grm being due to inert gases or vapour. Then calculating the arsenic content on the assumption that the tube contained 0.6grm. of real salvarsan, 35.16% of arsenic was indicated by titration with tenth - normal iodine.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available