COLUMBIA LIBRARIES OFFSITE HEALTH SCIENCES STANDARD HX641 66708 RC201 .M912 The therapy of syphi RECAP ri=.»: . — - =ii^--: Columbia ®nibergitp COLLEGE OF PHYSICIANS AND SURGEONS Reference Library Given by Digitized by the Internet Archive in 2010 with funding from Open Knowledge Commons http://www.archive.org/details/therapyofsyphiliOOmulz THE THERAPY OF SYPHILIS ITS DEVELOPMENT AND PRESENT POSITION BY DR. PAUL MULZER OF BERLIN WITH A PREFACE BY PROF. P. UHLENHUTH, M.D. PRIVY COUNCILLOR TRANSLATED BY A. NEWBOLD ^^^ NEW YORK REBMAN COMPANY 1123 BROADWAY Entered at Stationers' Hall All rights reserved DEDICATED WITH THE GREATEST RESPECT TO HIS ROYAL HIGHNESS LOUIS FERDINAND, M.D. PRINCE OF BAVARIA PREFACE It is not to exact scientific research that we owe a number of the best and most effectual of our drugs used in combating infectious diseases, but instead to rough empiricism. I may mention here quinine, iodine, saHc^dic acid, mercury^ and arsenic. The phrase '' practice surpasses theory " has even now a certain justification; and, indeed, in the present era of exact experi- mental therapy, we cannot quite dispense with these unscientific - sounding words- The difference between now and formerly only consists in the fact that, in many infectious diseases against which we wage war, armed with these drugs, we have become acquainted with the instigators of the disease ; further, we can to a certain extent transfer these to animals, and conse- PREFACE quently carry out our experiments upon them. These latter, however, are now performed quite differently to what they were formerly, for, as the result of our exact knowledge, we can ocularly ob- serve and follow under the microscope the destructive action of many drugs upon the microparasites in question. This is an enormous advance, and is highly grati- fying to both physician and researcher, who are thus able to realise the attractive and fertile stage the study of chemotherapy has attained. From the empirical a causal therapy has been evolved. It is also conceivable that the knowledge of the expert and purposeful application of this expedient is due first of all to bacteriological science, the duty of which consists, not only in searching for the causes of infectious diseases, but also in destroying the exciters both in- side and outside the human and animal body. This applies to-day especially to aromatic vi PREFACE arsenic preparations, which are of para- mount medical interest ; their efficacy has been tested in bacteriological laboratories, and they have been proved to be powerful weapons in the struggle against diseases due to trypanosomes and spirochaetes. In relapsing fever and syphilis — the most dreaded human spirochaete diseases — these arsenic preparations have already yielded many gratif^dng results. Nevertheless, we must acknowledge that even now we are far from possessing an ideal specific drug, as, apparently, with nearly all the arsenic preparations which have been employed so far, there is a certain neurotropic action. At the same time, we must not abandon aromatic arsenic preparations in the treat- ment of syphilis, especially as they are effective in those cases in which iodine and mercury fail. In the book before us, by Dr. Mulzer, my esteemed colleague in the domain of experimental s^^philis, the general practi- tioner will be enlightened as to the present vii PREFACE position of modern specific therapy ; he will be shown what was formerly accom- plished, and at the same time its develop- ment up to the present day will be demon- strated to him. As the work of the Imperial Health Bureau paved the way for this improve- ment and practically promoted it by the discovery of the Spirochceta pallida, by researches in experimental syphilis of rabbits, and, above all, by the construction and development of the experimental basis of the organic arseno-therapy of spirilloses, and especially of syphilis, it is a particular pleasure to send this book on its way with a foreword and to associate this with the wish that arseno-therapy in its present form and future evolution may bring a blessing to suffering humanity. PAUL UHLENHUTH {Imperial Health Bureau)^ Berlin, Gross Lichterfelde, December i6, 1910. viii INTRODUCTION After F. Schaudinn discovered the Spiro- chcBta pallida at the Imperial Health Bureau, in 1905, and, in common with E. Hoffmann, reported on the constant appearance of this peculiar micro-organism in the most varied infectious products of specific dis- ease, the pendulum of syphilitic research swung forward unexpectedly and vigor- ously. The epoch-making communications of Schaudinn and Hoffmann were further tested by many researchers. Within a short time numerous works appeared which confirmed and extended these results, so that the probability of the 5. pallida being the exciter of syphilis became greater and greater. It was soon proved that specific disease must exist in the organism if one could testify to the certain presence of the ix INTRODUCTION S. pallida. If found in an ulcer or erosion, which could not be positively diagnosed clinically, this might be pronounced to be a primary syphilitic affection. Later, the appearance of secondary phenomena always confirmed the accuracy of this diagnosis. Subsequently, when syphilis was experi- mentally produced in animals, it was regu- larly possible to prove the presence of the S. pallida, and to therapeutically influence this form of disease by means of specific remedies. All these facts have taught us that the 5. pallida is really the exciter of syphilis. These results were first practically applied in confirming the diagnosis of syphilis. To Erich Hoffmann is due the service of having again and again referred to the extraordinary diagnostic importance of the presence of S. pallida in doubtful cases of disease. A further advance in modern syphilitic research is indicated by the introduction of serum diagnosis by A. Wassermann, INTRODUCTION A. Neisser, and C. Bruck. Supported by the experience and observations of numerous teachers, there is no longer any doubt that the positive result of the Wassermann test in all probability indicates that the in- dividual, whose blood -serum gives this reaction, must at some time have suffered from specific infection. A preliminary con- dition for such a conclusion is naturally skill in carrying out the reaction and an irreproachable technique. Some time before the discovery of the 5. pallida Metschnikoff and Roux had succeeded in transmitting syphilis to apes. Acting on this discovery, it was possible for A. Neisser and his collaborators, after working for years in Batavia, to experi- mentally solve upon apes many highly valuable problems of the pathology and therapy of syphilis. Bertarelli, Levaditi, Parodi, Hoffmann, Lohe and the author, Uhlenhuth, and Weidanz, Grouven, Trufh, and other researchers also succeeded later in experimentally infecting rabbits with xi INTRODUCTION syphilis ; these results, however, were re- garded more or less as accidental and exceptional. Uhlenhuth and I, after sys- tematically arranged experimental studies on syphilis of the scrotum in rabbits were the first to demonstrate that these animals, more than all others, including the lower apes, are specially adapted for this kind of experimental research. It is on this fact, which was later also confirmed by other authors — such as Truffi, Menzincesku, Tomasczewski, and M. Koch — that the results which indicated the modern chemo- therapy of syphilis were finally based. xu CONTENTS HAGE Preface by Privy Councillor Uhlenhuth v Introduction (Discovery of the Spirochceia 'pallida, Wassermann Reaction, Experi- mental Syphilis) - - - - ix Influence of the Results of Syphilitic Research upon the Former Mercurial Therapy of Syphilis - - - i Chemotherapy of Syphilis : I. Atoxyl - - - - - 12 II. Arsacetin (Ehrlich) - - - 27 III. Atoxylate of Mercury (Uhlenhuth) 29 IV. Hectine - - - - - 37 V. SOAMIX - - - - - 3S VI. Arsenophenylglycin - - - 40 VII. DiOXYDIAMIDOARSENOBENZOL (EhRLICH- Hata " 606 ") - - - 44 I. Chemical Constitution, Experi- ments ON Animals - - -45 xiii CONTENTS PAGE VII. DioxYDiAMiDOARSENOBENZOL — continued : 2. Suspension of Solutions which are Ready for Use - - - 50 [a] Alkaline Solutions - - 51 (&) Neutral Emulsions - - 58 (c) Kromayer's Paraffin Emulsion 65 3. Technique OF Injection - - 71 [a) Intramuscular Injection - 71 (&) Subcutaneous Injection - 73 (c) Intravenous Injection - - 75 4. Direct Local Secondary Effects OF the Injection - - 81 5. Effect of Arsenobenzol upon the Organism in General - - 86 6. Effect of Arsenobenzol on Syphi- litic Diseases of the Primary, Secondary, and Tertiary Periods - - - - 89 (a) Primary Affections - - 92 (6) Early Stage of Secondary Syphilis - - - - 98 (c) The Late Stage of Secondary Syphilis and Tertiary Syphilis iio {d) Malignant Syphilis and Ulcer- ous Tertiary Forms respec- tively - - 119 XIV CONTENTS PAGE VII. DioxYDiAMiDOARSENOBENZOL — continued : (e) Treatment of Syphilitic Dis- eases OF the Eyes with Arseno- BENZOL - - - - 122 (/) Syphilis of the Internal Or- gans - - - . 126 (g) Meta- and Para-Syphilitic Dis- eases, including Tabes and Paralysis - - - 128 (h) Hereditary Syphilis - - 133 7. Dosage - - . . 13^ 8. Influencing the Result of the Wassermann Reaction by Means OF Treatment with Arseno- benzol - - - - 141 9. Relapses - - . . 149 10. Secondary Effects - - - 172 11. Epicrisis _ _ - - ig6 Literature - - - - - 205 Index - - - - - - 225 Authorities referred to - - - 245 XV THE THERAPY OF SYPHILIS INFLUENCE OF THE RESULTS OF SYPHILITIC RESEARCH UPON THE FORMER MERCURIAL THERAPY A The experience of a century has taught ^ us that, of all the drugs used in the treat- ment of syphilis, without doubt mercury is the most powerful and effective. In earlier tim.es many errors in its therapeutic application, from ignorance of cause and effect, often resulted in the serious injury of the individual, who had been treated too drastically. If, in consequence, this drug is to-day still discredited in many lay circles, we know that, with expert medical applica- tion and control, mercury is at the present time the sole drug capable of effecting THE THERAPY OF SYPHILIS the definite cure of syphilis, even if this is not so in all cases. The accuracy of this statement is testified to by the fact " that severe tertiary symptoms appear most frequently in untreated or inade- quately treated cases, whereas, on the other hand, the best protection against this is early, energetic mercurial treat- ment " (E. Lesser). I will not go into further details here, as to the special indications for this therapy, and respectively as to the different mercurial preparations and their application in the individual stages of syphilis. I will merely briefly recapitulate when we began the general treatment — i.e., until the discovery of the exciter of syphilis. There were two opinions with regard to this. In the one, the specific treatment was begun as soon as possible — i.e., immediately after the recognition of the primary affection ; in the other, it was believed that it was necessary to wait until the appearance of the first secondary symptoms indicated a generalisa- THE THERAPY OF SYPHILIS tion of the syphilitic virus ; the adherents to this view included some of our most celebrated syphilidologists. In this thera- peutic procedure, they relied upon their experience and that of other teachers, who considered the action of mercury was most lasting in the general syphilitic stage, and that it had never been possible to succeed in arresting the disease by early treatment, and thus prevent an outbreak of general infection. Above all, however, it was believed that one must wait until the eruption of roseola appeared, because it was only then that one could diagnose syphilis with absolute certainty, as even the most experienced teacher might be deceived by the manifold and frequently uncharacteristic forms of the phenomena of the primary affection. This hesitation disappears now that we are capable of obtaining the proof of the presence of the Spirochceta pallida in doubtful cases of diseased tissue, occasion- ally after repeated careful examinations, 3 THE THERAPY OF SYPHILIS and of recognising these absolutely as primary syphilitic lesions. Further, animal experiment has also removed the objection that it is only with the outbreak of the secondary symptoms that the virus is spread over the organism, and is then more accessible to general specific treatment. Hoffmann was able to prove experimentally that the blood of syphilitics induced syphilis in apes, which had been inoculated with it, about the sixth week after the infection, therefore several weeks before the outbreak of the secondary symptoms. Neisser was able to demonstrate that the internal organs of apes already contained syphihtic virus at the time of the appearance of the primary affection, and, indeed, mostly much earlier, from the fact that, by inoculating the spleen-liver-bone-marrow pulp of an animal diseased in this way on to other healthy animals, typical forms of syphilitic disease could be induced. In the same way, Uhlen- huth and I were able to confirm this fact 4 THE THERAPY OF SYPHILIS by the primary inoculation syphilis of rabbits. Another circumstance which must be taken into consideration as testifying to this is the fact that, according to the state- ment of most authors, the Wassermann reaction shows a positive result in nearly half the cases in the primary stage. From the clinical observations of Hol- lander, Hoffmann, Thalmann, and others, we know, however, that in the so-called '' early treatment " of syphilis by excision of the primary affection, with subsequent drastic doses of mercury, even if perfect cure is extremely rare, it is possible to diminish the intensity of the further course of the disease to some extent. It is, therefore, necessary for the practi- tioner to begin general treatment as soon as ever syphilis has been diagnosed — i.e., directly it has been possible to prove the presence of the 5. pallidcB in the suspected diseased material. By extending the ex- cision into the healthy part as far as possible, one must endeavour to remove the primary 5 THE THERAPY OF SYPHILIS afection, so as not to renounce the possi- bility of arresting the syphiUs, or at least of preventing a further immigration of the spirochaetes into the organism from here. Where this is not possible, in consequence of the anatomical position, we must try to destroy them by cauterisation, hot air treatment, or by covering with mercurial plaster, and finally annihilate the spiro- chaetes everywhere, by injections of soluble mercurial or arsenical preparations (for example, hydrargyrum oxycyanatum, atoxyl, Ehrlich-Hata). '' From the point of view of prophylaxis also, it is very desirable to reduce the chancre as soon as possible, and so avoid its being the source of fresh infections '' (Hoffmann). From my experience, I find we do not select our strongest mercurial preparations at the beginning of general treatment, so that there is a possibility of increasing the dose in individual cases. But instead, we try to augment the intensity of the pre- liminary treatment by its longer duration. 6 THE THERAPY OF SYPHILIS The animal experiments of Neisser and his collaborators have demonstrated that mercury is a direct remedy for specific disease, and, indeed, not only of manifest syphilis, but also in the latent stages. From this Neisser infers the justice of our former therapy — namely, that in human syphilis mercury is not to be administered solely as a systematic remedy, but also in those cases where clinically we can deter- mine no symptoms, but, nevertheless, know, partly from general experience and partly from the serum diagnosis, that there is still specific poison in the body. Further, if we reflect that in most of the forms of disease spirochaetes are present during the second period, and are therefore capable of re- maining for a very long time in the body, all these facts testify fully to the justice — indeed, the necessity — of chronic inter- mittent treatment of syphilis. With regard to the question as to how far the result of the Wassermann reaction should influence our therapeutic treatment, 7 THE THERAPY OF SYPHILIS this has not been explained at the present time. As long as we do not definitely know the genuine nature of this reaction, a complete solution of the problem cannot be anticipated. The majority of authors agree that the positive result of the Wasser- mann reaction indicates with absolute cer- tainty that active syphilitic virus is still present in the organism. It naturally follows that, in every case in which the serum reaction gives a positive result, anti- syphilitic treatment should be introduced, quite immaterially whether manifest symp- toms are present or not. Other teachers, amongst whom I include myself, acknow- ledge, it is true, that the specific therapy exercises a certain influence upon the result of the reaction, but they believe that this has too little constancy and proportion to require a special therapy to which the organism is not quite indifferent, especially in the more advanced cases of syphilis. In my opinion, the practical value of the Wasserm.ann reaction lies principally in the 8 THE THERAPY OF SYPHILIS diagnostic domain, and respectively of differential diagnosis. Therapeutically this reaction can be taken advantage of, in that a positive result of the same proves, with a probability bordering on certainty, that specific infection has occurred in the in- dividual whose blood gives this reaction. We must then make an exact anamnesis of the course of the disease and of former treatment, our further therapeutic measures being first of all dependent on this result. The same thing applies, certainly in a far less degree, to an occasional negative result of the Wassermann reaction. In itself this naturally proves nothing. It is only when the examination of the blood, repeated at varying periods, has always given an irreproachable negative result, and there are no certain indications of syphilis present, either anamnesically or clinically, that the negative result of the reaction may be considered diagnostically. Otherwise it cannot in any way influence the treatment of the practitioner, either 9 THE THERAPY OF SYPHILIS with regard to prognosis or therapy, as we know that, even when syphiUtic symp- toms are manifest, a negative result of the Wassermann reaction is not always ex- cluded. In my opinion, it is incorrect that specific treatment, and respectively its dura- tion and intensity, should be undertaken under the constant control of the Wasser- mann reaction, its effect and duration being made dependent upon the occasional result of the Wassermann test, as is done by some authors. For, according to my researches, the result of the Wassermann reaction may often fluctuate backwards and forwards during a mercurial cure. Besides these results, which are valuable for modern mercurial specific therapy, a whole series of other important questions have been explained by syphilitic research, or their solution has been approached very closely, and of these I will briefly mention a few. Finger and Landsteiner, Neisser and Hoffmann succeeded in proving the infectiousness of gummata from observa- 10 THE THERAPY OF SYPHILIS tions on animals. Finger and Landsteiner, Neisser, Tomasczewski, Uhlenhuth, and I were able, by animal experiment, to con- tradict the dogma of absolute and per- manent immunity set up by Ricord, which a single attack of specific infection is sup- posed to bestow, but which, on the ground of clinical observations, had appeared doubt- ful to some of his contemporaries and also to many later teachers. Questions of in- dividual prophylaxis were also touched upon, and enabled us to recognise a good, but not absolutely certain, protection against specific infection in the administration of the 30 per cent, calomel salve (Metsch- nikoff and Roux) . By means of comprehen- sive serological examinations, the accuracy of the law of Colle and Profata was de- termined by Bruck, Boas, Blumenthal, Michaelis, the author, and others. The triumph of syphilitic research, how- ever, consisted in its being the basis of the modern chemotherapy of syphilis. II THE CHEMOTHERAPY OF SYPHILIS I. ATOXYL. The constitution of this preparation, which was originally described as meta-arsenic acid anilide, was first explained by P.Ehrlich and Bertheim. They proved that by heat- ing the arsenic acid anilin, under a base corresponding to the sulphanilic acid presentation, para - amino - phenyl - arsenic acid is formed. This acid is very difficult to dissolve in water (i : 255) and by other usual methods of solution, but will dissolve without decomposing in caustic and car- bonic acid alkalies. By dissolving in the estimated quantity of alcohol, the mono- sodium salt, ^-aminophenylarsenic acid, atoxyl is formed, the constitution formula 12 THE CHEMOTHERAPY OF SYPHILIS of which is given as follows by Ehrlich and Bertheim : \//OH + 4H20 AsfO ^ONa The crystalline watery content is not con- stant, but instead varies with the manner of preparation, and the condition of crystal- lisation thus caused. Atoxyl is a crystalline powder without either colour or smell, with a cool, weakly saline taste. On heating it decomposes slowly, gradually assuming a brown colour without melting. It is soluble in 4-3 parts water at 20° C. The aqueous solution saturated at this temperature contains i8*8 per cent, of atoxyl. The solubility in water is greatly increased by a heightened temperature. It is very difficult to dissolve atoxyl in alcohol. The solutions assume a browoiish-yellow colour if they stand in 13 THE THERAPY OF SYPHILIS the air and light, and similarly if they are boiled for long, when they lose their curative power, and become toxic instead. If the solution is to be sterilised, it should be heated in sterile vessels for two minutes at 70° to 80° C, or it should be filtered after Uhlenhuth's method, by means of Berke- feld's bougies. In this way, a sterile prep- aration which is perfectl}^ irreproachable is obtained. The aqueous solution has a weakly acid reaction. If it is transposed with diluted acids, then the atoxylic acids will be pre- cipitated in thick white flakes, which dissolve ver}^ easily in the overflow, but not in that of acetic acid. F. Blumenthal was the first to employ the new drug in medical practice, in 1902. By means of valuable pharmacological researches, he proved the relative non- toxicity of the preparation, and drew attention to its favourable qualities. Ac- cording to the reports of F. Blumenthal, atoxyl is forty times less toxic than Fowler's 14 THE CHEMOTHERAPY OF SYPHILIS solution. Further, he considers this prep- aration has the advantage over Fowler's solution and other arsenic preparations, in that the arsenic from this atoxyl, although bound fast to the benzol nucleus, is split up in the organism, and so acts in statu nascendi. The researches of Blumenthal and Jakoby place the principal action of atoxyl in the blood, where it either acts directly by splitting up the arsenic acids, or may appear catalytically in function, while acting upon such in the cure of important processes. It was through the English ph^^sician W. Thomas that atoxyl, which had already been found to be tolerated in the treat- ment of diseases of the blood and of the nervous system, as well as in various cutaneous affections, was introduced into the therapy of trypanosome diseases (1905). Thomas and Breinl obtained excellent results in the experimental infection of rats, mice, rabbits, etc., with the trypanosomes of surra, nagana, sleeping sickness, etc. 15 THE THERAPY OF SYPHILIS The results of the experiments of Mesnil, Nicolle, and Ehrlich were less favourable ; independently of Thomas, they adminis- tered atoxyl to animals infected by the tsetse fly, surra and mal de caderas. Atoxyl, recommended by Thomas, was further tried with advantage by Kopke, Broden, Rod- hain, and others in the treatment of sleep- ing sickness ; but it was Robert Koch who first carried out a systematic and purposeful atoxylic cure, when the material at hand was on a large scale. Amongst other things, R. Koch was able to prove that, eight hours after the injection of atoxyl, the trypanosomes had already dis- appeared from the lymphatic glands and from the blood. Moreover, with the dis- appearance of the trypanosomes from the lymphatic glands, a distinct improvement took place in the patient's condition. Instigated by the reports which had been published, and particularly by Koch's favourable results, Uhlenhuth commenced some experiments at the Imperial Health i6 THE CHEMOTHERAPY OF SYPHILIS Bureau, Berlin, in 1906, which consisted first in treating dourine disease with atoxyl. As has been reported by Uhlenhuth and his collaborators Hiibener, Woithe, and Bickel, the results of the protective and curative experiments undertaken in this direction were favourable. Further, the authors recorded that certain considerations had led them to try atoxylic treatment in other protozoal diseases also. The opinion laid down by Schaudinn, that many spirochaetes represent special stages of development of trypanosomes, caused them first of all to try atoxyl in spirillosis of fowls. The exciter of this disease is the 5. gallinarum, which was discovered by Mar- choux and Salimpeni at Rio de Janeiro, in 1903. The disease, which frequently sets in as septicaemia with a fatal result, begins with high fever and diarrhoea. The animals soon become somnolent, and some- times succumb from paralysis and also from spasms. If fowls are infected with blood 17 B THE THERAPY OF SYPHILIS containing spirochsetes, the parasites can generally be detected in the circulation on the second day after infection ; they increase rapidly up to the fourth to sixth day, when they can be found in the blood in great convoluted colonies. The crisis sets in on the seventh to ninth day ; the spirochaetes disappear spontaneously from the circulation, and the animals are then immune, if they do not succumb to the disease. A natural immunity is obviously rare. Here, also, the authors succeeded in proving in an absolutely trustworthy manner that atoxyl exercises a protective and cura- tive action in spirillosis of fowls ; that it is capable of destroying the spirochsetes in the blood of the diseased fowls and of causing their disappearance. Uhlenhuth, Gross, and Bickel conclude their communications, which appeared in No. 4 of the Deutschen Medizinischen Woch- enschrift, January 24, 1907, with the follow- ing words : *' As atoxyl has a destructive 18 THE CHEMOTHERAPY OF SYPHILIS action on the most varied trypanosomes, it is easy to reflect that it may develop a similar action to that of the S. gallinarum on various other spirochaetes. Appropriate experiments with the spirochsetes of re- lapsing fever and of syphilis are in progress, the positive result of which would be of practical importance in combating these diseases/' It was soon possible to report on the results of researches of this description. The experimental work of Uhlenhuth and his collaborators in relapsing fever of mice and rats did not, it is true, enable one to come to a definite conclusion as to the efficacy of these preparations in this disease, on account of their toxicity for these animals ; but, on the other hand, the ex- periments undertaken by Glaubermann at Moscow, at the instigation of Uhlenhuth, in Russian relapsing fever, were on the whole favourable. It seemed most impor- tant to Uhlenhuth, however, that atoxyl should be tried in the spirochaete disease 19 THE THERAPY OF SYPHILIS of most frequent occurrence — namely, syphilis. As long ago as December, 1906, Uhlen- huth, with Hoffmann, Roscher, and Weidanz, had endeavoured to obtain a definite answer to the question whether atoxyl exercised a direct influence on the process of specific disease. In S3^philis of apes, as well as of rabbits (disease of the cornea) the authors actually observed a noticeable prophylactic and curative effect of atoxyl. Equally good results were ob- tained soon after by A. Neisser, who also proved, by means of experiments on apes, that energetic treatment with atoxyl, which is best when administered in large single doses, has a very marked influence on syphilis. Therapeutic experiments on human subjects at the Lesser Clinique, at Uhlenhuth's suggestion, were extraordin- arily successful with the correct dosage, after having failed at first when the dose administered was too small. The results of this treatment are reported in detail 20 THE CHEMOTHERAPY OF SYPHILIS in a work by Uhlenhuth, Hoffmann, Roscher, and Weidanz. Further, Salmon, Lassar, Hallopeau and others shortly afterwards recorded very successful curative results obtained in human s^^philis with atoxyl. E. Lesser spoke very favourably of atox^dic treatment of specific disease, which he re- garded as equal to the customary doses of calomel in rapidity of result. Of further authors who tested the therapeutic effect of atoxyl on syphilis, and generally obtained good results with it, I should like to men- tion Hoffmann, von Zeissl, Lesser, Nagel- schmidt, Finger, Moses, Darier, Heuck, Balzer, Rouviere, Kreibich and Kraus, Scherber, Rapiport, and others. If we compile a resume from these com- munications, references, and clinical ob- servations in specialist literature, then, according to Salmon, the favourable effect of atoxyl in syphilis is shown : — I. As regards the Constancy of the Results. — The favourable curative effect appeared in all stages of syphilis — viz., primary, 21 THE THERAPY OF SYPHILIS secondary, and tertiary — and was most brilliant in malignant forms. 2, As regards the Rapidity of the Action of the Drug. — After a few injections, chancres diminish and are absorbed, the hardness often disappears remarkably quickly. Fresh roseola, maculo-papulous exanthema, im- petigo capitis disappear after ten to four- teen days, psoriasis palmarum after twelve days. The exanthema becomes paler until it is invisible. Papules lose their redness, and, with the absorption of the plastic exudation, flattening, and typical brown- ing (regressive metamorphosis) is evident. Ulcerations close and skin over, annular syphilides dry up, and gummatous infiltra- tions yield to the treatment in a similar way. Papules, plaques, tuberculous syphi- lides, tertiary ulcers, diminish rapidly and generally heal over. The headache, which is characteristic of syphilis, often ceases surprisingly rapidly (eighteen hours) after the first injection, the dysphasia and dysphagia of angina syphilitica decrease 22 THE CHEMOTHERAPY OF SYPHILIS after two to three days. According to Darier and others, iritis syphilitica can also be very favourably influenced by treatment with atoxyl. Cases which are refractory to mercurial treatment, or are only slightly influenced by it, such, especially, as cases of syphilis ulcerosa prsecox (malignant syphilis) , gener- ally react rapidly and promptly to atoxyl. 3. ^5 regards the Favourable Effect on the General Condition. — The patients feel well, and nearl}^ all of them increase considerably in weight. Unfortunately atoxyl did not subse- quently fulfil the hopes which had been centred on it for the therapy of syphilis. The observations on atoxylic resistance, to which Ehrlich first referred, and the prac- tical experience gained in combating syphilis, showed that favourable results could only be obtained with large doses of atoxyl. These doses, however, approached pretty closely to toxic ones, and undoubtedly there was danger that with them the limit of 23 THE THERAPY OF SYPHILIS isotonicity of the preparation, which varies in individual cases, might be exceeded. That this was actually done in the thera- peutic administration of atoxyl was proved by observations of injury to the central nervous organs (transitory visual disturb- ances extending to blindness, and respec- tively total atrophy of the visual nerves).^ In order to prevent relapses, it was necessary to repeat the application at short intervals, and thus the danger of over- dosage was still further increased. After the cases of blindness which were first observed in the treatment of sleeping sick- ness had been reported, naturally the general administration of atoxyl in syphilis had to cease. Uhlenhuth himself was the first to demand this, and wished to reserve the employment of atoxyl for those cases which had proved refractory to mer- ^ Schanz assumes that this process in the visual nerves must have its origin far from the bulbus, as for a long time the ophthalmoscope gave a negative result, even if the visual disturbances were already extensive. 24 THE CHEMOTHERAPY OF SYPHILIS cury, or had been only slightly influenced by it. In all the cases of visual disturbance observed, it was possible to regularly build up the distinct progress of this disease, and give sharply-defined pictures of the disease and development of atoxylic blindness respectively. According to Sowade, its individual phases were pre- sented as follows : — 1. Beginning with '' cloudiness '' or ** a veil before the eyes.'' 2. Intense diminution of the visual power within a few days and weeks. 3. At first there were no changes in the fundus oculi, and often it was only after months that there was perceptible atrophy of the papilla of the optic nerve, without previous neuritic phenomena. Contraction of the vessels of the retina. 4. Frequent maintenance of the normal papillary reaction. 5. As a rule, impossibility of arresting the advance of the affection. 25 THE THERAPY OF SYPHILIS By means of experimental researches on rabbits and dogs, Birch - Hirschf eld and Koster proved that if atoxyl was adminis- tered for a long time until the death of the animal, the optic nerve microscopically showed disintegration of the medullary sheath over the entire transverse section. It was thought at first that these toxic secondary effects of atoxyl were due to chemical impurities, and attributable to the German preparation. A change in the production of the preparation, however, did not result in any noticeable diminution of its toxicity. In order that the undoubtedly favourable specific action of atoxyl in the treatment of trypanosome diseases and syphilis need not have to be abandoned altogether, especially in cases in which Hg and other drugs fail, various combinations were tried of atoxyl with other preparations or alterations of the chemical structure of atoxyl, which were supposed to be less toxic in their effects. Thus we have : — 26 THE CHEMOTHERAPY OF SYPHILIS II. ARSACETIN (EHRLICH), which was obtained from atoxyl by chemical changes. It is the salts of sodium of the acetyl combination of ^-aminophenylar- sanilic acid of sodium. Arsacetin is represented by a white powder ; the crystalline water contains three to four molecules, and dissolves easily in cold water at lo per cent., in hot at 30 per cent. It does not decompose on boiling, and has been proved to be constant through- out (according to So wade), even when heated in an autoclave for an hour and at 130° C. It has been pharmacologically deter- mined by Ehrlich, Browning, Uhlenhuth, and Salmon that healthy, as well as diseased, animals can tolerate much higher doses of arsacetin than they can of atoxyl. Neisser states that it has been proved experimentally that, in the trypanosome and spirilla diseases of various animals, arsacetin is at any rate found to be quite as good as atoxyl. 37 THE THERAPY OF SYPHILIS Neisser and the few teachers who have tested this preparation therapeutically, have obtained a good effect on the diseased syphilitic tissue with it, similar to that of atoxyl. Here, again, the tertiary forms of the disease, as well as malignant syphilis, appeared to be specially favourably in- fluenced by the drug. The experience of Heymann and Sowade, however, showed that, in the majority of cases, the effect of mercury was undoubtedly more certain and durable. Soon after the employment of arsacetin, reports came to hand from different sources of '' considerable phe- nomena of intoxication," such as headache, nausea, vomiting, giddiness, abdominal pain, shooting pains in the extremities, nephritis, and finally visual disturbances (Heymann, Klemperer, Sowade, etc.), from which it appeared that arsacetin, especially with regard to a toxic action on the optic nerve (in Africa, 5 to 10 per cent, atrophy of the optic nerve), was more poisonous than atoxyl (Jenssen, Oppenheim, Paderstein, a8 THE CHEMOTHERAPY OF SYPHILIS Ruele, Hammer, Pflughoft, Borcher). Further, it seemed, as Uhlenhuth reported at the Colonial Congress, 1910, according to the records of Feldmann, that arsacetin exercised a toxic action on the auditory nerves. In Africa, out of fifty-one patients treated with arsacetin, nine became blind and two simultaneously deaf. As Heinrich has cited, Ehrlich himself is of opinion that arsacetin possesses no advantages over atoxyl in a number of diseases, especially those of syphilis and sleeping sickness, which '' to a certain ex- tent are difficult to steriHse.'' On account of the threatened danger to the eyes, Ehrlich no longer recommended it. III. ATOXYLATE OF MERCURY (UHLEN- HUTH) (P-AMINOPHENYLARSONATE Hg). At the Imperial Health Bureau, Berlin, Uhlenhuth, Hiibener and Woithe obtained good results in dourine, in experiments carried out by the combined application of atoxyl and sublimate. Further, the 29 THE THERAPY OF SYPHILIS therapeutic experiments in relapsing fever, reported by Manteufel, showed that mer- cury had a certain therapeutic effect on this spirochaete disease in colloid form. On the basis of these results, and in con- sideration of the fact that mercury is known empirically to act organically on syphilis and respectively on the spirochsetes, the exciters of this disease (Uhlenhuth and Manteufel), Uhlenhuth, at a meeting of the Association of Internal Medicine, Berlin, June 24, 1907, proposed that a combination of atoxyl and mercury should be used for the treatment of S3^philis. In trypanosome diseases, treatment with these two drugs had already been recommended by Moore, Nierenstein, and Todd. Soon, as the results of experiments on animals made with a new atoxylic prepara- tion brought out by the United Chemical Works, Charlottenberg, from Uhlenhuth's formula, Uhlenhuth and Manteufel were able to record good results obtained with this new drug, atoxylate of mercur}^, which 30 THE CHEMOTHERAPY OF SYPHILIS promised to be of practical importance in the treatment of syphilis. Both authors first made researches with atoxylate of mercury by experimentally infecting rats with relapsing fever. Al- though in themselves apparently very un- suitable for such treatment, as they tolerate atoxyl, and mercury especially, very badly, nevertheless, it was distinctly possible to recognise the antiparasitic qualities of the preparation from the experiments. Further experiments made on spiro- chaetic septicaemia of fowls proved that atoxylate of mercury actually exercised a very energetic action on the spirochaetes. After these preliminary exploratory ob- servations, the authors proceeded to in- fluence experimental syphilis with atoxylate of mercury therapeutically. The effects ob- served in corneal syphilis of rabbits entirely confirmed the results obtained in the study of spirochaetosis of fowls. Uhlenhuth and I succeeded in completely curing three large typical syphilitic ulcers in ten and 31 THE THERAPY OF SYPHILIS eighteen days respectively, two being scrotal ones in rabbits. Later, we were able to confirm these results on a large quantity of rabbits. We simultaneously made the obser- vation that even as soon as twenty-four hours after the first adequate dose no spirochsetes at all, or only very few, could be found in the diseased material, and that, after a further twenty-four to twenty-six hours, they had entirely disappeared. It is evident from the above, that in these healing processes we have to do with a specific action of this preparation on the spirochaetes themselves, as was already shown by Uhlenhuth and others in their experiments on fowls suffering from spiro- chaetes ; for that tissue was first influenced therapeutically which contained large quan- tities of spirochaetes. As Uhlenhuth and I first showed, these are typical forms of syphilis induced experimentally in rabbits. This drug reacts most markedly on syphi- litic indurations — the sclerotic, hard tissue, characteristic of primary specific disease. 32 THE CHEMOTHERAPY OF SYPHILIS When induced in rabbits, this tissue con- tains spirochaetes in genuinely pure culture.^ After one or a few injections (with small doses) the sclerotic tissue disappears alto- gether, no spirochaetes can be discovered, the scrotal tissue has apparently again become normal, and the former deep ulcers are healing smoothly under good granula- tion formation. The specific reactions be- tween the 5. pallida and the arsenic and mercurial preparations, as I mentioned at the beginning, give us visible proof of the irritant nature of the spirochaete in human syphilis, as well as that of rabbits (Uhlenhuth and Mulzer). After a few exploratory preliminary ex- periments on human subjects, which gave similar results to the successful ones on animals, Uhlenhuth recommended that ^ It is a mistake if Hata, in the Ehrlich book " On the Chemotherapy of Spirilloses/' asserts that we recommended syphiloma of the scrotum, which con- sists of loose myxomatous tissue and also contains a great quantity of spirochsetes, for the purpose of testing chemotherapeutical experiments. 33 C THE THERAPY OF SYPHILIS atoxylate of mercury should be employed for the therapy of syphilis. This new preparation was first used extensively in therapeutics by Miekley at the Lesser Qinique. The administration of the drug was as follows : It was begun with doses of 0-05 gramme twice in the first week, and then continued with o*i gramme per week until a total amount of 0*5 gramme had been given (with women, 0*48 gramme). The results obtained with these patients were well worthy of notice. Cases of syphilis in various stages were treated with atoxylate of mercury. It was specially interesting to notice that frequently even after 0*05 gramme, or at most after o-i gramme, the papu- lous syphilides began to dissolve, the in- filtrations especially disappearing very rapidly. '' After the third injection, as a rule, all that was left of the papulous exanthemata was the pigment residue without any infiltration being clinically 34 THE CHEMOTHERAPY OF SYPHILIS evident," Miekley reports. He was further able to testify to a markedly favourable effect of hydrarg. atoxyl in malignant syphilis, and in the ulcerous and gummatous cutaneous processes of tertiary syphilis. The secondary effects — in some cases stoma- titis and albuminuria — were very slight, and easily disappeared when the drug was stopped. According to a report of E. Les- ser's in the Charite Annates, 1910, up to that time 127 cases had been treated in the Lesser Clinique with hydrarg. atoxyl. '' The result on the whole was good, despite the relatively small dose, the phenomena gener- ally retrogressed rapidly, and often dis- appeared after the first injection. The effect of hydrarg. atoxyl seemed to be specially favourable in galloping syphilis." Lesser states that out of these 127 cases, 16 relapses came under observation after the course of a few months. The result of the Wasser- mann reaction with 13 men was positive once and negative 12 times ; with 17 women, 12 times positive and 5 times negative. 35 THE THERAPY OF SYPHILIS Blaschko also mentions good results he obtained with atoxylate of mercury ; only he gave larger doses than Lesser, as he extended them up to ten injections. The principal secondary effect Blaschko noticed was unusual pain during the in- jection, such as is not common to other mer- curial preparations. He attributed this to the suspension of the preparation in olive oil. Soon afterwards Fabry briefly recorded very good curative results in syphilis with atoxylate of mercury ; similar experiences were communicated by Lambkin. A more detailed account, completing Fabry's report, was given by Boethke in his inaugural dissertation. Bergarth's results were less favourable, despite the fact that he injected larger doses than teachers had done previously. Atoxy- late of mercury failed especially in his cases of syphilis gravis and maligna. According to the experience of this author, atoxylate of mercury, in the doses which were formerly administered in syphilitic processes, did 36 THE CHEMOTHERAPY OF SYPHILIS not appear to have the effect of salicylic acid mercury. Neither could this author detect any kind of increased secondary effects. Zieler is said to have observed that patients, who were first treated with atoxy- late of mercury, and were then given grey oil, suffered less from the kidneys. IV. HECTINE. Mouneyrat called a '' benzolsulphonepara- minophenylarsenate of sodium," which he produced syntheticall}^ shortly '' hectine.'' This body is supposed to be more active than the other arsenic preparations, and less toxic than atoxyl. The injurious optical secondary effects are also supposed to be absent. According to Balzer and Mouneyrat, hectine is specially effective in the secondary period of syphilis, in the tertiary stage with gummata and ulcers, and in very obstinate cases, which require prolonged treatment. Hectine can be administered in a daily dose of 20 centigrammes, and continued for 37 THE THERAPY OF SYPHILIS about twenty to thirty days. From his experience, Hallopeau considers fifteen days' local treatment of the primary affec- tion, combined with about thirty days' general treatment, is sufficient to cure syphilis. Certainly this must be com- menced at once, if the presence of the S. pallida has been detected in any form of illness suspected of being a primary affec- tion. At the present time I am not aware that these statements of Hallopeau's have been further tested. According to the communications of Neisser, hectine is said also to induce optical disturbances. V. SOAMIN. At the end of 1907, an atoxylic preparation, '' soamin " (sodii ^-amino- phenylarsonas) was employed in England, which was supposed to be absolutely with- out toxic secondary effects. It was said to have a more constant arsenic content 38 THE CHEMOTHERAPY OF SYPHILIS than atoxyl, and was, therefore, capable of being administered with greater certainty than the inconstant atoxyl. So far, there are very few reports of the therapeutic application of this preparation in syphilis and other diseases ; in reality, it is not dis- tinguishable from atoxyl, and, like it, has given rise respectively to blindness and atrophy of the optic nerve in isolated cases (Lambkin, Pritchard, Johnston and others). As we have seen, the correct chemical constitution of atoxyl was first recognised by Paul Ehrlich, together with its thera- peutic application in trypanosome diseases. Starting from this, the purposeful and inde- fatigable effort of this researcher was to pre- vent '' the uncertain and doubtful action of atoxyl in trypanosome diseases by means of appropriate alterations of the arsenic- fast residue,'' and so ''procure a reliable arsenic drug of which there could be no doubt." In other words, Ehrlich set him- self the task of finding curative substances for the treatment of trypanosome diseases 39 THE THERAPY OF SYPHILIS in which the parasitotropic grou-^s — i.e., those which destroy the parasites — are increased, while, on the other hand, the organotropic, which have an injurious effect on the vital organs, are diminished as much as possible. The toxic organotropic action of atoxyl and of arsacetin was attributed by Ehrlich to the fact that these preparations contain a quinquevalent arsenical residue. By con- tinuously reducing this substance, Ehrlich was able to form the arsenic combination in such a way that a trivalent arsenic residue was substituted, and therefore, in his opinion, this new preparation must be less toxic and distinctly parasitotropic in its action. In this way, by means of chemical syn- thesis, Ehrlich, after numerous experiments, succeeded in obtaining VI. ARSENOPHENYLGLYCIN, a preparation, which appeared to possess in a high degree the characteristics Ehrlich had endeavoured to obtain, by means of 40 THE CHEMOTHERAPY OF SYPHILIS comprehensive experimental tests. In con- sequence of the strong parasitotropic action of this preparation, Ehrlich hoped to en- tirely destroy the parasites in experimentally induced trypanosome diseases, by means of a single adequate application [dosis efficiens tolerata), and to a certain extent to '' sterilise '' the organism. Ehrlich describes this new therapeutic procedure in the treatment of diseases of this kind, as Therapia sterilisans magna, in contradistinction to the usual gradual treat- ment with smaller doses, the administration of which was repeated at shorter intervals. The chemical constitution formula of arsenophenylglycin is as follows : As =^As I \/ \y NH NH CH2 CH2 COONa COONa 41 THE THERAPY OF SYPHILIS The preparation is represented by a yellow powder easily soluble in water. It can be preserved for some time in her- metically sealed vacuum tubes, whereas, when it comes in contact with the atmo- sphere, it gradually discolours, becomes a reddish-brown, and oxidises into a more toxic product. Uhlenhuth reported at the Colonial Con- gress (October 6, 1910) that, from the reports of Ulrich and Scherschmidt in Africa, it appeared that, in treating sleeping sickness with arsenophenylglycin, injurious effects had been observed in numerous cases, which were partly of a threatening nature. These consisted in cutaneous eruptions, paralyses, emaciation, and in some cases of epileptic attacks. The cutaneous eruptions, which covered the entire body, were very un- pleasant, and gave rise to the formation of vesicles and necrosis. Uhlenhuth stated that Scherschmidt reported as specially unfavourable the fact that, even after a single administration of i to 2 grammes of 42 THE CHEMOTHERAPY OF SYPHILIS arsenophenylglycin in quite fresh cases, emaciation and prostration were observed, and even death in some, a few days after the injection. Von Raven, who also observed toxic secondary effects, specially gave a warning against the employment of repeated small doses, as these are followed by hyper- sesthesia and phenomena of intoxication. For the rest, his results in the treatment of sleeping sickness were more favourable in Togo than they were in East Africa ; ob- viouslv, also, the course of this disease is much slighter in Togo. On the recommendation of Ehrlich, Alt for the first time administered this prepara- tion to patients suffering from mental disease, idiotcy, and epilepsy with a syphilitic foundation. He administered this prepara- tion in a single concentrated dose. In accordance with Ehrlich' s therapia magna sterilisans, instead of the customary gradual treatment which had been employed pre- viously, Alt firmly believed that he would 43 THE THERAPY OF SYPHILIS be able to testify to the specific action of arsenophenylglycin in these diseases. Conjointly with a rapid and durable improvement in a great number of cases, he perceived the disappearance, or at least the diminution, of the positive result of the Wassermann reaction. Further experiments of this kind, especi- ally in florid or tertiary syphilis, have not been undertaken with arsenophenylglycin, or have not been published. On the occasion of a post - graduate lecture, delivered during the winter term of 1909-10, Ehrlich first reported that he had found a new preparation, which in its chemotherapeutical action surpassed arsenophenylglycin. VII. DIOXYDIAMIDOARSENOBENZOL (EHRLICH- HATA, ''606"), like all the arsenic preparations already mentioned, belongs to the group of aromatic arsenic combinations. Ehrlich sent it to Professor Alt in September, 44 THE CHEMOTHERAPY OF SYPHILIS 1909, to be tested clinically. The extensive experiments on animals of his collaborator Hata had already proved its extraordinary efficacy in relapsing fever of mice and rats and in syphilis of rabbits. The Ehrlich-Hata preparation, ''606/' as it is now briefly called, has been produced by Dr. Bertheim, who has for years worked with Ehrlich. Its formula is as follows : As As /\ /\ I NHg V /NH2 = Dioxydiamido- QTT Qjj arsenobenzol. In Ehrlich's opinion, this must be regarded as the genuine destructive agent of the arsenic residue, while the side-groupings cause the primary anchoring of the para- sites. I. Experiments on Animals. Analogously with the experimental tests of atoxyl made by Uhlenhuth and his collaborators, Ehrlich and his co-worker Hata studied the effect of the new prepara- 45 THE THERAPY OF SYPHILIS tion on the spirilla of relapsing fever, spirillosis of fowls, and syphilis of rabbits, by means of observations on animals. Thus, from a large series of chemical preparations, Hata succeeded in finding the maximum spirillicide action in two substances produced by Bertheim — namely, in arsenophenylglycin, discussed on pp. 40 to 44, and in the one just mentioned, '' Ehrlich-Hata ' 606/ " Mice, infected with the spirilla of the relapsing fever, were cured by a single dose, which contained a third of the dosis maxima tolerata. According to the statements of Ehrlich, Hata obtained most excellent results with this preparation in spirillosis of fowls, 1-5 milligrammes per kilogramme of the animal's weight of this combination being sufficient to effect a cure. When transferred to man, this dose would only correspond to one of -^ gramme. When a dose of arsenobenzol is injected intramuscularly into fowls, infection only takes effect at the end of thirty to forty days, but after intravenous injection it 46 THE CHEMOTHERAPY OF SYPHILIS does so after three or four days. Hata was also able to obtain most brilliant results in syphilis of rabbits. The cure of very large chancres could be effected by means of a single dose. On the day following the injection, the spirilla, which before had been present in large quantities, had disappeared, and this was followed in the course of two to three weeks by complete cure with a smooth cicatrix. Tomasczewski was also able to testify to a good effect of arseno- benzol on the products of experimental syphilis in rabbits. At latest, thirty-six hours after the injection, and at the earliest, twelve hours after, the spirochaetes had disappeared. The symptoms began to re- trogress after ten to fourteen days. Neisser's curative results were less favour- able with apes in which syphilis had been experimentally induced. Out of twelve S3rphilitic apes, which had been treated intramuscularly with 0'025 per kilogramme weight, and intravenously with 0'0i5 per kilogramme, up to the time of publication 47 THE THERAPY OF SYPHILIS only three had been definitely cured ; two were probably cured, and the remaining seven at the present time must be regarded as uncured. Two apes were given an intramuscular injection of 0*025 P^^^ kilo- gramme eleven days after inoculation. Here the primary affection set in much later, and to a much slighter extent than in the control animals, which had been inoculated simultaneously, but not injected. Uhlenhuth and I, in the observations we made on animals in this direction, could not determine any special difference be- tween the effect of arsenobenzol, atoxyl, and atoxylate of mercury respectively. With the last preparation especially, the larger doses had precisely the same effect as arsenobenzol on the spirochaetes of spirillosis of fowls, and syphilis of ra;bbits, as well as on their clinical manifesta- tion. We were, however, able to prove the prophylactic power of an injection of arsenobenzol against infection with 48 THE CHEMOTHERAPY OF SYPHILIS spirillosis of fowls during a period extending over twenty-five days. Observations on animals have proved the superiority of ' ' 606 ' ' to other preparations in relapsing fever. If we again glance at the path which led Ehrlich and Hata to the discovery of this new syphilitic drug, we see that the start- ing-point was atoxyl, the spirillicide and specific anti-syphilitic action of which had been experimentally proved by Uhlenhuth. There can, therefore, be no doubt that the experimental foundation of the modern arsenic therapy of spirilloses was laid by Uhlenhuth and his co-workers. Uhlenhuth himself, when the toxic secondary effects of atoxyl became known, was one of the first to issue a warning against its general employment in the treatment of syphilis. In the firm conviction, however, that the organic arsenic compounds were called upon to play a great part in the therapy of syphilis, he, as well as Ehrlich, endeavoured to discover new, less toxic, modifications of atoxyl. 49 o THE THERAPY OF SYPHILIS The practitioner who wishes to success- fully employ the new remedy '' 606 " must be accurately instructed as to its action and secondary effects, mode of application and height of dosage. In the following pages, therefore, I shall attempt to sum- marise the most important points from the literature on the subject, which is already considerable. 2. Suspension of Solutions which are Prepared Ready for Use. The preparation ''Ehrlich-Hata '606'*' is a sulphur-yellow powder, hermetically sealed in a vacuum tube in correct doses. ^ It dissolves in hot water as double hydro- chloride salt, but Ehrlich states, and the experience of Alt, Schreiber, and Hoppe show, that it should not be injected in this condition, as it is liable to become toxic. By the addition of solution of caustic soda, ^ According to the most recent communications, it has been placed on the market under the name " Salvarsan," in doses of 0-6 gramme in hermetic- ally sealed glass tubes. 50 THE CHEMOTHERAPY OF SYPHILIS it can be transposed into mono- or di-sodium compound and dissolved. This solution, however, is not very stable, and must always be freshly prepared. Now, during the time required for testing this preparation clinically, the production of solutions which are ready for use has undergone the most varied changes and modifications. As no definite decision has yet been arrived at as to their relative value, I \\dll, as far as possible, give all the methods known up to the present time. [a) ALKALINE SOLUTIONS. I. Iversen's Method. — Iversen first in- jected a 0*5 to 2 per cent, aqueous solution of the preparation '' 606 " under the shoulder-blade or intramuscularly. He gave the following prescription for intra- venous injection : *' For this purpose I dissolve the sub- stance as for intramuscular application, in about 15 c.c. of aq. dest., add normal solution of caustic soda, drop by drop, THE THERAPY OF SYPHILIS until the sediment is dissolved, then neu- tralise the excess of caustic soda solution, drop by drop, with i per cent, acetic acid (about 2 c.c. of i per cent, solu- tion to 0-3 arsenobenzol), pour this to half a litre of physiological salt solution heated to 40° ; shake the bottle (infusion apparatus) moderately, and inject by means of a hollow needle direct into the cubital vein/' 2. Alt's Method. — The method origin- ally employed by A|lt for the suspension of solutions ready for intramuscular injections of arsenobenzol is the following : *' A single dose, 0*3 and about 10 c.c. sterile water, is poured into a low measuring glass of about 50 c.c. content and shaken. Sterile N solution of caustic soda is added, until only a slight residue of the substance remains undissolved ; for this 2*0 to 2*3 c.c. N solution of caustic soda is necessary. The cylinder is now filled with sterile water up to the stroke 20 c.c, sometimes after having added a sterile anaesthetic. With 52 THE CHEMOTHERAPY OF SYPHILIS a syringe containing lo c.c. of the solution the injection is made deep into the right and left gluteal muscles, while slowly pressing the knob." Alt still adheres to the plain alkaline solution, which is prepared solely by the careful addition of normal solution of caustic soda. After exact and compre- hensive experiments on animals and man, it has been proved to be the most effective and simultaneously the least injurious. Alt's recent instructions for the rapid suspension of a good alkaline solution are as follows : '* Put about thirty glass beads of medium size (similar to those used for filling pen- holders) into a slender graduated glass cylinder of about loo c.c. content, with a narrow neck and glass stopper. Add 10 c.c. of distilled water, and then the sub- stance. Shake energetically, and the whole will dissolve quite clearly. To every O'l gramme of substance add about 0*5 c.c. of normal solution of caustic soda, and then shake energetically for about half a minute. 53 THE THERAPY OF SYPHILIS A perfectly wine-clear, weakly alkaline solution has now been obtained, which can be further diluted at will by the addition of distilled water. As the preparation is not always equally soluble, a slightly greater or smaller quantity of solution of caustic soda may be necessary, in order to obtain the wine-clear suspension. This can be produced in the shortest time without any preliminary preparation, and is easily steri- lised ; it has the further advantage that only a small quantity of solution of caustic soda is required, and consequently less pain is caused.'* 3. Wechselmann's Method. — The fol- lowing is Wechselmann's report of this : '' At first I dissolved the dose of di-hydrochloride of diamidoarsenobenzol, which was hermetically sealed in a vacuum tube, with a little methyl alcohol or glycol ; to this about 10 c.c. of distilled water was added, then i to 2 c.c. y^ normal solu- tion of caustic soda; finally it was filled up to 25 c.c. with water, and this strong 54 THE CHEMOTHERAPY OF SYPHILIS acid solution injected. Later we added sufficient y^ solution of caustic soda to give a slight trace of opalescence, when the monohydrochloride was formed. We also employed the drug dissolved only in water or in a little fluid as above. We observed little difference herewith regard to the pain." 4. Ehrlich's Method. — Instructions, which Ehrlich himself gives for the sus- pension of clear solutions of his prepara- tion, run as follows (according to Schreiber and Hoppe) : Solution of " 606 '* 1 : 100 {Intramuscular Injection). — ''Dissolve 0*6 gramme of the substance in 3 c.c. glycol while stirring well with a glass rod ; the addition of a few drops of water will assist the solution. Now add 12 c.c. water, shake and dilute with 10*3 c.c. |-NaOH in one portion. On shaking, a clear solution is formed, which can be made up to 60 c.c. with water. ''It is advisable that this entire process should be carried out in a graduated cylinder." 55 THE THERAPY OF SYPHILIS Attenuated Solutions {for Intravenous In- jections). — Solution A: o-6 gramme of the substance, 0-3 to 0*5 c.c. methyl alcohol, or 3 c.c. glycol. Solution B : 240 or more c.c. physiological NaOH solution, 10-3 c.c. §-NaOH. While shaking well, solution A is poured into solution B. 5. The Method of Schreiber and HoppE. — '' A single dose 0*6 to 0*7 gramme and 0*5 methyl alcohol are placed in a mixing cylinder of 150 c.c. content. As soon as the substance is moistened, about 10 c.c. of sterile water is added and thor- oughly shaken. Then add sufficient sterile y — NaOH solution to almost entirely dis- solve the substance, so that after prolonged vigorous shaking only the slightest residue remains undissolved ; for this about 3^ to 4 c.c. of y — NaOH solution is required. Fill up to 60 c.c, and of this solution inject 30 c.c. through a fine cannula, under the most regular pressure possible, into the right gluteal muscle, and 30 c.c. into the left/' §6 THE CHEMOTHERAPY OF SYPHILIS For intravenous injection, the authors first of all used this solution without diluting it, but later they cautioned opera- tors against the employment of a concen- trated solution. The exact description of their suspension for intravenous injection is as follows : '' Into a graduated measuring cylinder of 250 c.c. capacity (with a glass stopper and narrow neck) put about 10 to 20 c.c. of sterile water. Then add the substance (0-3 gramme for women and 0*4 for men), and shake thoroughly until a clear solution is obtained. The addition of methyl alcohol is now no longer necessary, as the preparation in this present form ('' Hyperideal 606 ") dissolves easily in water. This solution is brought up to 100 c.c. with sterile water or physiological common salt solution. Then per O'l of the substance, add about 07 c.c. of normal NaOH solution, and shake well until the existing residue is thoroughly dis- solved. If after a good shaking the solu- tion is stiU opaque, a few drops of normal 57 THE THERAPY OF SYPHILIS NaOH are carefully added until the solu- tion is perfectly clear, and then this is filled up to 200 c.c. (of course, instead of 200 ex., it is possible to select either 150 c.c. or 250 c.c). For solution as well as for fining up, it is best to use warm water." {b) NEUTRAL EMULSIONS. I. Method of Leonor Michaelis. — '' A wide measuring cylinder of 50 c.c. capacity is filled with 25 c.c. of water, which has been boiled a short time before, and is still quite hot. Then add 0*6 gramme of the sub- stance, and dissolve by rubbing and stirring backwards and forwards with a glass rod. If the whole substance has been dissolved without leaving any residue, then 6 c.c. of normal (not /^) NaOH is added, and it is stirred until the precipitation which has resulted is entirely dissolved. Then 3 drops of a J per cent, alcoholic solution of phenolphthalein are added, and normal acetic acid, while stirring all the time, until the reaction is neutral — i.e., until the 58 THE CHEMOTHERAPY OF SYPHILIS phenolphthalem has lost its colour. The neutral suspension is now formed, the appearance of which is bright yellow. In order to definitely prevent the rise of an alkaline reaction, normal NaOH is again added, drop by drop, until the phenol- phthalein appears to be tinged very slightly red. This fluid is poured off into a flat sterile shell, and injected subcutaneously into the back." Later, Michaelis deviated somewhat from the above-described method, in that he moistened the solid preparation with i c.c. absolute ethyl alcohol in the measuring cylinder, and pricked through with the glass rod until the preparation was thoroughly wetted everywhere with the alcohol. The hot water was then poured on, and solu- tion rapidly obtained by simply stirring with the glass rod. 2. Method of Wechselmann and Lange. — Almost simultaneously with L. Michaelis, Wechselmann devised the follow- ing methods of suspension : 59 THE THERAPY OF SYPHLHS {a) '' 606 " is dissolved as before, a few drops of phenolphthalein solution, as an indicator, and xtt NaOH carefully added, until a fine yellow powder is again preci- pitated. This weakly acid or neutral suspension of 25 to 30 ex. is injected intramuscularly or subcutaneously into the gluteal region. (b) After rubbing " 606 " in a mortar, it is dissolved in i to 2 c.c. of commercial NaOH solution. By adding glacial acetic acid drop by drop, a fine yellow sediment is precipitated, which can be sterilely sus- pended with I to 2 c.c. of distilled water, and then neutralised by the addition of Y^ NaOH or i per cent, acetic acid most accurately with litmus-paper. The absence of pain depends upon the accuracy. The suspension is drawn into the syringe, and injected slowly subcutar^eously under the shoulder-blade, at a place which has been previously disinfected. 3. Spiethoff's Method. — By modify- ing the instructions laid down by Michaelis 60 THE CHEMOTHERAPY OF SYPHILIS for the preparation of an emulsion, it is possible, according to Spiethoff, to reduce the amount of the injection when using 0'6 gramme arsenobenzol from 9 to 10 c.c. 0'6 gramme of the substance is placed in a large centrifugal glass. To this is added a few c.c. of hot sterile physiological saline solution. It is shaken thoroughly and broken up with the glass pestle, with the addition of further hot physiological saline solution. For the preparation of a complete suspension, 8 c.c. of saline solution is adequate. Then add 2 drops of phenol- phthalein and about 3 drops of concen- trated NaOH solution. A few rough reddish flakes will form, which on stirring become more and more numerous and finer, until finally a pulpy mass appears, which becomes a fine emulsion with further stirring and occasionally warming the glass in hot water. Add a few drops of concen- trated NaOH until a light reddish colour appears, when a few drops of strong acetic acid solution must be added, till the red 61 THE THERAPY OF SYPHILIS colour again disappears. The excess of alkali is again removed at the bedside immediately before the injection itself, by means of a few drops of normal NaOH. Any residue left in the glass is washed out by I ex. of sterile distilled water. In this way, one can reduce the volume required for the injection of 0-6 gramme to about 9 or lo c.c, which has the result of diminishing the pain." 4. Method of Blaschko. — According to Blaschko, one should only add just suffi- cient soda to again precipitate the base out of the salt. '' The amount can be deter- mined just as well by calculation as by rubbing. For 0*5 gramme of the salt it requires 0*45 gramme = 0*36 of a 20 per cent. NaOH; for 0*45 gramme of the preparation, 0*41 gramme = 0*33 c.c. NaOH; for o*o6 gramme of the precipitation, 0*55 gramme =0*45 solution of caustic soda. If the soda is added carefully, and a little sterile water, it is possible to at once pro- duce a neutral suspension, or at most one 62 THE CHEMOTHERAPY OF SYPHILIS that requires one or two drops of weak acetic acid or, better still, hydrochloric acid. If the emulsion is then filled up to 8 or 9 ex., we have a physiological com- mon salt solution of 0*82 to 075 per cent, which contains a suspension of the base. It is sufficient, however, if it is filled up to 5 ex., for a saline solution of 1-3 per cent, is not so hypertonic that it is painful in any way." 5. Method of H. Citron and the Author. — Starting from the fact that all manipulations for the suspension of ready- prepared solutions of arsenobenzol already described, are associated with certain details which may appear undesirable for the busy medical man, and more especially because the possibility of chemical changes in the very subtle preparation may render sterile work difficult, we have devised the follow- method : '' The necessary amount of Hat a powder for injection is shaken into a sterile Record sjnringe of 15 c.c. capacity, which is closed 63 THE THERAPY OF SYPHILIS with a cone at one end of the cannula, and moistened with a few drops of alcohol. The stopper has been previously removed. The syringe is filled up to mark 5 with hot distilled water, the stopper readjusted, the ligature ring put on, and thoroughly shaken. A clear golden- yellow solution results. The stopper is now taken out again, and 40 drops of a 10 per cent, sus- pension of calcium carbonate in physio- logical NaCl solution added slowly while shaking continuously. By removing the cone, a little carbonic acid is allowed to escape from time to time. A creamy, extremely fine emulsion is formed, some- what of the appearance and consistency of egg brandy. The addition of 40 drops of the 10 per cent, calcium carbonate sus- pension is found from experience to be suffi- cient for the complete precipitation of the base. As we have been able to convince ourselves by centrifugalisation, the fluid decanted is entirely without colour. In contradistinction to the old methods of 64 THE CHEMOTHERAPY OF SYPHILIS suspension, a small excess of the precipi- tate is without importance. The resulting amount injected consists of about 5 to 6*5 ex., but we have no doubt that one could make smaller quantities suffice. After the precipitation is finished, the stopper is screwed on, and a cannula appended, which is not too fine. We select the upper external quadrant of the gluteal region ex- clusively as the seat of injection." The 10 per cent, calcium carbonate sus- pension is sterilised by placing it in a drop- glass, which is closed by a wadding plug, and sterilised in the autoclave. {c) kromayer's paraffin emulsion. Kromayer employs the preparation *' 606 " in the form in which it is sent — viz., as a dichlorate — by making an emul- sion with paraffin, analogous to a mer- curial paraffin emulsion, which he prepares as follows : '' A certain amount of Ehrlich's ' 606 ' — for example, 3 grammes — is mixed with 65 E THE THERAPY OF SYPHILIS a little liquid paraffin in a sterile mortar, and is carefully rubbed very fine, while more paraffin is gradually added. It is put in a sterile bottle, of 50 c.c. capacity, with a glass stopper, and is filled up to 30 c.c, so that each c.c. of the emulsion contains o-i gramme of Ehrlich's '' 606." It must be shaken before using until all sedi- ment has disappeared and be protected from light. On account of the fear of the cannulas becoming blocked, they should be selected somewhat stronger than those used for Hg salicylic injections, and it is best to keep them in Petri saucers, covered with liquid paraffin. In this case, it is no more necessary to sterilise the cannula each time before using than it is in Hg injections. The injections with ''606'' are made exactly in the same way as the former, and ambulant patients can also be treated.'' These are the principal methods which have been proposed and clinically tested by many authors up to the present for the purpose of making the new Ehrlich 66 THE CHEMOTHERAPY OF SYPHILIS preparation '' 606 " ready for use. Still further small alterations of these methods have been proposed by various authors. Thus, Loeb adds i to 3 c.c. i per cent, acetic acid to the alkaline solution^ as, in his experience, the pain of the alkaline solution is thus considerably diminished. The fact that this solution is less painful is obviously due to the solution of caustic soda being partially neutralised, which is evidenced by the gelatinous-nuclear pre- cipitation. Saalfeld, Frankel, and Grouven only add i to i| c.c. of ^u NaOH solu- tion to the hydrochloric solution, which certainly does not intrinsically influence the acid reaction. Junkermann does not employ normal NaOH solution for the purpose of alkalisation, but, instead, the strong official 15 per cent, solution of caustic soda. Passini prepares a neutral or very weakly acid emulsion by means of NaOH and glacial vinegar in the usual way, and then rubs this mass carefully with a mixture of 67 THE THERAPY OF SYPHILIS adeps lanae anhydricum and vaseline oil in equal parts. Nearly all these methods for the prepara- tion of ready-tO"Use solutions have been found to be equally good in animal experi- ment and by the sick-bed. According to Hata's observations on animals^ the pre- paration is quickly secreted when injected intravenously, whereas, when administered subcutaneously and intramuscularly, it re- mains deposited in the body a long time, and develops a prolonged action. With regard to the rapidity of the disappearance of the spirochaetes from the syphilitic diseased tissue, Spiethoff was unable to discern any difference between the effect of the solution and that of the emul- sion. Nevertheless, from the researches of various authors (A. Neisser and others), the action of neutral emulsions appears to be slower, but more persistent. Alt, Schreiber, Hoppe, and others, attributed a more rapid, but at the same time less lasting, effect to the intravenous incorpora- 68 THE CHEMOTHERAPY OF SYPHILIS tion of the preparation. For this reason, Iversen combined this mode of appUca- tion with intramuscular injection — a method which is also recommended by Ehrlich — in such a way that he first injected a little over half (0-4 to 0-5 gramme) the dose of arsenobenzol intravenously, and at the end of forty-eight hours injected the remainder (0-3 to 0*4 gramme) intra- muscularly. Wechselmann, L. Michaelis, Herxheimer, Sieskind, and others, as a rule prefer to make a subcutaneous injection in the interscapular region or between the shoulder-blades, whereas the majority of teachers like an intramuscular injection deep in the gluteal region. In the experience of Alt, the incorpora- tion of acid solutions, as already men- tioned, is apparently not innocuous, and even in small doses they may have an un- favourable effect upon the heart's action. Even Ehrlich himself, as well as Junker- mann and others, suspects that the prepara- tion as dichlorohydrate may have an irri- 69 THE THERAPY OF SYPHILIS tant and occasionally a toxic action on the tissue. This suspicion would also apply to Kromayer's paraffin emulsion, in which, further, the bad absorptive capacity must be taken into consideration. If these sus- picions, however, are got rid of, as Kro- mayer has reported^ after extensive clinical application and observation, then the par- affin or vaseline oil emulsion he recom- mends may possibly be used for injection and for the practical employment of the preparation. Meirowsky, however, could not confirm Kromayer's assertions that this method of injection only caused slight pain. Further, he fears the possibility of the great quantity of parafhn injected favouring embolism, a circumstance which he verified in an observation of his own. Similarly, the method which Citron and I worked out should be recommended for medical practice, as the ready-prepared solution, which guarantees the smallest imaginable chemical changes, is absolutely sterile and perfectly neutral, and conse- 70 THE CHEMOTHERAPY OF SYPHILIS quently fairly painless in itself. The momentary action of this emulsion is apparently like that of others, but whether the conditions of absorption are also the same can only be determined after a larger number of cases have been treated with it. Still, one may assume that these would certainly not be more unfavourable than with Kromayer's paraffin emulsion, de- scribed above. As regards the 3. Technique of Injection, the following points are worthy of observa- tion, from experience gained up to the present : {a) INTRAMUSCULAR INJECTION. This is made in the muscles of the gluteal region, as in the intramuscular application of mercurial preparations. It is best for the patient to lie on his abdomen when on the operating- table. The gluteal region is disinfected in the usual way 71 THE THERAPY OF SYPHILIS (according to Fiirbringer, with tincture of iodine or iodine benzine), and the puncture is made in the upper external quadrant. In order to remain as far as possible from the sciatic nerve, and so avoid more in- tense pain, Junkermann advises that the injection should be made at the height of the connecting line of the spinae iliacae anteriores superiores, and the cannula in- serted slowly into the gluteal region in a sagittal direction, and as far laterally as possible. This is done in order to avoid piercing the larger vessels of the gluteal region. When employing solutions of the preparation, the injection can follow at once with the usual cannula. Air bubbles must obviously be prevented. When in- jecting emulsions, it is better to employ somewhat larger needles, and, as in insoluble mercurial preparations, remove them from the syringe before the inj ection, in order to convince oneself that no vessel has been pierced (Lesser's handle should be used). The injection itself is always made extremely 72 THE CHEMOTHERAPY OF SYPHILIS slowly, in order to avoid tearing the tissue as much as possible (Kromayer) . If neutral emulsions are injected, then the relatively small amount required can be syringed into one side of the gluteal region. It is best to select the side on which the patient as a rule does not sleep (Spiethoff and others) . It is advisable that the patient should remain lying on his abdomen for a little time longer. After the seat of injection has been fastened with a sterile plug, covered with a wide piece of sticking- plaster, the region should be vigorously massaged for about half an hour. Vibra- tory massage may also be applied as after a mercurial injection. {b) SUBCUTANEOUS INJECTION. This is recommended chiefly by Wech- selmann and Lange, L. Michaelis and Kromayer. The patient, according to L. Michaelis, is placed in a completely perpendicular position, and the cannula in- serted in the region between the shoulder- 73 THE THERAPY OF SYPHILIS blades. *' After emptying the syringe, the dispersion of the injected mass follows, which is the most important part of the entire procedure. The patient is seated transversely on the bed in an upright position, and then, by means of careful massage, the ball of fluid is spread over the greatest possible surface, so that no further protuberances are visible. Then a moist dressing is applied to the back, and the patient put to bed.'' Michaelis now makes the injections somewhat deeper into the dorsal muscles ; he no longer injects quite at the back, but instead laterally and under the thorax. Wechselmann and his collaborators (Lange and Sieskind) make the subcutaneous injection in the right interscapular region. Blaschko injects into the subcutaneous tissue of the nates, and considers that in this way, with hardly perceptible infiltra- tion, all functional disturbances are avoided. Moreover, in order that the conditions of absorption may be more favourable, he 74 THE CHEMOTHERAPY OF SYPHILIS spreads the dose injected over various places in smaller quantities. Larger '' Record '' syringes are most suitable for both intravenous and intra- muscular injections. (c) INTRAVENOUS INJECTION. An accurate description of the intra- venous injection is given by E. Schreiber, which I will quote here in his own words : '' The solution (see p. 57) is then put into a sterile measuring glass, from which it can be easily sucked up with the syringe. '' The syringe we now employ is a simple Liier one. The cannula is bayonet-shaped, bent, and has a lateral attachment-piece with a three-way stopcock, so that not only can the fluid be drawn up, but after the tap is turned it can be injected into the vein. Further, the cannula has also a small plate bent at right angles at the first joint, for the purpose of fixing the syringe better. It is now made to screw off, so that it can be easily changed. 75 THE THERAPY OF SYPHILIS '* It is very important that the cannula should rest properly in the vein, and that on puncturing no further injury should be done, which may easily happen with the cannula if the syringe is too long ; there- fore, I only have the syringe obtusely bevelled. In order to be absolutely cer- tain, we use a short handle, which I can thoroughly recommend, especially to those who are making the injection for the first time. '' We first fill the syringe with physio- logical saline solution ; then, with the tap open, pierce into the vein, and while the ligature is still in position, make the injection, only syringing in the saline solution after blood has poured in dis- tinctly. Now, if the cannula does not rest completely in the vein, or this has been injured in any way by the puncture, in- filtration will at once resujlt on injecting the saline solution. If this occurs, we withdraw the cannula from the vein and try to find another better position. In every 76 THE CHEMOTHERAPY OF SYPHILIS case care must be taken to prevent any of the solution getting under the skin in the subsequent injection ^ because this causes unpleasant infiltrations. In some instances these are very painful and per- sist for weekSj although later^ without exception J they recover well. Consequently, we, as a rule, select a vein which lies out- side the elbow-joint, so that, in the event of such infiltrations, movement is not in- terfered with. Similarly, when the whole of the solution has been injected, we again syringe out the vein with saline solution, in order to avoid any irritant action upon the lower parts of the vein. If, during the injection of the solution, the cannula should be withdrawn from the vein, or have injured it, then a protuberance will at once appear on injecting, and the patient will at the same moment complain of a burn- ing feeling. The syringe should be at once withdrawn, the ligature replaced, and a reasonable amount of bleeding allowed, because we have found that this is the best n THE THERAPY OF SYPHILIS way to avoid infiltration. If technically the injection has been a complete success, the patient will have no pain apart from the small punctm*e/' Besides the intravenous injections with a cannula provided with a tap and syringe, described by Schreiber, an infusion into the vein through rubber tubing and a funnel (Weintraub) has been practised successfully. Assmy has brought out a small set of instruments for this purpose, with which it is possible to give an intra- venous injection without any assistance ; this could hardly be done with the Schreiber method. Another advantage of the Assmy set of instruments over those of Schreiber is their cheapness and greater durability. On a stand about I millimetre high (volumetric stand) two funnels are fastened for the reception of the '' 606 '' and saline solutions respectively ; two tubes start from them. These are united by a two-way stopcock (Posner's catheter tap) ; on its attachment a thin 78 THE CHEMOTHERAPY OF SYPHILIS rubber tubing, about 12 c.c. long, is fixed, which has a metal cone at the end for the reception of the cannula. The latter cor- responds in form to the Strauss cannula, as it is generally applied for the removal of blood for the Wassermann reaction, only, naturally, it is thinner, shorter, and its end is bevelled off obtusely in the same way as the Schreiber stopcock cannula. The arrangement of the rubber tubing between the cannula and stopcock makes it possible to carry out all possible manipu- lations with the latter without the cannula, which is resting in the vein, participating in the movements thus caused. This is a great advantage, as with the Schreiber method the danger of injuring the walls of a vein naturally persists during the entire interference. In consequence of the long lever which is formed by the syringe and the stopcock cannula, even the slightest movements, such as cannot possibly be avoided in the individual phases of the injection, are unpleasantly perceived in 79 THE THERAPY OF SYPHILIS an exaggerated form on the syringe cannula. Assmy, who has carried out numerous intravenous manipulations in both ways, states that the infusion method is incom- parably easier, and demands less expertness than the Schreiber injection technique. Whereas Ehrlich, even in his book^ (p. 152), recommended the intramuscular injection, and attributed a more persistent and intense action to it, in a circular letter of October 25, 1910, he advises that, in the further treatment of syphilis with his preparation, the intravenous injection should be employed whenever possible. From the standpoint of guaranteeing a permanent result, Ehrlich now considers that the following are most effective : 1. The intravenous injection of alkaline highly attenuated solution. 2. The intramuscular injection of alka- line solution. ^ '' The Experimental Chemotherapy of Spirilloses " (Rebman Limited, 1911). 80 THE CHEMOTHERAPY OF SYPHILIS 3. The strongly irritant acid solutions (mono-dichlorhydrate) . 4. Finally, the so-called neutral emul- sions (intramuscularly and subcutaneously) . 4. Direct Local Secondary Effects of THE Injection. Whereas with correct technique no local secondary effects are attached to the intra- venous injection, various local disturbances are evident with the intramuscular and subcutaneous application of the Ehrlich preparation. These are induced partly by the kind of solution, partly as the result of pressure of the greater or smaller quantity of the substance injected. These local secondary effects are most intense and unpleasant with the injection of alkaline solutions, especially when larger quantities of fluid are employed, as was done almost always at the beginning. These secondary effects appear first of all as pain in the buttocks. When alkaline 81 F THE THERAPY OF SYPHILIS solutions are employed, the pain generally sets in during the injection, and increases in intensity within the following hours. Consequently, it is advised that the in- jection should be made in the morning, so as to interfere as little as possible with the patient's night's rest. As already mentioned, the pain increases the following day. It is of a boring character, something like toothache, and, further, there is generally a feeling of pressure in the gluteal region, which mean- while has become as hard as board, in- filtrated, and diffusely swollen. This pain affects the patients most when walking, sitting, and lying down. Very often the tension makes it almost impossible to move the thigh. Moreover, the pain may be localised in the region of the os coccyx (Spatz). With the intramuscular injection of neutral emulsions, the pain as a rule only begins on the following day, attaining its highest point on the second or third day, during which time, under symptoms 8« THE CHEMOTHERAPY OF SYPHILIS of regular fever, a fairly circumscript, hard infiltration has been formed, the size of which varies with the larger or smaller amount of emulsion Vv^hich has been in- jected. The sensation of pressure here is markedly less severe than with alkaline solutions, and the pain is no longer felt as a boring one, but, instead, as a dull, painful pressure. Latterly, various authors have observed severe necrosis extending up to the bone at the seat of puncture, in intramuscular as wel] as subcutaneous ad- ministration. Thus Dreuw in two cases observed necrosis of the gluteal muscles, almost the size of a small fist, and in another case there were two necroses the size of hazel nuts in the back. Bayet saw eight severe gangrenous affections in eight patients, which were in part connected with necrosis of the bone at the seat of injection. The greater percentage of patients are supposed to tolerate the injection excel- lently and without reaction in cases of subcutaneous application (Sieskind, L 83 THE THERAPY OF SYPHILIS Michaelis, Kromayer, and others). Accord- ing to Sieskind, however, with the subcu- taneous method also reaction phenomena were observed in about lo per cent, of the cases. The occasional infiltration only sets in here after three or four days. It was frequently possible to determine a fluctuation in the infiltration, which, how- ever, in Sieskind's opinion, owed its origin to a serous fluid, as was proved by the exploratory puncture. Out of 275 cases, Sieskind only five times observed genuine suppuration. The pus was sterile in all five cases. '' Quite small necroses at the seat of puncture are not rare, which is not surprising when one considers the inflammatory and necrotic effect of arsenic preparations. The small necroses healed by granulation.'' Two patients had ne- croses as large as two-shilling pieces ex- tending to the muscle. According to Sieskind's observations, necrosis always sets in if any of the preparation has been left behind in the puncture canal. 84 THE CHEMOTHERAPY OF SYPHILIS The very unpleasant irritation of the sciatic nerve may be regarded as a direct effect of this infiltration, and this may make itself evident in neuralgic pains, which extend right down to the calf of the leg. In cases in which there is a pronounced inclination to sciatic troubles, or in which sciatica exists, an intramuscular injection should be avoided, as this pain, as I my- self saw in one case, is increased thereby, or may again break out. In order to prevent — or at least diminish — the pain of injection, which under some circumstances may be very considerable, not only with neurasthenics, but also with healthy, robust persons, it was at first recommended from various sources that an anaesthetic should be added to the injection fluid. Thus, Alt advised the addition of an ampulla of eusemin. Wech- selmann renders the seat of injection anaes- thetic by means of a preliminary injection of 0*02 novocain ; others, again, add cocaine, alypin, or morphia. But the transitory S5 THE THERAPY OF SYPHILIS nature of all these precautions made them no protection against subsequent pain. Apparently the best prophylactic, as already mentioned, is to neutralise the liquid as accurately as possible, and to massage the seat of injection immediately after the operation. Good service is rendered by permanent bandages moistened with acetic acid. Fuller's earth, or spirit, as a pro- tection against the pain of pressure. Further, the usual narcotics, such as opium, are best here as suppositories and hypnotics. 5. Effect of Arsenobenzol on the Organism in General. As far as the influence of the preparation concerns assimilation, Hoppe was able to testify to a favourable effect on the lecithin assimilation. With most patients, a few days after the injection fairly considerable leucocytosis sets in. A. Neisser also saw very pronounced hyperleucocytosis (up to 86 THE CHEMOTHERAPY OF SYPHILIS 38,000), the dissonance of which occurred slowly. Brandle and Clingestein obtained almost the same result (up to 15,000), whereas in isolated cases Lange only saw a slight increase of leucocytes. Klausner and Bardachzi noticed great variations in the number of red blood- corpuscles after an injection of arseno- benzol, generally during the first eight to twelve hours, accompanied by the appear- ance of urobilinuria ; the latter again dis- appeared usually after twenty-four hours. Alt states that in intravenous injection the secretion of arsenic is almost com- pleted at the end of two days, and on the third day only traces are found. '' Within this period, one can detect nearly the whole of the arsenic in the faeces and urine, apart from small quantities which are lost through perspiration, the skin, hair, etc.*' In in- tramuscular injections the secretion of arsenic lasts at least twelve to thirteen days (Treupel and others), whereas in intravenous injections it has already ter- 87 THE THERAPY OF SYPHILIS minated at the end of four days (Hoppe). A methaemoglobin formation, such as might be expected in an intravenous injection, Heuber says does not take place, even with the strongest concentration. W. Fischer, on the other hand, reports that, according to the researches of Pro- fessor Loeb (Chemical Institute of the Rudolph Virchow Hospital), in three cases the presence of arsenic was discovered in the urine, although in some of them only in small quantities — in the first case, eleven and thirteen weeks after the subcutaneous dose of 0*15 gramme; in the second, eight and ten weeks after ; and in the third case, seven to eight weeks after the injection. Fischer concludes from this that arsenic may still be circulating in the body almost three months after the injection. Nearly all teachers agree that an in- jection of arsenobenzol has a very good effect on the patient's general condition, which is frequently evidenced first of all by considerable increase in weight. Ac- 88 THE CHEMOTHERAPY OF SYPHILIS cording to Wechselmann, many patients feel ''as if they wanted to drag up trees." He and other authors have even been able to testify to increased potency. As I have already stated above, it has been possible to observe these specific arsenic effects with atoxyl and atoxylate of mercury. True, other authors have also reported marked emaciation. 6. Effect of Arsenobenzol on Syphi- litic Diseases of the Primary, Secondary, and Tertiary Periods. The first reports of the effect of arseno- benzol on syphilitic diseased tissues were made by Professor Conrad Alt, of Ucht- springe, on the occasion of a lecture de- livered before the Magdeburg Medical Society in March, 1910. From January 31, 1910, up to the time of publication, in common with Dr. Schreiber at the Magde- burg Old Town Hospital, Alt had treated twenty-seven cases of florid syphilis by 89 THE THERAPY OF SYPHILIS means of a single injection of 0*3 gramme of the new preparation, '' and has had quite startling results to report/' Alt briefly summarises the facts as follows : '' The initial sores showed marked diminution at the end of a few days ; the indurating action was also reduced ; the maculo- papulous eruptions, which were partly of a moist and ulcerating character, had be- come paler in colour or had dried up, and then healed, leaving behind fiat pigment flakes. Ulcerations on the labia healed quite smoothly within a few days. Large, swollen papules on the anus and vagina lost colour and flattened very soon, and in a few specially severe cases disappeared with- out leaving a trace behind after four weeks' treatment. Further, a very large, obstinate tertiary ulcer on the thigh is now almost completely cicatrised after hardly three weeks' treatment. The numerous cases of specific angina with difficult coatings, which are generally very obstinate, were reduced most rapidly.'* 90 THE CHEMOTHERAPY OF SYPHILIS According to the first reports of Wechsel- mann, even with the most sceptical criti- cism there could no longer be any doubt as to the rapid and fundamental action of the new drug on the symptoms of syphilis in all their infectious forms, in a way that had been impossible with any previously known remedy. " The curative effects are so rapid that the patients cannot be ex- hibited, because generally after a few days there is nothing more to demonstrate, and they leave the hospital/' Unfortunately, the great expectations were only partly fulfilled, which were antici- pated for this drug, as the result of the first enthusiastic and favourable reports of Alt, Wechselmann, and others. The longer the observation period of the cases treated lasted, and the more teachers received arsenobenzol for the treatment of syphilis, the more was it recognised that this new arsenic preparation of Ehrlich's, although it is true it developed a very good therapeutic action on manifest syphili- 91 THE THERAPY OF SYPHILIS tic symptoms in most cases, did not effect a complete cure of syphilis in the sense Ehrlich anticipated, and certainly this cannot be obtained. If we group together the opinions of the teachers who have been able to work v/ith this preparation, and the results of their experience with it, reported up to the present,^ regarding the therapeutic effect of arsenobenzol on the forms of disease of the various syphilitic periods, the result is as follows : {a) PRIMARY AFFECTIONS. As we have already seen, Alt states that the primary sores were markedly reduced within a short time, the indurations dis- appearing after a few days. With one patient, who was injected by Wechsel- mann on July i8, 1910, for about twenty roseola specks on the trunk, and a greasy crusted erosive chancre on the penis, the chancre was already clean by the follow- ^ Up to the beginning of December, 1910. 92 THE CHEMOTHERAPY OF SYPHILIS ing day, almost without induration, and on June 22, it was closed down to a residue the size of a lentil. With the same patient, a destructive deep-seated primary affec- tion, the size of a five-shilling piece, situated in the lower lip, together with a maxillary bubo the size of a goose's egg, had been anointed in May, at first without an}^ great effect. On Ma\^ 20, 0-4 gramme of ''Ehrlich-Hata" was injected intramus- cularly. On June 2, the ulcer was flat, the size of a penny, and the gland was quite small and almost healed on June 8. In cartilaginous primary forms, in the experi- ence of Wechselmann, Miekley, and others, the cleansing process proceeds very rapidly, but the complete cure lasts longer, corre- sponding to the absorption of the tissue proliferation. According to Dorr, Ivensen, Juliusberg, Schreiber, and Zeissl, the phenomena of the primary affection are rapidly reduced, generally more quickly than with Hg. Neisser has seen the rapid disappearance of the primary symptom^s in 93 THE THERAPY OF SYPHILIS many cases, and, further, the curative results of ChrzeHtzer, Miekley, Bethmann, and others were surprising in this direction. Spatz stated that ulcerous primary forms were skinned over and softened within six days. Geronne and Huggenberg reported that ten ulcera dura, the size of sixpences, had closed up within ten to fourteen days. According to Solomon, also, the average cure of the primary affection, when treated with '' 606,'' was effected in a similar period. Herxheimer considers that the primary affection requires on an average eight to fourteen days to disappear. In four cases, however, the indurations remained almost unchanged during the iirs''' three weeks. Grouven and Frankel saw the primary affection frequently recede within a few days. Pinkus considered that, on an average, nine days was required for this. Iversen, however, reported that primary sclerosis and glandular swellings persisted the longest in consequence of the anatomical conditions, but then became softer, and 94 THE CHEMOTHERAPY OF SYPHILIS gradually melted away. Their complete disappearance would certainly be effected within three to four weeks. Spiethoff saw primary syphilis completely epithelialised within one to three weeks. Phimoses, which had appeared as the result of primary affection, receded altogether without any local treatment in about three weeks with a dose of 0-3 gramme, and after six days with one of 0'6 gramme. L. Michaelis similarly considers that an injection of '' 606 " is quite sufficient to cure primary syphilis, without any local treatment, with- in one to three weeks. Jadassohn also saw a very rapid and prompt result ob- tained on the primary affection with arseno- benzol. In Welander's experience, the primary affection skins over very rapidly, but induration persists for a long time. Geronne later came to a similar conclusion. Gennerich also was able to testify to severe sclerosis in several cases even after three or four weeks, whereas superficial primary forms only slightly indurated were often 95 THE THERAPY OF SYPHILIS skinned over and softened two to three days after the injection. Rille found that the shortest time required for heahng the primary affection was seven days, the longest twenty-four. Pick frequently ob- served rapid epithelialisation of exulcerated scleroses. Schulz reported that primary forms healed on an average within five to eight days after the injection. Halber- stadter also considers that here there is generally a prompt and rapid retrogression. According to Duhot, the chancre disap- pears within three to thirteen days, having regard to whether it is indurated or not. The experience of Halberstadter, Deneke, and Schindler, with scleroses of the lips, was that these were influenced relatively slowly, or not at all, by the new prepara- tion. Less favourable results of the effect of arsenobenzol on primary syphilis, despite higher doses (0*5 to 07 gramme), were re- corded by Stern, who was obliged to have recourse to local treatment with calomel. 96 THE CHEMOTHERAPY OF SYPHILIS Sclerosis of the portio appears to be most obstinate in resisting the curative effect- In nine such cases, the average duration of the heahng process, according to Gliick, was eighteen days. The observation of Sieskind is interesting, that after the dis- appearance of the scleroses in the treat- ment of chancres mixtes, ulcers of the character of tdacs molle still remain behind, which are uninfluenced bv arsenobenzol. Now, how does the case stand with regionary syphilitic lymphatic glandular swellings, which are known to appear a short time after the primary affection, and even before the outbreak of the general phenomena ? From my experience, and that of most other authors (Blumen- feld, Schulz, von Zeissl), these are in part very favourably influenced therapeutically by the new preparation. Blumenfeld re- cords a case of strumous bubo, which diminished within eight days to about a fifth of its original size. True, it is but seldom that it disappears altogether. 97 G THE THERAPY OF SYPHILIS Pinkus states that a diminution of the regionary lymphatic glands can regularly be observed, but without these disappearing completely. In most cases lymphatic cords and smaller lymphatic glandular swellings are left behind (Geronne and Huggenberg). In Miekley's experience, on the other hand, these glands only recede very gradually ; apparently they are the slowest to be in- fluenced of all the diseased tissues. {b) EARLY STAGE OF SECONDARY SYPHILIS. It appears from the results and opinions of most teachers, that the most favourable influence of arsenobenzol is obtained upon the phenomena of the secondary stage of syphilitic diseased tissues of the mucous membranes. Spiethoff saw mucous plaques completely disappear two to three days after the injection. According to the statements of G6ronne and Huggenberg, in specific angina the plaques healed within seven to ten days. Isaac also observed 98 THE CHEMOTHERAPY OF SYPHILIS similarly rapid healing of plaques and condylomata of the mucous membrane. Severe erosive and papulous diseases of the mucous membrane reacted specially sympathetically, while a previous mercurial treatment had remained without result (Grouven and Frankel). It appears from Miekley's communications that the coat- ings on the tonsils melt away during the first days following the injection, so that this may be compared to the effect of Behring's serum on diphtheritic surfaces. The splitting and moderate hyperplasia of the tonsils remaining soon disappear. Frequently on the eighth day after in- jection the angina is perfectly cured. Ac- cording to the observations of Gliick, it is only the redness of the pharyngeal organs which persists so long, while the plaques on the tongue, tonsils, and soft palate have disappeared at latest five days after the injection. In specific hoarseness the voice has cleared three to eight days after the injection (Blumenfeld, Gliick, and others). 99 THE THERAPY OF SYPHILIS The effect of the injection of arseno- benzol was equally rapid in simple macu- lated exanthemata (Wechselmann, L. Michaelis, Kromayer, Spiethoff, Spatz, Gennerich, Dennecke, Rille) ; they generally disappeared within the course of a few days (Brandle and Clingestein, and others). Miekley alone testified to the surprisingly slow softening of the roseola, pigment of which was often visible several weeks after the injection, with simultaneously per- sisting hyperplasia. Sieskind confirmed this statement in the case of roseola urticata. Papulous and pustulous syphilides dis- appeared rapidly and dried up (Spiethoff, Dorr, Iversen, Miekley). In papulous ex- anthema as a rule a slight pigmentation is left behind (Chrzelitzer and others). A papulous crustaceous exanthema had dried up completely at the end of two days after 0'6 gramme, and the crusts had fallen off (Spiethoff). According to Sies- kind, it is only the micropapulous and 100 THE CHEMOTHERAPY OF SYPHILIS lichenoid exanthemata respectively which respond to a certain extent favourably to arsenobenzol ; whereas one can assert of the large papulous syphilides that they appear to be refractory to "606." Ulcer- ous syphilides also, and even rupice syphiliticcB, can be rapidly cured (Isaac, Brandenburg, Juliusberg). Moist papules dry up and flatten out, often in a short time (Spatz, Geronne and Huggenberg, Miekley), but still they may persist for a fairly long time (Welander, Schreiber, Ledermann) . Condylomata form new skin visibly, and often disappear with almost miraculous rapidity (Grouven and Frankel) . An excellent therapeutic effect has been obtained with arsenobenzol, according to Volk and Lipschiitz, in renitent syphilitic paronychia. Psoriasis palmaris and plan- taris had disappeared at the end of ten days (Geronne and Huggenberg, Saalfeld), but Bruhns stated that several cases of specific psoriasis had been very obstinate. Wechselmann once saw a leucoderma colli lOI THE THERAPY OF SYPHILIS disappear within a few days, while the white places healed up. In contradistinc- tion to this, there are the observations of Volk and Lipschiitz, among others, that leucoderma especially remained uninflu- enced by " Ehrlich-Hata/' Generalised lymphadenitis, as well as isolated glands in the secondary stage, may disappear within the course of a few days (Dorr, Spiethoff, Sieskind), or at least show a marked inclination to recede (Hoff- mann, Grouven, and Frankel). On the other hand, in the experience gained at the Lesser Clinique, it is especially the glands in the secondary stage which are longest in reacting to the influence, as already mentioned. A haemorrhagic exanthema of the leg re- ceded at the end of eighteen days ; a severe impetiginous syphilide under the hair of the head, and one on the back, disappeared after sixteen and twenty-one days respec- tively (Geronne and Huggenberg). Headache, the appearance of which is 102 THE CHEMOTHERAPY OF SYPHILIS specially characteristic of secondar}^ syphilis, often disappears at the end of twenty- four hours (Blumenfeld, Neisser, Halber- stadter, Sieskind). Syphilitic bone disease reacts promptly, according to the experi- ence of Sieskind and others. The most difficult to influence are appar- ently anal papules (Brandle and Clinge- stein) and hypertrophic papules (Volk and Lipschiitz), as well as more severe papulous exanthemata (Hoffmann), especially the hard cutaneous papules, which, in Wechsel- mann's experience, onh^ disappear at the end of two to three wrecks. Most authors, as is evident from the foregoing references, are able to testify to very good results, as regards the momentary curative effect, especially with the diseased tissue of early secondary syphilis. In the experience of other teachers, however, the clinical phenomena of this period did not disappear mth such striking rapidity (Bruhns). In some instances the effects were slow and unsatisfactory (Kromayer), 103 THE THERAPY OF SYPHILIS and often not more rapid than with Hg treatment (Saalfeld, Ledermann, Buschke, Volk, Blaschko, and Lipschiitz). In the treatment of certain cases in the early secondar}^ period, the phenomenon of the Jarisch-Herxheimer reaction was mostly observed (by Trufh, Wechselmann, Neisser, Herxheimer [in 60 per cent.], Chrzelitzer, Kromayer, Halberstadter, Wolters, Volk and Lipschiitz, Hoffmann, myself, and others). This phenomenon is known from mercurial therapy, and ex- presses itself chiefly in the fact that often twenty-four to forty-eight hours after mercurial treatment has been inaugurated there is an increase of the existing exan- themata. Before the discovery of the 5. pallida, this circumstance was fre- quently brought forward for diagnostic purposes, in order to determine whether isolated flakes present, which were only just visible, might be pronounced as roseola or not. Ehrlich regards the Herxheimer reaction in the *' 606 " treatment and 104 THE CHEMOTHERAPY OF SYPHILIS similar phenomena as an inadequate action of the injection. In his opinion, in such cases the parasites are not at once de- stroyed, but, instead, only irritated, and in this condition produce an increased quantity of toxines. If the Herxheimer reaction appears in exanthemata, Sieskind beheves that it must be regarded prognos- tically as an unfavourable sign. Besides this '' local '' reaction, A. Neisser distinguishes a '' general " one in the treatment with arsenobenzol, which is characterised b}^ transitory increase of the headache in cerebral syphilis, and of the irritant spinal phenomena in tabes. In treating syphilitic infected tissues of the primary and secondary periods, it is naturally of great interest and importance, in estimating the effect of arsenobenzol, to study the behaviour of the spirochaetes after one injection. In many of these forms of disease they can be distinguished more or less easily, and generally in greater numbers. (In the tertiary and malignant 105 THE THERAPY OF SYPHILIS forms it is known that this does not suc- ceed, or only very rarely.) By means of animal experiments (Hata, Tomasczewski, Uhlenhuth, and the author) we know, as already mentioned above, that the spirochsetes have disappeared from the infected tissue of experimental syphilis and of spirillosis of fowls sixteen, twenty-four, or thirty-six hours after the injection of the dose of arsenobenzol. In man, accord- ing to Sieskind, Schreiber, Sellei, and Gliick, they mostly disappear at the end of a day from the manifested phenomena of primary and secondary syphilis. If spirochsetes can still be detected on the second day after the injection, these appear swollen and altered in their motility. According to Spiethoff's observations, the spirochsetes disappear from the irritant serum, on an average, twenty-four to forty- eight hours after the injection. In thirty- two carefully controlled cases, Scholtz saw the spirochaetes disappear permanently at io6 THE CHEMOTHERAPY OF SYPHILIS the end of twenty-four hours fifteen times ; twelve times they could be detected for two to three days ; and only five times were they evident longer than four days. Iversen punctured the glands in ten cases of very pronounced primary lymphadenitis a few days before treatment with ''606'' as well as a few days after. In all these cases, he was unable to discover any spiro- chaetes in the glandular juices three to five days after the injection, whereas before they had been present in great numbers. True, Hoffmann proved that in a series of cases spirochaetes were not evident on the surface of papules and plaques after twenty-four to seventy-two hours. He had, however, seen cases where they were still to be found in perfect motility on the genital and tonsillar papules at the end of eight days. In one case of papules of the mouth and anus, which had reappeared twelve days later, despite a successful Ehrlich-Hata in- 107 THE THERAPY OF SYPHILIS jection, Oppenheim found numerous well- preserved PallidcB. According to Bruhns, in many cases the spirochsetes had already disappeared at the end of two days, whereas in others they were still present later. Grouven was able to prove the presence of living well-preserved spiro- chsetes in a facial papule at the end of two months. Fiirth, in sclerosis of the urethral orifice, saw lively mobile spirochaetes seven da5/s after an arsenobenzol injection, and after the chancre had healed. If at the end of twenty-four to forty- eight hours the spirochsetes have not yet disappeared, this, in the opinion of Ehrlich, is an indication that either the dose was too small, that the absorption was in- adequate, or that one had to do with an arsenic-fast strain of spirochsetes. Hecker only attributes slight importance to the negative spirochsete result in specific efflorescences a few days after the injection of Ehrlich-Hata '' 606." Although in some 108 THE CHEMOTHERAPY OF SYPHILIS of the cases he treated the spirochaetes dis- appeared promptly, a little later relapses, with numerous spirochaetes, set in at these places. Moreover, in two cases of congenital syphilis in which the patients died two and four days after the injection of arseno- benzol respectively, Herxheimer found no specific spirochaetes in any of the organs, with the exception of the lungs. Here, the spirochaetes appeared to be agglutinated and degenerated to the fullest extent up to complete disintegration. Herxheimer considers that the enormous syphilitic spirochaeticide action of the new drug is especially demonstrated in these two cases, in that a large quantity of spirochaetes are almost constantly found in the internal organs in cases of congenital syphilis. Gerber was able to testify to the dis- tinctly destructive influence of arseno- benzol on the spirochaetes of the mouth in one case of severe tertiary syphilis. Refer- ence must also be made to the spirillicide 109 THE THERAPY OF SYPHILIS effect of this preparation in the curative results obtained with '' 606 '' in Plaut- Vincent's angina (Rumpel), (c) THE LATE STAGE OF SECONDARY SYPHILIS AND TERTIARY SYPHILIS. It is just in these periods that the most obstinate forms of the disease often occur, which are either uninfluenced by specific mercurial or iodine therapy, even when ad- ministered in the strongest doses, or are only affected very slightly and slowly. In the manifold and frequently severe dis- turbances of tertiary syphilis, the thera- peutic action of the new Ehrlich preparation is generally found to be most effective. Wechselmann gives the following report of the excellent effect of arsenobenzol in one case : A patient had developed the primary symptoms seven months previously, and an eruption appeared four weeks later. From November 28, 1909, to the middle no THE CHEMOTHERAPY OF SYPHILIS of March, 1910, he was given thirty-five injections of hydrarg. sal and calomel. For three months he had had pain in the joints of both knees. On May 5, 1910, he came under Wechselmann's treatment. ** The patient is emaciated to a skeleton ; his skin is as pale as a corpse, and his face like a death's-head, with an intensely painful expression." On the face and body there were ulcers and cicatrices the size of sixpence (ten pfennige), and even bigger, covered with crusts, and extending down to the subcutaneous cellular tissue. An odious smell proceeded from the nose, in which the septum was perforated, and the left lower muscle and vomer were about to be shed. He had intense pain in swallowing, and had to be fed with pharjm- geal probes and nutrient enema. The pulse was very small, with bad tension, and was 120 and more. As his condition constantly deteriorated under iodine in- jections, and a fatal issue was anticipated within a conceivable time, he was injected III THE THERAPY OF SYPHILIS by Wechselmann on May 21, with 0*4 gramme " Ehrlich-Hata." This was not followed by any rise of temperature, and the pain remained moderate. Even at the end of two to three days the patient's general condition had improved distinctly, and on May 26, general recovery began. The diseased bony nasal framework fell off altogether, and the foetor disappeared. On May 30, the ulcers were responding per- fectly to the healing process, or were com- pletely healed. The patient had increased in weight from 41*5 kilos on May 21, to 49 kilos on June 22 (according to Bressler). An equally brilliant result is recorded by Michealis in one case : A patient became infected in 1906, and, despite treatment in 1907 with mercury, atoxyl, and iodide of potassium, ulcers appeared in the gums on the right and left of the uvula, and, further, a saddle-nose had developed. The uvula was only hanging by a stalk, '' and it might drop off any day." Three days afterwards the surroundings of the walls 112 THE CHEMOTHERAPY OF SYPHILIS of the ulcers were red, and eight days after the injection only small fragments of the former ulcers remained on both sides of the uvula. In two cases of very extensive ulceration of the thigh and subcutaneous gummata with exposed bones, Kromayer observed an extraordinarily rapid absorp- tion of the infiltration and quick skinning over of the ulcers. ^' The epithelisation occurred in a formerly unknown manner/' According to Iversen, an excellent curative effect is shown especially in ulcerous pro- cesses, gummata, and gummatous wounds. Gliick reports that in three cases of gum- mata of the larynx an injection of arseno- benzol practically saved the patients' lives. Spiethoff records one case of tertiary nasal syphilis in which, twenty-four hours after an injection of 0*6 gramme of *' 606,'' the purulent secretion of a disintegrated gumma located in a muscle ceased. The ulcer had closed by the second day, and only slight infiltration remained. A patient who had been antisyphilitically treated in 113 H THE THERAPY OF SYPHILIS several ways from 1906, and was now suffering from an unusually large gum- matous ulcer, was injected by Ledermann with 0'5 gramme of Ehrlich's preparation. The necrotic eschar of the ulcer fell off the day after the injection ; two days later the skinning over began ; and on the thirteenth day half of the ulcer, which was the size of a hand, was closed. The epithelial margin pushed forward daily from I to I c.c. Herxheimer treated nine cases of re- tarded (secondary) syphilitic phenomena (tuberous syphilides and gummata). Peri- ostitis of the vault of the cranium disap- peared after seven days (there was intense swelling on the fourth day) ; a gumma of the left tonsil disappeared in six days after 0*3 gramme ; multiple gummata of the hard and soft palates in ten days after 0*45 gramme. An ulcerated gumma of the left testicle, the size of the fist, receded rapidly at the end of twenty-four hours, after 0*5 gramme (the patient had tubercle 114 . THE CHEMOTHERAPY OF SYPHILIS of both lungs). A gummatous disintegrated hard and soft palate, which had been refractory to mercurial and iodine treat- ment for seven years, healed so rapidly that at the end of a week the patient could again eat solid food, and at the end of three weeks there were only quite small frag- ments remaining. In one case of testicular and cerebral syphilis, Wechselmann was able to effect a cure in about four days after an injection of 0-405 gramme of '' 606." Geronne and Huggenberg saw an orchitis gummosa, the size of a small fist, shrink almost to the size of the healthy testicle within sixteen days after the injection. Isaac stated that a serpigino-ulcerous syphilide, which had appeared four years after the infection, to- gether with disintegrated gummata on the" roof of the larynx and papules on the vulva and anus, healed completely within ten days of the injection. Meirowsky, amongst other things, re- cords the prom.pt cure of large tertiary 115 THE THERAPY OF SYPHILIS ulcers of the hard palate and of the vault of the cranium after the injection of arseno- benzol. Wolters describes the influence of the Ehrlich preparation on advanced forms of syphilis as generally startling. '' Ulcerated gummata heal in a surprisingly short time. Bony processes, after a very energetic reaction (pain), at first show a slow but constant recovery.'' Aschaff en- burg and Gesser were able to testify to a brilliant result in a case of cerebral syphilis. According to the reports of von Zeissl, gummata of the mucous membrane of the mouth, tongue, and throat clear up, so that patients can soon take solid and liquid food without hesitation. Cutaneous malignant syphilis (one large and one small gumma- matous syphilide) healed rapidly under '' 606,'' whereas the previous injections with insoluble Hg had remained unsuccess- ful. Periostitis of the end of the radius, which was of some years' standing, dimin- ished visibly within four days, and the pain disappeared altogether. 116 THE CHEMOTHERAPY OF SYPHILIS Ehrlich himself records one case which shows very markedly the rapid action of arsenobenzol in diseases of the pharyngeal organs : *^ A patient with gumma of the tonsil, who for two months had been treated without result, was given an in- jection at two o'clock ; five hours later the medical man was able to testify to the fact that the patient, to his great joy, had been able to swallow a piece of bread- and-butter without pain." Chrzelitzer sav/ a laryngeal gumma disappear at the end of four days. Fried- lander reported the extraordinarily suc- cessful result of this treatment in fifteen cases of severe ulcerations and gummatous processes in the mouth, nose, larynx, and trachea. Weber was able to report a very good result in a case of severe cerebral syphilis and specific meningitis. Within a few days recovery took place, and the markedly disturbed pupillary reflex, speech, and power of movement of the right side 117 THE THERAPY OF SYPHILIS returned, as well as complete mental power. Gennerich found, from experience, that cerebral syphilis offered a specially favour- able domain for Ehrlich-Hata treatment. " In many cases here it is life-saving ; in others it preserves whatever there is to preserve.'' In one case of cerebral syphilis [arteritis obliterans) I observed and treated, it was not possible to save the patient with an injection of 0*5 gramme arsenobenzol. It is true the case was very far advanced in the secondary period, with flabby paralysis of the left side, as well as facial paralysis. Miekley has also seen extraordinarily favour- able results in the treatment of tertiary syphilis. Thus, a muscular gumma on the ulnar side of the left forearm, which was the size of a large goose's egg, diminished to that of a pigeon's egg four to five days after the injection, and healed completely in under fourteen days. Tertiary ulcers of the leg only required a week and a half for complete cure. A deep ulcerous thrombo- phlebitis of the knee diminished within 118 THE CHEMOTHERAPY OF SYPHILIS fourteen days to the size of a sixpence (ten pfennige). Miekley, as the result of these observations, summarises his opinion of the effect of arsenobenzol on tertiary syphihs as follows : '' The graver the case, the more surprising the effect/' In the experience of Zieler, Bayet, and others, on the other hand, it is not always possible to prove the superiority of arseno- benzol over mercury in tertiary syphilis. Thus, Zieler states that out of thirteen such cases, only four were favourably influenced. {d) MALIGNANT SYPHILIS AND ULCEROUS TERTIARY FORMS RESPECTIVELY. - The same thing appears to apply to malignant syphilis and early ulcerous syphilis respectively, as has been said of the curative effect of arsenobenzol in tertiary forms. According to the researches of Grouven, Hoffmann, Ledermann, Juliusberg, and 119 THE THERAPY OF SYPHILIS most other authors, mahgnant syphilis is in- fluenced equally favourably. In two cases of malignant syphilis, in one of which a fatal prognosis had been given, Dorr also saw excellent results, both with regard to the cure of the infected processes as well as in marked improvement of the general condition. Pick observed the dis- appearance of the symptoms (of pharyneal ulcer and gumma, and papules of the tonsil, respectively) a few days after the injection, in two cases of malignant syphilis, in which iodine and mercury had been in- effectual. Grouven and Frankel perceived the influence of arsenobenzol treatment especially distinctly in a case of extensive ulcerous formations on the leg, which skinned over and cicatrised in the very shortest time. Brandle and Clingestein obtained most excellent results, especially in the treatment of malignant syphilis. As Herxheimer has mentioned, three cases of malignant syphilis responded very well. In one of these cases, large ulcers of the 120 THE CHEMOTHERAPY OF SYPHILIS entire skin of the head, of the hard palate, the throat, and tongue, healed in ten days with 0'4 gramme, without local treatment. From the report of 375 cases treated with the Ehrlich-Hata preparation, collected by Sieskind, it appears that symptoms of malignant s^^philis and lues prsecox offer the most gratifying field for treatment with *' 606," therefore just those cases which are commonly known as the gravest in syphilis. Meirowsky, on the other hand, was unable to distinguish the slightest thera- peutic effect after the intravenous injection of 0*4 gramme arsenobenzol in one case of malignant syphilis. Relapses were ob- served in three cases of malignant syphilis by Gennerich. One directly unfavourable effect of the Ehrlich-Hata treatment was seen by Fischer in a case of this description, which was also refractory to all Hg and iodine therapy. For the rest, it is remarkable that apparently the best, and perhaps also the most lasting, effect of arsenobenzol is 121 THE THERAPY OF SYPHILIS testified to in the tertiary and malignant forms of syphilis respectively, although in these products one can never, or at most only very rarely, verify the presence of isolated spirochaetes. In my opinion, the principal part is played here by the re- hounding factor of the arsenic preparation, which excites the tissue to fresh activity. {e) TREATMENT OF SYPHILITIC DISEASES OF THE EYES WITH ARSENOBENZOL. I should like to class together in a par- ticular group the cases of specific diseases of the eyes which have been treated with Ehrlich-Hata '' 606/' After the experi- ence with atoxyl and other arsenic prepara- tions, it was precisely here that one feared there might be an occasional unfavourable effect of the arsenobenzol. Sieskind saw four cases of iritis papulosa promptly im- proved. Gliick treated two cases of specific ophthalmic disease (keratitis parenchy- matosa and iritis) with very good success. 122 THE CHEMOTHERAPY OF SYPPHLIS Von Zeissl saw a case of iritis disappear four days after the injection ; a paresis of the accommodation was very favourably influenced. I myself saw a bilateral specific iritis with posterior synechia disappear promptly and rapidly. Fehr and Seelig- sohn obtained good results in episcleritis and iritis. Grosz treated eight patients with fresh specific disease of the eyes, amongst them a case of ulcus durum conjunctivce, with arsenobenzol, and was able to prove that this drug is very effective in specific oph- thalmic disease. Good results have also been obtained in hereditary syphilitic eye affections with Ehrlich - Hata '' 606 " by Grosz, Treupel and others, without injury to the optic nerves. Schanz has successfully treated five cases of keratitis parenchymatosa. In some cases in which the visual nerves were not quite intact (fresh neuritis optica) Wechsel- mann has even employed arsenobenzol suc- cessfully without arousing any kind of dis- 12^ THE THERAPY OF SYPHILIS turbances in the disease itself. In six cases also of commencing or advanced atrophy of the optic nerves, he has given the injections without increasing this. Anscherlick has also twice made an injection of '' 606 '' in diseases of the eyes without being able to perceive that the optic nerves had been injured in any way. Exudative processes of the choroid and of the retina respectively were favourably influenced. In one case of atrophy of the optic nerves, Gliick was unable to obtain any therapeutic result. Neither could Igersheimer discover any in- fluence on the corneal process in a case of congenital specific corneal disease, after an injection of 0*4 gramme of '' 606," although the Wassermann reaction was negative. Wechselmann calls attention to the fact that in over 1,400 cases, which he has treated with arsenobenzol, he has never ob- served amaurosis or any other kind of dis- turbance of the visual apparatus, and that even with the great number of injections which have been made by now — in his 124 THE CHEMOTHERAPY OF SYPHILIS estimation, 20,000— nothing of the kind is known/ Despite all these good results in specific eye diseases, it is, in my opinion, abso- lutely necessary first of all to convince one- self that the visual nerves are perfectly healthy before an injection of arsenobenzol is given. Wechselmann has recently ex- pressly demanded that there should be a thorough ophthalmological examination of the eyes, occasionally from the specialist's side, particularly of the field of vision. Cases in which the optic nerve is not quite intact would be better excluded from treatment with arsenobenzol, for reasons which I shall mention when discussing the secondary effects of atoxyl, especially if there is a question of repeating the injec- tions. One must wait to see whether this will not cause injuries of the optic nerve, like atoxyl ; as far as my knowledge goes, it is only after protracted atoxylic treat- ment that amauroses have been observed, 1 See Secondary Effects, p. 172. 125 THE THERAPY OF SYPHILIS and not after only a single larger dose. Syphilitic diseases of the eyes without participation of the optic nerves can naturally be subjected without hesitation to treatment with arsenobenzol, as is evident from what has been stated in the foregoing pages. (/) SYPHILIS OF THE INTERNAL ORGANS. Very good curative effects are often ob- tained in specific diseases of the internal organs, which fall into t'ais period. Thus, F. Lesser has recorded the case of a patient with severe pulmonary syphilis, who was treated and cured with the Ehrlich prepara- tion. Simultaneously, L. Michaelis stated that he had been able to observe distinct improvement, both in chronic amyloid as well as in acute syphilitic forms of nephritis, when treated with arsenobenzol. In two cases of syphilis with nephritis, Scholtz saw recovery in one case and distinct improve- ment in the other. 126 THE CHEMOTHERAPY OF SYPHILIS According to the observations of Alt, Weber, and others, as I have already men- tioned, cerebral syphilis forms a very gratifying and convincing object for treat- ment with arsenobenzol. Meirowsky reports a favourable influence on syphilitic nephritis, which, however, was not permanent. As Wolters recorded, a case of incipient diabetes on a specific basis was also favourably influenced. Ac- cording to Duhot, gummatous internal diseases are cured with the same rapidity as tertiary ulcers. Geronne successfully treated a case of specific disease of the liver. Gennerich observed that visceral syphilis of six months' duration was free from pain the day following the Ehrlich- Hata injection, whereupon the miserable condition improved. Wechselmann records a case of the healing up of severe ulcerous syphilis of the rectum ; icterus of long stand- ing disappeared within ten days. In one case of bilateral labyrinth deafness, accord- ing to Grouven and Frankel, an unmis- 127 THE THERAPY OF SYPHILIS takably distinct improvement in hearing set in at the end of twelve days after a single injection of 0'6 gramme. (g) META- AND PARA-SYPHILITIC DISEASES, INCLUDING TABES AND PARALYSIS. As is known, the first communications, with regard to the therapeutic efficacy of the new Ehrlich preparation '' 606 " in nervous and mental diseases on a syphilitic basis, originated with Alt. The curative results reported, especially in tabes and paralysis, were altogether so good, and were stated so convincingly, that they aroused the greatest general interest. It seemed as if, in arsenophenylglycin, and more still in arsenobenzol, an effective drug had been found '* which might pave the way for the remission of paralysis, and provide a prophylaxis for this terrible disease." Thus, for example, a justice of the peace, who had been admitted to hospital on account of progressive paralysis, 128 THE CHEMOTHERAPY OF SYPHILIS according to the report of Alt at the BerUn Medical Society (Meeting of March 3, 1910), had been completely cured by a single injection of a relatively small dose of arsenobenzol and was again able to transact his business thoroughly well. To- day, unfortunately, we know that it is just these syphilitic nervous diseases, and especially the most terrible forms of them, tabes and paral^^sis, which are least in- fluenced by Ehrlich-Hata " 606,'' and generally not at all. Proportionately, even Alt had soon to restrict his earlier opinion as to the efficacy of arsenobenzol. He stated that a favourable action of this drug was only to be expected at the begin- ning of tabes and of paralysis — to a certain extent, when the " first lightning pains " set in. In the early stages of so-called ''tabo- paralysis '' it appeared to Alt that treatment with the new Ehrlich preparation was specially indicated, and was very efficacious. In the case of those suffering from spinal 129 I THE THERAPY OF SYPHILIS paralysis, Alt's experience was that in the early stage their chief trouble was removed by such treatment; this was demonstrated chiefly by continuous marked diminution of their previous unbearable pain. Thus, the shooting pains especially were said to cease at one stroke, Wechsel- mann also was able to testify to a distinct improvement in the sense of constriction, of headache, of intercostal neuralgia, and of weakness in the muscles of swallowing and of the bladder, in patients suffering from tabes. Selley was able to confirm the statements of Alt to this extent — that he had been able to obtain a two-months' cessation of gas- tric attacks, from which a patient with tabes suffered, by treating him with arsenobenzol. True, the attacks returned at the end of that period. He saw an improvement of dysarthria in paralysis. Torday does not expect much in ad- vanced cases of tabes and paralysis. '* If, however, there are manifest syphilitic 130 THE CHEMOTHERAPY OF SYPHILIS symptoms present, one can naturally ad- minister arsenobenzol as an anti-syphilitic procedure." Favourable results were obtained in para- lysis to a certain extent by Dorr, Treupel, Duhot, Michaelis, and others. In treat- ing nervous patients on a specific basis, Friedlander has also observed a favourable effect on existing pain. Gliick was twice unsuccessful in advanced paralysis, and so was Geronne in twenty cases of different syphilitic sequelae. Behring saw no effect in six cases, and Meyer none in sixteen. Further, von Zeissl was unable to testify to any specially favourable results in similar diseases. Ledermann had to report failure in a case of facial paralysis on a specific basis, and with a patient with paraplegia of both legs. Salmon, on the other hand, in two cases of hemiplegia without contracture, was able to testify to cure in one case, and at least to distinct improvement in the other. In his opinion, the drug is contra- 131 THE THERAPY OF SYPHILIS indicated in progressive paralysis. Schreiber saw marked improvement in a large number of epileptic cases, which were due to syphilis. I will not here go farther into the records, which for the most part can only be regarded as problematical, up to the present. We must wait until reports have come in of extensive employment in large psychiatrical institutions and longer periods of observation have elapsed. I should like, however, to join issue with Grouven in the opinion that, at the present time, the first '' lightning pains '' of para- syphilitic diseases should not form the absolute limit of our therapeutic treatment with arsenobenzol, and that in all cases of tabes and paralysis, where fresh symptoms are still present, they should be subjected to treatment with this drug (A. Neisser). True, the greatest caution is required in all diseases of the central nervous system, and, according to von Zeissl, those cases should be excluded in which destruction 132 THE CHEMOTHERAPY OF SYPHILIS has already set in. As with such patients, disturbances of the blood-pressure and of the circulatory apparatus may arise (Alt, Schlesinger, and others), Schlesinger recommends that it might be well to administer a cardiac a few days after or before the injection. '' Strict asepsis is important, five da3^s' unconditional rest in bed, corresponding diet, and regulation of the bowels. It is advisable that magnesia usta should be administered internally'' (von Zeissl). [h) HEREDITARY SYPHILIS. As far as I am aware, the first case of con- genital syphilis was treated with arseno_ benzol by Wechselmann, who effected a cure with it in a short time in an infant with a severe partly pemphigoidal syphi- lide. Two other infants with pemphigus neonatorum were also cured. Michaehs showed a child before the Berlin Medical Society, in whom, after an injection of 133 THE THERAPY OF SYPHILIS o*o6 gramme of the new Ehrlich prepara- tion, the symptoms of hereditary syphiHs — maculo-papulous exanthema, with infiltra- tions on the soles of the hands and feet — had disappeared within eight days. Only choryza remained behind. Recovery had com- menced on the second day. Pick obtained a rapid curative effect in a case of hereditary infantile syphilis — lues cutanea maculosa, papulae frontis, palmae et plantae. In the Lesser Chnique five infants with hereditary specific disease, with the most varied symptoms (pemphigus neonatorum. Par- rot's pseudo-paralysis of the arm, large papulous syphilide, rhagades around the mouth, choryza, etc.), recovered completely very rapidly after intragluteal injections of 0*03 to 0*05 gramme of '' 606.'' According to Spiethoff, Frankel and Grouven, Pick, Jun- kermann and Kalb, surprising results are often obtained here with arsenobenzol treat- ment. Hoffmann treated with 0*3 gramme a fifteen-year-old congenital syphilitic youth, with ozaena syphilitica, excessive caries, 134 THE CHEMOTHERAPY OF SYPHILIS intense headache, paralysis of the left abducens, and protuberance of the bulb. The symptoms of the disease were sur- prisingly improved ; the bulbar protuber- ance and the abducens paralysis disappeared altogether. The Medizinische Klinik, on the other hand, reports that, from the private com- munications of different teachers, the Ehrlich-Hata drug apparently fails in a relatively small number of cases of heredi- tary syphilis. Moreover, Wechselmann recommended that only well-nourished children should be subjected to the new treatment with arseno- benzol. '' Through the rapid liberation of colossal quantities of spirochaetes, on the administration of ' 606,' such a number of endotoxines were released, that a tem- porary injury was caused, which the child's organism could not stand/' Particular interest was aroused by a com- munication from TaegCj on the good thera- peutic result obtained in the case of a 135 THE THERAPY OF SYPHILIS syphilitic infant, by treating its nursing mother with arsenobenzol. A young woman, with manifest syphilitic symptoms, had given birth to a colourless, shrivelled, old-looking, apathetic child, weighing 2,400 grammes, on July 4, 1910. On July 13, the child developed pemphigous blisters on the soles of the feet and parony- chia on the hands. On July 14, the mother was given 0*3 gramme of arsenobenzol ; from the third day onward a surprising diminution of the condyloma and dis- appearance of the spirochaetes was per- ceptible. On the same day the syphilitic symptoms of the child, which up to now had increased in intensity, simultaneously came to a standstill, and then suddenly all of them began to recede. On the fifth day the skin looked pink, the paron^^chia had disappeared, and likewise the pemphigus up to a small patch. On July 29, the child weighed 3,900 grammes, and exhibited no further specific symptoms. Taege assumes that antitoxines had been transferred into 136 THE CHEMOTHERAPY OF SYPHILIS the child's organism through the milk, which had been formed from the endo- toxines liberated in the mother's organism from the disintegrated spirochaetes. Taege claims, therefore, that for s^^philitic children the syphilitic mother should be treated with '' 606." If she is not able to suckle her child herself, then a syphilitic wet- nurse should be procured, and treated with arsenobenzol before commencing her duty, a demand which at the present time appears somewhat hazardous. Duhot describes an analogous case. He is, however, of opinion that an insufficient quantity of spirochaetes are destroyed in the child's organism by taking the anti- infectious substance through the mother's milk. He, therefore, recomm.ends that the child itself shall also be treated with '' 606." As Ehrlich mentions, similar cases have been observed by Raubitschek, Dobrowicz, and others. Ehrlich agrees with Taege's conclusions ; still he advises that such children should have a small dose of arseno- 137 THE THERAPY OF SYPHILIS benzol injected, in order to destroy any remaining spirochsetes. Meirowsky was able to cure pemphigous blisters in a child with hereditary specific disease, by injecting serum taken from syphilitic patients who had been treated with "606." Similarly, Marinesco, Plant, and Scholz observed a favourable influence on syphi- litic products, especially those of congenital syphilis, by injecting serum from patients who had been treated with '' 606/' In my opinion, it is not yet clearly decided whether an action of this kind, of mother^s milk and serum, on patients treated with arsenobenzol, should be attributed to traces of arsenic, which might be found in the milk or blood. The following case, described by Kalb, may be given to a certain extent in contra- distinction to those already mentioned : A pregnant woman, who was suffering from fresh specific disease, was treated with an inunction cure during pregnancy and with calomel while suckling. Despite this, the 138 THE CHEMOTHERAPY OF SYPHILIS child, although born without syphilitic symptoms, soon developed firm papules on the face and trunk. Finally, severe visceral syphilis set in, and the child died. Grouven was able to cure the syphilitic products induced experimentally in rabbits, by means of serum from patients treated with " 606." Von Zeissl mentions that many medical men have had goats and asses rubbed with mercury, and have then fed and cured hereditary syphilitic children with the milk taken from these mercurialised animals. 7. Dosage. With conceivable caution, at first only small doses of the Ehrlich-Hata preparation " 606 " were administered for the treatment of human syphilis. As Ehrlich has reported, Truffi used only 0*025 "to o*o5 gramme in his first experiments. The transition from the doses of 0'3 to 0*4 gramme, v/hich were originally almost generally employed, to 139 THE THERAPY OF SYPHILIS higher ones has been gradual. According to the clinical observations of most authors, one can go up to from o*6 to o*8 gramme with adults, and even to i*o to 1*2 gramme, especially with Ehrlich's newest prepara- tion '' hyperideal ' 606,' '' which is less toxic, without causing any particular secondary effects. It is only in nervous diseases that Alt and Torday claim, and Ehrlich agrees with them, that small doses should be retained (not exceeding 0*4 gramme), as in these cases one must be very cautious because of the weakness of the whole organism to the new arsenic preparation. Salmon believes that a smaller dose of 0*3, 0*4, or 0'5 gramme will bring about the disappearance of the syphilide just as quickly as a larger one of about i*o gramme. Schreiber considers that in intravenous injection one should not exceed 0*4 to 0-5 gramme. Weintraub and others inject larger doses, up to 07 to 0*8 gramme. Iversen follows up the intravenous injection (on an average with a dose of 0*5 gramme) 140 THE CHEMOTHERAPY OF SYPHILIS two or three days later with an intra- muscular one, until altogether a total of 0*8 to 1*0 gramme has been injected. Ehrlich considers that at the present time it is impossible to give any general figures with regard to the height of the dose ; in his opinion this depends upon the quality of the disease. 8. Influencing the Result of the Wassermann Reaction by Means OF Treatment with Arsenobenzol. According to the first communications of Wechselmann and Lange, if the observation period were sufficiently long the Wassermann reaction, which before the injection was positive, would be negatived in lOO per cent, of the specific cases treated with an injection of the Ehrlich-Hata preparation. The time at which the negative result set in appeared to be dependent on the preliminary strength of the reaction before the injection. The strength of the reaction itself should fall into a proportionate curve without any 141 THE THERAPY OF SYPHILIS greater irregular variations. Weber, Gen- nerich, von Zeissl, Pick, and McDonagh also confirmed the fact that in loo per cent, of the cases the previously positive reaction was changed into a negative one. Accord- ing to Gennerich, the appearance of the negative reaction was accelerated by a subsequent second injection of ''606.'' Similar results were obtained by Hoppe and Schreiber ; they got a negative re- action in 84*6 per cent, of all their cases ; in a later report, however, Schreiber gave this as only 50 per cent. Iversen considers that the positive Wassermann reaction dis- appears twenty to forty days after the injection, and in some cases even on the eighth to tenth day. In none of the cases treated by Iversen, in which the reaction became negative, did the result again become positive. It happened in a few cases that, soon after the injection of arsenobenzol, the intensity of the Wasser- mann reaction increased, to again slowly diminish later. The same phenomenon 142 THE CHEMOTHERAPY OF SYPHILIS was observed by Grouven and Michaelis. Spiethoff considers that with this treatment the Wassermann reaction becomes negative after four, six, or eight weeks. '' In many cases the reaction gradually ceased, and in others variations set in before the permanent negative phase." Frankel and Grouven were able to testify to a negative result of the Wassermann reaction three weeks after the injection of a large number of tabetic and paralytic patients. In the other cases, a very considerable change of the conditions became evident in the form of a marked weakening of the reaction. With specific patients, on the other hand, although it is true these authors often saw the reaction distinctly influenced, ''fre- quently, despite noticeable cHnical improve- ment, the sero-diagnostic result remained unvaryingly positive." Alt also found that there was a negative reaction in a distinctly higher percentage of paralytics than there was of syphilitic patients. In Herxheimer's experience, the 143 THE THERAPY OF SYPHILIS reaction still remains positive in many cases, but in three-quarter of those which were observed constantly it was negative at the end of fifty days. Linser obtained a negative reaction in about 60 to 70 per cent, of the cases, while Kromayer and Stern only got one in 50 per cent. According to Bering, an occasional change of the reaction sets in after four to five weeks ; in forty cases the Wassermann reaction did not alter, while in twenty-six it swung back from a positive to a negative result. Geronne likewise was only able to obtain a negative reaction in thirty-seven out of seventy-seven patients. A second injection rendered nine more cases negative. A. Neisser was at first only able to prove a negative reaction in about 10 per cent., and later in 44 per cent., of cases after treatment with arsenobenzol. This occurred only in those patients who came under treatment very early after infection and after the appearance of the primary affection. Gliick only saw a subsequent negative reaction in 144 THE CHEMOTHERAPY OF SYPHILIS five out of twenty cases treated. Schlesinger found the Wassermann reaction after two to ten weeks ; Miekley, generally positive after more than two months ; Scholtz also considered that the reaction was still posi- tive five to six weeks after the injection. Similar results were arrived at by Loeb, Isaac, Hermann, Brandle, and Clingestein, Anscherlik, Pick, Halberstadter, Bruhns, Torday, and others. In my cases also the Wassermann reaction was only negative once. With regard to the result of the Wasser- mann reaction in hereditary syphilitic in- fants and children, the same conditions seemed to apply to those which exist in the case of children treated with mercury — namely, a very rare negative reaction. As is known, various authors, including Michaelis and I myself, have proved that in the case of hereditary syphilitic children, it is very difficult to change the positive re- action into a negative one by means of mercury. 145 K THE THERAPY OF SYPHILIS As is evident from the foregoing summary of the authors' results, apparently the Wassermann reaction remains positive in a fairly large percentage of cases after treat- ment with arsenobenzol. True, the majority of these results refer to a single treatment, often only with small doses. It is not possible at present to decide definitely whether, with larger doses and occasionally with repeated arsenobenzol injections, or with intravenous application, this reaction would be negative in all cases, and remain so permanently (Gennerich). Ehrlich con- siders the behaviour of the Wassermann reaction of the greatest importance in estimating *' 606 '' treatment. He says that every case in which the reaction per- sists after treatment must be taken as uncured. A negative reaction, if it remains lastingly negative, may be regarded as indicative of cure. It is, however, possible that it is only a negative phase, if the reac- tion subsequently again becomes positive. In that case, according to Ehrlich, the 146 THE CHEMOTHERAPY OF SYPHILIS injection only diminished the number of spirochaetes in the organism. The re- mainder were no longer capable of inciting a positive reaction. But if these had again increased, then the result would again become positive. Ehrlich, therefore, re- gards a renewal of the positive Wasserman reaction as analogous to a relapse without external symptoms, and hence as an indi- cation to repeat the injection. Taking this into consideration, Ehrlich claims that it will be possible to control the treatment within certain periods, by examining the blood with the Wassermann test. Now, however, even with the Ehrlich-Hata treat- ment, various teachers have observed that, despite the existence of florid specific symptoms, it is possible for the result of the reaction to be negative. Volk and Lipschiitz assert that in one of their cases which relapsed, the reaction was con- tinuously negative. Therefore, too much importance must not be laid on a negative result of the Wassermann test. In mer- 147 THE THERAPY OF SYPHILIS curial treatment, I have detected repeated backward and forward fluctuation of the reaction from a positive to a negative result, and vice versa during treatment. In order to obtain a certain and constant result as far as possible, the blood should not be tested during or immediately after finishing the mercurial cure, but one should wait until some little time after treatment- Similarly, the blood should not be examined immediately after the injection, for one might be deceived by the arise of a so- called '' negative phase," when forming an opinion as to the influence of the treatment on the result of the reaction. The phenomenon observed on various sides (Wechselmann, Neisser, Iversen, and others), that in many cases a reaction which was originally negative became positive after the injection, is explained by Ehrlich by the fact that the spirochaetes present before treatment were not sufficient to incite a positive reaction. These spiro- chaetes, however, were liberated by the 148 THE CHEMOTHERAPY OF SYPHILIS injection of arsenobenzol, and their endo- toxines freed. These became absorbed, and thus brought about a positive result. Citron considers that this phenomenon is simply due to the fact that the examination, and injection respectively, were undertaken shortly before the reaction had become positive. If one had only waited a short time, then the reaction would have become positive without an injection. 9. Relapses. Wechselmann stated, in March, 1910, that he received the new preparation *' 606 '' from Privy Councillor Ehrlich, and had not been able to discover any relapse within three months in the hundreds of cases he had treated up to then. Meanwhile, he had passed on from the original dose of 0*3 to 0*45 gramme for women, and 0*5 gramme for men. In a later report, August 11, 1910, on his 503 cases of disease treated with dioxydi- 149 THE THERAPY OF SYPHILIS amidoarsenobenzol, Wechselmann recorded three relapses ; certainly only a very small portion of the cases treated had come to see him again. In the meanwhile, however, reports of various recurrences had come to hand from other sides after a preliminary injection of arsenobenzol. Thus, at a dis- cussion held at the Gottinger Medical Society, on June 2, Schreiber and Hoppe stated they had seen relapses, and the reappearance of fresh specific efflorescences respectively, in ten cases within four weeks after 0*3 to 0*4 gramme of arsenobenzol. A. Neisser also reported various recurrences on June 30, 19 10. He attributed these to the fact that the doses administered had been too small — viz., 0*4 gramme. Geronne and Huggenberg recorded that after obser- vations extending over thirteen weeks they could testify to five relapses, amongst others *' three men we had treated intramuscu- larly and intravenously respectively for primary ulcer. Here the clinical phe- nomena first disappeared surprisingly 159 THE CHEMOTHERAPY OF SYPHILIS rapidly, the Wassermann reaction became negative soon after the injection, and re- mained so for several weeks, and then, after seven to eight weeks, in place of the primary ulcer, a fresh erosion was formed, in which spirochaetes could be detected. In these cases the Wassermann test had again become positive/' Hoffmann recorded relapses after an injection of the Ehrlich drug, and mentions that it is not uncommon to prove the presence of spirochaetes in these relapses at a time when the Wassermann reaction is still perfectly negative. On August 4, 1910, BohaC and Sobotka reported four relapses they had observed within a few weeks ; 0*3 gramme had been injected. Neisser and Kusnitzki saw alto- gether five relapses, which they attributed to the fact that the doses administered had been too small. Loeb observed a recur rence, certainly after the application of a very small intravenous dose of 0*14 gramme. Ehrlich stated, in a communication on 151 THE THERAPY OF SYPHILIS August 12, 1910, that up to that day there had been about 4,000 cases under careful observation. He declared that in man complete recovery was possible with the new drug in 90 per cent, of the cases. This calculation was probably made, in con- sideration of the fact that up to that time there were only a small number of cases in which the clinical symptoms of specific disease had recurred. According to a still later communication of Wechselmann's, the number of relapses, and partial failures respectively, out of the 900 cases he had treated up to the time of publication was small, almost down to vanishing-point; at any rate, ''the number of the earlier recurrences remained far behind those of mercurial treatment.'' Wechselmann specially emphasises the in- significance of the relapses. Kromayer, Brandle, and Clingestein, out of twenty- seven cases, saw five relapses after two and a half to three weeks. Gliick and Wolff observed four recurrences. Fischer re- 152 THE CHEMOTHERAPY OF SYPHILIS ported two severe relapses in patients treated by others with '' EhrHch-Hata/' and in one extensive primary affection contain- ing spirilla, which had been injected about eight weeks previously. Duhot saw a relapse in a patient who had been treated by another medical man with 0*3 gramme. Geronne saw fourteen relapses in about eighty syphi- litic patients, who had been at least ten to twelve weeks under careful observation ; he did not include in this summary the numerous patients who had been under observation for a shorter time. Eleven times there were reindurations of the primary affection, renewed appearance of a specific angina or of an exanthem ; three patients got other similar specific symptoms. Denecke testified to the certain recurrence of an early tertiary ulcerous process. Ledermann, up to date, records a return of periostitic swelling of the cranium, which had completely disappeared with its symp- toms, after an injection of 0*45 gramme ; the appearance of roseola fourteen days after 153 THE THERAPY OF SYPHILIS involution of the primary affection (with 0'3 gramme), and two other relapses. Rille saw a recurrence of the primary- affection about four weeks after cure. Weber observed two slight relapses, and Gennerich four in malignant syphilis after almost four weeks. In a recent com- munication, Schreiber put the total number of his relapses at sixteen after 0*3 and 0*4 gramme respectively ; one recurrence after 0*7 gramme ; he had no relapses after intravenous injection. Herxheimer also, in his last report of 230 cases, mentions two very slight local returns of secondary syphilis within four and a half months. Linser, on the other hand, repeatedly noticed relapses in all stages, some of which occurred within four to six weeks of the injection. In Bering's observations, three recurrences of secondary syphilis appeared in his cases at the end of three to four weeks, despite the fact that the normal dose had been injected. In tertiary syphilis he regis- tered a relapse at the end of four weeks. 154 THE CHEMOTHERAPY OF SYPHILIS Stern reported that in one of his cases of primary affection, with extensive exanthem, which had healed up by eighteen days after the appHcation of '' 606/' the exanthem having gradually retrogressed, there was a return of the papules on the thigh and of the mucous papules on the tongue and lip. Miekley observed two cases of relapse. In three cases of primary affection, Grouven was unable to prevent the appearance of the secondary phenomena, despite injections of 0*3, 0-4, and 0*5 gramme. He saw direct recurrences in a case of congenital syphilis (0-05 gramme), and in one of acquired specific disease (after o" 3 and 0*6 gramme) . Accord- ing to Friedlander, an injection of " Ehrlich- Hata'' did not prevent the appearance of later secondary phenomena in three cases of primary affection. Joseph records one relapse after 0*3 gramme ; Eitner two. I myself have had four certain relapses and two partial failures in the relatively small number of cases (twelve) I have treated with ''606" (on an average, o-6 155 THE THERAPY OF SYPHILIS gramme, partly in alkaline solution, partly in neutral calcium carbonate emulsion). In one of the cases which recurred after the prompt and rapid healing of two firm papules in both naso-labial folds, and in both angles of the mouth after 0*45 gramme of arsenobenzol, a new papule appeared at the left angle of the mouth, about fourteen days later, small plaques in the buccal mucous membrane, and a slightly indurated ulcer, covered with slime, in the sulcus coronarius. In the second case, a maculo- pustulous exanthem healed up completely within eight days. Fourteen days later this exanthem reappeared in an exaggerated form ; there was also an extensive impetig- inous syphilide at the back of the head. These phenomena then disappeared com- pletely after two to three injections of thymol acetin. With one patient, who had a hard infiltrated primary affection localised in a urinary fistula, and marked bilateral typical swelling of the lymphatic glands with large quantities of spirochaetes and 156 THE CHEMOTHERAPY OF SYPHILIS isolated roseola, a distinct Herxheimer reaction set in on the day following the injection, which disappeared at the end of forty-eight hours. The infiltration of the primary affection had partially disappeared, as well as half of the left inguinal gland. Ten days after the injection, there was a sudden outbreak of numerous slightly in- filtrated roseolce on the upper part of the body and on the face. Finally, in the fourth case, one of latent specific disease with positive Wassermann reaction, papules appeared on the palmar eminences and on. the arms four weeks after the injection of arsenobenzol. Urticarial roseola, with posi- tive spirochaete result in some of the roseolae, only healed partly ; sHghtly infiltrated and pigmented places still persisted. In one case the primary affection only healed up imperfectly, and a severe eruption of roseola soon appeared. Apart from these certain relapses, how- ever, there are a large number of other observations in which only a defective THE THERAPY OF SYPHILIS action of the arsenobenzol on the syphilitic process could be proved. In current literature such '' failures " are generally recorded apart from the relapses, although the latter, in the opinion of Stern, must also be counted as '' failures,*' and in this I thoroughly agree with him. Wechselmann especially reports a whole number of such cases in his last publication, " The Reinjection of Dioxydiamidoarseno- benzol," in which a single injection of '' Ehrlich-Hata " did not act as promptly and perfectly as Wechselmann had regularly observed previously. Thus, amongst others, infants suffering from pemphigus neona- torum, cases of severe malignant syphilis, which, it is true, were influenced in the most brilliant manner, but which still showed quite small ulcerations, and, further, an extensive papulous syphilide and a large flaked urticarial roseola, were all reinjected. In Wechselmann's experience, however, the number of partial failures, as contrasted with the number of prompt effects, is still 158 THE CHEMOTHERAPY OF SYPHILIS SO small as to be almost at vanishing-point. Grouven and Frankel were able to observe that sometimes the success of the treatment appeared much less rapidly. '* In a facial papule two months after the first injection, a large number of mobile spirochaetes were found. Another patient required three injections, extending over two months, to effect the disappearance of his tubero- serpiginous phenomena." Treupel observed a similar failure in a papule of the lower lip, which, it is true, reacted with redness and moisture, but did not become smaller. Gliick saw thick papules and a primary affection uninfluenced at the end of three weeks. Hartung also did not always obtain satisfactory results in anal and genital papules. Iversen was unable to effect the cure of large papules within three weeks; Hoffmann found the action inadequate for an intense papulous syphilide, and had to supplement it by inunction treatment. Pinkus stated that in two cases the secondary syphilitic papulous exanthem had 159 THE THERAPY OF SYPHILIS not disappeared at the end of four weeks (with 0'4 and 0*45 gramme) ; moreover, Spiethoff also records failures with these doses. Out of sixty-four cases of secondary syphilis, Bering five times saw the symptoms uninfluenced, although in some cases very high doses had been administered (o* 8 gramme per kilogramme of the weight of the body). Scholtz recorded three failures with smaller doses of 0*3 to 0*4 gramme ; in two cases of malignant syphilis, Geronne found that after 0*3 and o*6 gramme, not only was there no cure, but a week later he discerned distinct deterioration. Here belongs also the case mentioned by W. Fischer of considerable exacerbation of tertiary ulcerous syphilis after an arsenobenzol injection. In eight cases, out of eighty treated with Ehrlich's '* 606 '' up to September 15, 1910, Stern could not speak of a noticeable rapid result, neither could Taege in the cases of a man with papules in his beard and of a woman with tumour of the liver. Volk and Lipschiitz also saw two cases of atonic ulcers, which 160 THE CHEMOTHERAPY OF SYPHILIS were absolutely uninfluenced. Eitner also records four failures. Quite recently the Medizinische Klinik started a fresh inquiry, in which the par- ticipators in the earlier one were asked to make additions to their contributions, with regard to the number of cases treated. I will here briefly recapitulate the contents of this inquiry, in order to complete and extend the report of the relapses and failures up to the present time, as far as possible. Jadassohn treated eighty cases up to October 24. The relapse of one patient with plaques muqueuses was reported six weeks after he had had an injection of 0"5 gramme. A second patient was given 0*6 gramme arsenobenzol, and plaques were again evident five weeks later. In a third case, new papulous deposits appeared only twelve days after the injection of 0-6 gramme. Out of 789 cases, Herxheimer saw 33 relapses, Linser 4 out of 80. Spiethoff states that the number of cases he has treated amounts to 175 ; amongst them there 161 L THE THERAPY OF SYPHILIS were 5 recurrences, 2 of which were observed after a second injection. Bering was able to make a later examination of 211 cases ; amongst these he observed 25 failures, which equals 11 '8 per cent. Pinkus, 120 cases, 3 relapses ; Rille, 171 cases, 7 relapses ; Treupel, 120 cases, 4 relapses ; Juliusberg, 55 cases, and 2 recurrences and failures respectively. Grouven treated altogether 254 cases with arsenobenzol ; 15 of these were failures in the sense that the symptoms only retrogressed lingeringly or imperfectly : 9 cases relapsed. Bettmann observed 8 relapses amongst the cases he had treated previously (87). Schultz, i recurrence out of 28 cases ; McDonagh, 2 relapses out of 85 cases ; Wechselmann, 40 out of 1,250 cases. '' But the number is quite insignificant, as only a moderate percentage of those treated again presented them- selves " (Wechselmann). Amongst 120 cases of pure syphilis (not parasyphilitic diseases), L. Michaelis observed 4 relapses ; up to the present 162 THE CHEMOTHERAPY OF SYPHILIS Kromayer has treated 310 patients, and 7 of these relapsed. " I may add/' says Kromayer, '' that the majority of the cases treated have not entered upon the stage when a recurrence may be anticipated, so that the numbers 310 and 7 cannot be placed in relation to each other/' E. Saalfeld saw 5 relapses out of 36 cases ; Halberstadter 6 out of 55 ; Ledermann also 6 out of 52 ; Chrzelitzer only i recurrence out of 47 cases. Gennerich was able to treat 82 cases ; in 4 of malignant syphilis he had relapses at first, but later, in these cases also, by the aid of renewed injections, he was able to effect cures. Scholtz dis- covered 5 relapses out of 130 cases treated ; Schreiber had 18 recurrences out of 152 cases which had been subjected to intra- muscular injections, but there was only I relapse amongst 565 cases treated intra- venously. Geronne reports that out of 71 patients with specific disease, who were injected between the months of April and June, 22 clinical recurrences had been 163 THE THERAPY OF SYPHILIS observed up to the present date ; *' 24 of these patients were reinjected, on account of the persistence of the Wassermann re- action, by means of which the appearance of further chnical relapses was obviously prevented/' Since the middle of August, Bruhns has treated 74 cases with EhrHch- Hata '* 606 " ; up to now he has seen 5 relapses and 4 failures. Welander treated 65 cases altogether ; but in his opinion this number also is without importance in estimating the relapses. The result of his arsenobenzol treatment is better indicated by the fact that, of his 46 adult patients, in all probability no relapse occurred in 27 cases. Welander also received notifications of the relapse of 11 adult patients ; in 5 cases the symptoms were but little in- fluenced. A recurrence was observed in the case of a child (hereditary syphilis), and with another the treatment failed. Von Zeissl saw 4 relapses out of 149 cases. Finally, Dreuw was able to observe 4 severe relapses amongst the cases of 11 prostitutes 164 THE CHEMOTHERAPY OF SYPHILIS subjected to police inspection, who had been treated elsewhere by Ehrlich-Hata injections. Polland and Knaur saw 4 recur- rences in the secondary stage, and in one case an Ehrlich-Hata injection had not the slightest effect. Latterly, Wechselmann has observed severe eye trouble as a relapse. Cohn has also reported an iritis relapse, which reappeared fourteen days after a prompt cure had been effected with ''606.'' A probable specific neuritis of the optic nerve was seen by Kowalewski, in a secondary syphilitic woman, about two months after an Ehrlich-Hata injection. Fischer also testified to 5 severe cases of eye diseases out of 8 certain relapses. Fischer is inclined to connect this form of relapse with the arsenobenzol treatment. He, like Buschke, believes the neurotropic affinity of this drug to a certain extent produces a locus minoris resistentice, on which the syphilitic virus fastens itself and finds a favourable field for development. Wechselmann, who, as we have seen, 165 THE THERAPY OF SYPHILIS only observed the very slightest clinical relapses, believes that these " are only to be regarded as relapses of encapsulated foci, which have been made manifest under the action of the drug/' *' Our conception is that all the spirochsetes which come in contact with the drug are destroyed, and probably softening processes take place at the infiltration foci, which harbour encapsu- lated spirochaetes, and thus may make them accessible to the new drug." Wechselmann believes that the dose of 0*5 to 0*6 gramme for men, and 0*45 gramme for women, which has been found effective and generally ade- quate for cure, should not be exceeded. In the circular letter of October 25, 1910, already referred to, Ehrlich attributes the appearance of relapses to the fact that the subcutaneous injection of neutral emul- sions accomplishes less quoad duration of effect than other forms of application. It seems to him as though the ictus immuniso- toricus in this method is not intense enough to generally obtain a destruction of the 166 THE CHEMOTHERAPY OF SYPHILIS spirochsetes to the extent of sterilisation. As is known, it is for this reason that EhrHch now hopes to be able to anticipate better results from the treatment with intravenous injections. If, as is assumed by Ehrlich and a large number of syphilidologists, the positive or repeated negative result of the Wassermann reaction is a sure test as to whether the syphilis is healed up or not, then naturally amongst these clinical relapses and failures a large number of cases must also be reckoned, in which through a single and even repeated injection, the positive result of the sero-reaction was not lastingly trans- formed into a negative one. In estimating the number of relapses of manifest specific symptoms detected by individual teachers, there are, in my opinion, still some important points to be taken into consideration. In the first place, the statistics compiled by most authors from which they adduce and calculate the relapses are incorrect. 167 THE THERAPY OF SYPHILIS As has been claimed by Blaschko, not only must the stage of the disease be given accur- ately, but also how long the affection has been lying dormant in the cases treated. But^ above all, the observation period is still far too short to enable one to formulate any definite conclusions with regard to the action of the arsenobenzol. According to Alt's communication, the first attempts at treating florid syphilitic patients with '' 606 " were begun on January 31, 1910. Wechselmann first re- ceived this preparation from Ehrlich in March, 1910, and most other teachers were only able to commence their therapeutic researches with arsenobenzol much later. Hence the longest observation period of syphilitic cases which have been subjected to this method of treatment, in the most favourable ones, is only a little over nine months, in many at most half a year, while in most of those cases reported up to the present, it is only a few months. We know, however, that in the so-called early 168 THE CHEMOTHERAPY OF SYPHILIS treatment of syphilis — excision of the primary affection, with subsequent intense mercurial treatment — with apparently com- plete cure, the appearance of recurrences or secondary symptoms ma}', under some cir- cumstances, be delayed for above a year. I myself have had two observations of this kind, which I give. In one case, after excision of the primar^^ affection and after three intense injection cures, it was eight months after the excision that pronounced roseola, with impetigo capitis and character- istic fall of hair, appeared (the Wassermann reaction had fluctuated equally between positive and negative) . In the other case, the first hardly perceptible roseola showed itself about six months after the excision ; the second, which was not much more marked, about three months later. It is evident from these observations that the course of specific disease may deviate from_ its typical curve, if the development of the syphilitic process is inhibited early, by means of drastic cures or strong specific 169 THE THERAPY OF SYPHILIS drugs. There is no doubt that Ehrlich's arsenobenzol is a preparation which has a strong specific action on syphiHtic infected tissues of all kinds. Consequently, it is only possible to expect to be able to arrive at definite conclusions as to the possibility of a recurrence of the process of disease after at least twelve to eighteen months' careful observation of the cases thus treated. A further fact, which must be taken into consideration, is that perhaps at the begin- ning, in conceivable enthusiasm over the good s^^mptomatic effect of the new Ehrlich- Hata preparation, the results of the '' cures'' published were too rapid, and perhaps also too euphemistic. In the great interest which naturally was aroused by such publi- cations, even the smallest report was referred to in detail in the daily press. Thus the public at large got the firm belief that it only required a single injection of Ehrlich- Hata '' 606 " to render anyone exempt from syphilis for all time. This belief, 170 THE CHEMOTHERAPY OF SYPHILIS which to-day is still almost general, is the reason why most syphilitic patients who have been treated with " 606 '' have not watched themselves, and their bodies respec- tively, with the greatest care for the appear- ance of any suspicious symptoms. Neither have they reported themselves to the medical man at regular intervals, as is always required to be done with mercurial therapy, even when there is apparently a complete absence of symptoms. This may have contributed to the reason why Wechselmann and many other teachers have seen so few of their patients again who had been treated with arsenobenzol. There is no reason why all these patients who failed to report themselves should have been cured. Indeed, it is just the fact that the manifest symptoms, under some circumstances, may be so slight that they are hardly perceptible, and often disappear surprisingly rapidly, even without specific treatment, which makes this disease such a terrible one, and so full of danger for the 171 THE THERAPY OF SYPHILIS general public. Apparently healthy patients, who are suffering from this disease in the latent stage, may occasionally spread in- fection if rapidly passing specific symptoms arise, which are often slight and unnoticed. I have unfortunately been able to convince myself of the possibility of this in one of the early" cases described above, which I treated, in which a patient infected a girl with syphilis a,bout two months before the outbreak of the general symptoms. 10. Secondary Effects. In considering the question of the second- ary effects to which this new preparation may give rise, we must, like Neisser, dis- tinguish purely local disturbances, which appear at the seat of injection, and general secondary effects. As the former depend chiefly upon the manner of administering the drug, I have refrained from giving them until the different methods of solution and forms of application had been discussed. 172 THE CHEMOTHERAPY OF SYPHILIS Most teachers have expressed themselves as follows, with regard to the general secondary effects of the preparation '' 606 '' — namely, that these are comparatively of a very insignificant nature, and that arseno- benzol, even in larger doses, is relatively innocuous for the organism. Nevertheless, secondary effects have been seen on various sides, some of which were of a very grave kind, and these have made this innocuous- ness of the Ehrlich-Hata therapy appear in a somewhat different light. It is, however, important that the practitioner should be thoroughly acquainted with all these obser- vations, and therefore they are given in detail here. Fever is a regular symptom which appears after the administration of '' 606/' In the majority of cases with intravenous injec- tion it sets in with rigor a few hours after the injection, and runs up to 39*5° to 40° centigrade, but often falls within a few hours (Schreiber, A. Neisser, Geronne and Hug- genberg, and Iversen) . In intramuscular and 173 THE THERAPY OF SYPHILIS subcutaneous injections the fever generally begins one or even two days later, is not so high, and as a rule finally drops again. Schlesinger, however, observed high fever in one case for three weeks ; there was no local infection present. Neisser's observations show that no fever arises after the injection of non-syphilitic patients. He therefore regards fever after an arsenobenzol injection as a general reactionary phenomenon, and attributes it to the toxic action of the endotoxines liberated by the destruction of spirochaetes. Very often phenomena of drug exanthemata accompany the appear- ance of fever. Thus, Wechselmann observed a morbillous exanthem with conjunctivitis. Spiethoff and Saalfeld also, twenty-four hours after the infection, saw an exudative confluent erythema of the extensor sides of the leg and thigh, with pain in the joints, which reminded one vividly of exanthem exsudativum multiforme. Twenty - four hours later it had ceased altogether. Frankel, Rille and Grouven, and others, 174 THE CHEMOTHERAPY OF SYPHILIS perceived diffuse exanthemata, and true erythema respectively. In one case, six hours after the injection, Spatz was able to detect " elevated, irritating, bright red, nettle-rash-like infiltrations, varying in size from a crown to a five-crown piece,'' over the whole body and face, which again dis- appeared twenty-eight hours later, without leaving a trace behind. Herxheimer also noticed urticaria in one case, which began on the hands, and then gradually extended over the whole body. Gliick also saw urticaria and exanthemata in some cases. Treupel once perceived a slight desquama- tion of the cutis of the face. Schreiber saw slight drug exanthem in two patients, which first appeared after eight to ten days, with rise of temperature, and then again dis- appeared rapidly. Finger was able to observe toxic erythema in four cases, amongst them being one similar to scarla- tina, which arose with high temperature, and persisted for over a week. Further, it is not unusual for the fever to 175 THE THERAPY OF SYPHILIS be accompanied by flatulence, nausea, retch- ing (Alt, Kromayer, Rille, and Spiethoff), and in some cases with genuine vomiting (Wechselmann, Schreiber, Neisser, Iversen, Geronne, Rille, Gennerich, and von Zeissl). In intravenous injections especially, fever, vomiting, vertigo, and similar symptoms, were observed almost regularly, but as a rule they passed off equally quickly. The fever, however, is pretty frequently accom- panied by acceleration of the pulse, tachy- cardia, and increase or diminution of the blood-pressure (Alt, Spiethoff, Schlesinger, etc.). Ledermann once saw pronounced slowing of the pulse. In my experience these symptoms may persist for a long time ; indeed, up to fourteen days, while the temperature remains perfectly normal. The severest phenomena of the circulatory System, however, were seen by Hoffmann in two cases ; in these were not only grave disturbances in the heart's activity, but also slight diffusion towards the right, and a systolic bruit after treatment. Hauck 176 THE CHEMOTHERAPY OF SYPHILIS also discovered marked disturbance in the heart's activity after a dose of 0-3 gramme. Whether the Ehrhch drug is really so non-irritant for the kidneys, as has been asserted on various sides, is a question I must doubt after the experience of Schle- singer, who observed transitory albuminuria in about half the cases, or cylinduria without albumin. Bering also saw four cases of transitory albuminuria. Geronne records slight albuminuria in some cases, which, however, disappeared at the end of one to two days. The albuminuria was more pronounced in one case, and persisted four to five days ; on the first day the albuminous content was 8 per cent., but there were neither cylinders nor red blood-corpuscles in the urine. Finger also observed a transitory albuminuria in one case. Volk and Lipschiitz saw albumin and cylinders secreted from the urine eight days after one patient had had an injection. According to Pick, a frequently observed phenomenon is the diminution of the 177 M THE THERAPY OF SYPHILIS quantity of urine, which in some cases has been reduced from 400 to 500 c.c. per day, when the specific gravity was not too high (1015 to 1020). SHght isolated symptoms of disease of the intestinal tract have also been observed. Iversen saw transitory diarrhoea after intra- venous injections ; Bering reports intensely severe intestinal tenesmus, which lasted one or two days, in patients who had been treated with arsenobenzol. Pinkus saw transitory diarrhoea in one syphilitic patient, Schulz in two ; Bettmann, Geronne, and Huggenberg also occasionally. Spatz men- tions that the painful feeling of thirst, of which his patients complained particularly, occurred in cases in which the temperature did not exceed 37*5° centigrade, and hence could not be caused by fever. Bayet observed arsenical rheumatism^ in many of the patients who had been treated with arsenobenzol. about fourteen davs after the injection. Distinctly graver symptoms were de- 178 THE CHEMOTHERAPY OF SYPHILIS scribed by Bohac and Sabotka in the three following cases. They observed : '' I. Retention of urine, the duration of which varied, reaching to half a day. In one case, which could not be estimated at the time this work was con- cluded, it had certainly extended over a period of more than nine days ; after its cessation there was considerable difficulty in micturition left behind. It was sur- prising that, with patients who had been given the smallest amount of the prepara- tion, ver}^ severe symptoms did not at once set in. In two cases there were also slight quantities of albumin in the urine, without cylinders. ''2. The patellar reflex was absent m all the cases, as well as a whole series of reflexes which are usually tested. True, their condition conceivably had not been examined before the commencement of the treatment. ''3. In two cases there was unusually marked tenesmus of the rectum (in one 179 THE THERAPY OF SYPHILIS case this was perhaps favoured by previous proctitis). '' Further, in all three cases intense constipation was noticeable, which still persisted after an abundant amount of nourishment was taken. Despite the fact that it was soon overcome by means of a simple aperient, this should perhaps not be confounded with the usual sluggish- ness of the bowels of anyone confined to bed.'' The authors attributed the nervous symptoms to disturbances in the spinal cord, the rectal tenesmus to nervous irritation of the intestinal tract, and the retention of urine finally to detrusor paralysis. The authors are of opinion that this new arsenic preparation, as regards these symp- toms, has points of contact with the secon- dary effects described as due to atoxyl. In contradistinction to this communication from Bohac and Sobotka, Privy Councillor Ehrlich has published the following de- claration : i8o THE CHEMOTHERAPY OF SYPHILIS '* Frankfurt-a.-M., "August I, 1910. '' With regard to the article by Bohac and Sobotka, I may remark that 132 additional tubes with the same operative number as those employed in Prague were sent to Fauser (Stuttgart), Hauck (Erlangen), Linser (Tubingen), Rille (Leipzig), and Spiethoff (Jena). From all these places I have re- ceived reports to the effect that the dis- turbances described by the authors were never observed. Moreover, nothing of the kind has been reported to me from else- where in the administration of ^ 606.' '' On inquiry, Alt (Uchtspringe) tele- graphed to me : ' In more than 200 cases which were treated with '' 606 " in the Institution here, under the most exact control and careful examination, especially with regard to the nervous s^^stem, nothing similar to what occurred in Prague has been observed. There has never been any paralysis of the bladder, retention of urine, or the like, nor any disappearance of the 181 THE THERAPY OF SYPHILIS reflexes. There must, therefore, have been some toxic action which was brought about, either by decomposition of the preparation or by the addition perhaps of methyl-alcohol. I employ no basic additions, with the excep- tion of a little solution of caustic soda.' *' Dorr (Vienna) telegraphed also on my inquiry : * Sixty-eight cases, no paralysis of bladder ; reflexes tested day before yester- day by neurologists in all accessible patients ; not absent in a single one.' '' Similar telegrams were received from Finger (Vienna) of forty cases, Neisser (Bres- lau) of no, Michaelis (Berlin) of sixty-eight. '' It is evident from the above that the disturbances observed by the authors were connected neither with the preparation ' 606 ' itself nor with any decomposition of the special operative numbers. There must, therefore, have been sources of error in the preparation of the solution or in the application. According to telegraphic news received from Sellei (Budapest), ' Kreibich's failures are typical symptoms of methyl- 182 THE CHEMOTHERAPY OF SYPHILIS alcoholic intoxication/ This also agrees with Alt's telegram and earlier communica- tions from Aulic Councillor Emil von Gross (Budapest) ; they must have been due to an injurious effect of methyl-alcohol, which was perhaps not quite pure. '' In conclusion, I must express my regret that the authors did not consider it neces- sary to at once inform me of this occurrence, as then the sensational disturbance of a large circle, which was caused by the article, would have been prevented. '' Ehrlich." In a second report on the further course of these cases, Bohac and Sobotka state that the longest duration of the complete retention of urine was ten days, that of tenesmus a little more. The disturbances of the patellar reflexes, which, together with the remaining reflexes, had been re- established in the meanwhile, might, in the opinion of the authors, be explained as the influence of pain starting from the seat of 183 THE THERAPY OF SYPHILIS injection, in the sense of a voluntary or involuntary inhibition. For the remainder of the secondary effects observed, however, this circumstance could not be taken into consideration. Neither, in the opinion of the authors, could these unpleasant secon- dary effects be attributed to a toxic action of the methyl-alcohol, as previously, in many cases in which methyl-alcohol had been employed for the preparation of the solution of arsenobenzol, no similar effect had been observed. Further, Ehrlich himself expressed the opinion {Munch. Med. Wochenschrift, 1910, p. 1576) that no objection could be raised to the employ- ment of methyl-alcohol in such small quantities as come into consideration here. The authors believe that the explanation of this toxic action is due to the fact that the preparation in question had undergone a chemical change and was decomposed. This view is shared by Eitner, who quite recently was able to observe similar symptoms in one case — retention of urine, constipation, 184 THE CHEMOTHERAPY OF SYPHILIS absence of patellar and other reflexes. Buschke and his assistant Fischer, however, regard this action, like those they them- selves observed, and which are given below, as well as many reports published pre- viously, as being due to the neurotropic action of the arsenobenzol. Another thing, which perhaps speaks in favour of the possibility of a neurotropic action in Buschke's sense, is the fact that slight relapses occur in the eyes and organs of hearing particularly, and to this I have already referred. Latterly, Finger has reported some obser- vations, and these directly confirm the assumption of Buschke. In one of these cases, a patient developed violent headache, vertigo, and optic disturbances two months after a Hata injection of 0*45 gramme. Objective examination revealed oculo- motoric paresis on the right side, paralysis of the levator palpebrae superioris and of the rectus internus, as well as commencing optical neuritis of the left side. As it was 185 THE THERAPY OF SYPHILIS assumed that this was perhaps due to a relapse, the patient was given a fresh Hata injection also of 0*45 gramme. Neverthe- less, this, as well as mercurial and iodine treatment, remained not only unsuccessful, but optical neuritis of the right side set in. With a second patient, optical dis- turbances set in three months after the injection, and were characterised by abdu- cens paralysis. In a third similar case which Finger observed, the patient complained of optical disturbances three months after an injection of 0*45 gramme. On examination, it was found that there was sluggish reaction of the pupils, anisocoria, bilateral contraction of the visual field, retraction of the temporal halves of both pupils, therefore, commencing bilateral optical atrophy. Finally, in the fourth case, three months after the injec- tion and eight after infection, optical dis- turbances were perceived, and right ocular peripheral chorioiditis, with central vitreous opacity. In three further cases *' peculiar phenomena, partly of a disturbing nature," 136 THE CHEMOTHERAPY OF SYPHILIS were found in the auditory organ/ Once Finger saw isolated interruption of the vestibular nerves, although certainly this was only transitory. In another case, a patient complained of vertigo and difficulty in hearing nine weeks after the injection and three months after infection. There was bilateral labyrinthal difficulty of hear- ing, which subsequently remained un- changed. In the third case, the patient, a girl, aged eighteen, with specific disease of about three months' standing, had been given 0*45 gramme arsenobenzol on August 5. By August 15, all syphilitic symptoms had disappeared, and the patient was discharged as cured. On November 7, she returned on account of giddiness, head- ache, and difficulty in hearing ; she was free from syphilis, and the Wassermann reaction was negative. Here also labyrinthal diffi- culty of hearing, vertigo, and spontaneous nystagmus, were detected, and later the condition remained stationary. ^ Compare the secondary effects of Arsacetin, p. 27 187 THE THERAPY OF SYPHILIS Distinct confirmation of the experience of Bohac and Sobotka was obtained in the communications of Bonhoffer, who, in the case of one patient with fresh spinal syphilis, after an injection of a neutral emulsion, observed complete paralysis of the bladder, and an augmentation of the paralytic symptoms in the legs. With a second patient, a paralytic, he witnessed a severe epileptic attack, with residuary bilateral hemianopsy, etc. According to Pollack and Kaur, with one patient who had had 0'5 gramme, fever up to 40* i° centi- grade set in, with strong acceleration of the pulse and retention of urine, which persisted for seven days. Rille also once observed an epileptic attack and repeated pain in the knees and legs. Schlesinger several times testified to transitory vesical disturbances in his patients. Herxheimer had a case of retention of urine ; and even Wechselmann found that for a time one patient was incapable of emptying the bladder. Behring also once saw detrusor 188 THE CHEMOTHERAPY OF SYPHILIS paralysis. Chrzelitzer discovered arsenic intoxication in patients with excessive nervous disturbances, and Wechselmann, Pick, Fischer, and Buschke were able to prove the presence of slight arsenicism in isolated cases. In Wechselmann's wards three cases of paralysis of the peroneus were observed after intramuscular application. In the opinion of Sieskind^ these cases are to be attributed to the mode of application, because the peroneus, from its superficial position, suffers external injury far oftener than the tibial fibres of the sciatic nerve. Now, as these cases of paralysis appeared after a latent period of a few days, Wechselmann regards them as arsenic intoxication neuritis proceeding from a deposit. Here probably we have to do principally with the effect of pressure of the intragluteal injection. According to Buschke and Fischer, it is possible that they may be explained as paralysis of the extensors, and thus as a symptom of an existing arsenic intoxication. That under 189 THE THERAPY OF SYPHILIS some circumstances the internal organs can also be injured is proved by a case of Hoffmann's, in which, after the injection of 0*3 gramme arsenobenzol in acid^ solution, he saw central embolic pneumonia through escaped thrombus from the gluteal muscles. Finger once perceived symptoms of slight pulmonary embolism after an injection of a paraffin emulsion into the gluteus. Duhot three times observed haemorrhagic excre- scences. Rille saw dyspnoea and icterus thrice. Pinkus also was once able to testify to icterus after the administration of the Ehrlich-Hata preparation *' 606,'' and Behring to augmentation of exist- ing diabetes. That occasionally pregnant women do not tolerate the new Ehrlich drug as well as Wechselmann and others assume, is shown by the observations of Loeb and Gliick, each of whom observed an abortion after the injection. ^ As is known, Alt, Schreiber, and Hoppe warn practitioners most emphatically against the injection of acid solutions. .190 THE CHEMOTHERAPY OF SYPHILIS The practitioner is naturally particularly interested in the communications of fatal cases which have occurred after injections of arsenobenzol, and, respectively, whether these could be connected with the prepara- tion either directly or indirectly. Wechselmann himself had three infants with pemphigus neonatorum, who were treated with '' 606,'' and died after fever, anaemia, and in one case opisthotonus, had set in. Herzheimer also reported two such cases of the deaths of syphilitic infants. As I have already stated, Wechselmann explains these fatal cases as the effect on the weak infantile organism of the endotoxines, which have been liberated by the destruction of large quantities of spirochsetes. Schreiber and Hoppe record two fatal cases in adults, which, in the opinion of the authors, were not connected with the treatment. Iversen reports a fatal case in a woman who re- lapsed after a dose of 0-3 gramme. Acute nephritis, with haemorrhagic exanthem, set in, and the post-mortem revealed arterio- 191 THE THERAPY OF SYPHILIS sclerosis, myocarditis, and other excessive changes, which already existed in the vitally important organs. In a patient who had been ill for years, with severe disturbances of speech, auditory aphasia, etc., on a syphilitic basis, Frankel and Grouven ex- perienced typical arsenical intoxication. This occurred a quarter of an hour after an intravenous injection of 0*4 gramme arseno- benzol diluted with 15 c.c. water, and the patient succumbed three and a half hours later. Hoffmann mentions a case of death after 0*3 gramme ''606" in acid solution, and Spiethoff a further one after 0*5 gramme in a badly nourished, anaemic person. Orth showed preparations from two cases of necrosis of the gluteal muscles, after an injection of '' 606/' at the Konigsberg Meeting of Natural Philosophers. In one of the cases, death had occurred ten days after the injection ; in the other, the fatal issue had been caused by a pharyngo- laryngeal carcinoma. Quite recently details of a fatal case were 192 THE CHEMOTHERAPY OF SYPHILIS reported by Ehler. This occurred in August, 1910, subsequent to an injection of 50 centigrammes " 606/' under increasing symptoms of intoxication exclusively of the nervous system (tremor, shivering, attacks of perspiration, loss of power, etc.). True, the patient in question was paralytic, and had already suffered from two apoplectic attacks. '' Nevertheless, before he came under treatment with ' 606,' he could vege- tate, walk, read the newspapers, and under- stand various things in them.'' Post-mortem revealed no other cause of death beyond acute parenchymatosic degeneration of the organs. With regard to these fatal cases, Ehrlich expresses himself as follows : '' Out of a large number of cases, only one fatal one has been observed (at Jena) which concerns a patient, who would not have succumbed to the disease in any event. She was a weakly person, with tertiary syphilis of the larynx, to whom, for external reasons, an injection of an acid solution 193 N THE THERAPY OF SYPHILIS was given, a solution which has a par- ticularly strong local irritant effect. I believe, therefore, that in this case death was due to the effect of shock, which I hope I shall be able to avoid in future with the new methods of administration." The other groups of fatal cases, which hardly reach a dozen, concern patients ex- clusively with severe affections of the nervous system — such as tabes with cystitis and cachexia with bulbar symptoms; further, patients with extensive cortical softenings and similar cases. In one of these, microscopic examination gave the following result, which I repeat word for word : " In the case of the dead patient, micro- scopic examination showed that at the seat of the exit of the phrenic nerve from the upper cervical spinal cord, the anterior roots were embedded in diseased (infil- trated) tissue, and showed slight degenera- tive changes. It is quite possible that, in consequence of the reaction, irritant or swollen conditions (oedema ?) may have been 194 THE CHEMOTHERAPY OF SYPHILIS induced by compression of the phrenic nerve which was already sUghtly diseased, and resulted in sudden respiratory paralysis. '' Now, granting that this case in itself is grievous, I believe that its chief importance is that it shows the greatest caution is necessary in administering ' 606 ' in syphi- litic diseases of the upper cervical spinal cord. Unfortunately, as in our case, it is not always possible to diagnose these diseases with certainty.'' It is evident, from the communications on the secondary effects of arsenobenzol detailed above, that a certain organotropic action may also be attached to this prepara- tion, which occasionally leads to extremely unpleasant organic disturbances. The toxic action of arsenobenzol on the facial and auditory nerves, which Finger observed, un- fortunately gives rise to the conviction that arsenobenzol, under some circumstances, may have a very injurious toxic effect on the nerves, although to a slighter extent than atoxyl and arsacetin. 195 THE THERAPY OF SYPHILIS II. Epicrisis. There is no doubt that a great advance in the therapy of syphiHs is marked by the introduction of organic arsenic preparations into specific therapy by Uhlenhuth, and especially by Ehrlich's discovery of dioxy- diamidoarsenobenzol . For, on the one hand, the new Ehrlich- Hata preparation '' 606 '' — i,e,, arseno- benzol — appears, from evidence before us up to the present, to be at least less toxic than other similar arsenic preparations, and, on the other hand, with regard to its generally prompt and rapid action on manifest syphilitic symptoms, to surpass mercury in many cases. Even if, as the numerous relapses teach us, in the doses and application up to the present, a sterilisatio magna of the organism has certainly not been obtained in the way Ehrlich imagines, and in such a chronic and complicated disease as human syphilis certainly cannot be obtained (Uhlenhuth) ; still we must 196 THE CHEMOTHERAPY OF SYPHILIS acknowledge that arsenobenzol forms a valuable drug for us medical men in the treatment of syphilis. True, some time must still elapse, and much experience must be collected and questions explained, before we learn to employ the new remedy cor- rectly and appropriately. By means of summarising the reports on the subject before us, which have been kept as objective as possible, I think the practitioner will be in a position to judge for himself when, and respectively in what cases, he may make use of the new Ehrlich- Hata drug, how he has to administer it, and what result he may hope to obtain. With the apparently relatively slight toxic action of arsenobenzol, the prac- titioner will certainly be able to employ this new preparation in all stages of syphilis. He must use it in cases which are refractory to mercurial and iodine therapy, or which have been but little influenced by them. Fortunately, in nearly all similar cases, arsenobenzol exercises a particularly good 197 THE THERAPY OF SYPHILIS and satisfactory action. Further, it has been observed in such cases that, after an injection of arsenobenzol, mercury has again had a more favourable effect on any residue that still persists. This is also the case in forms of the disease, especially of the tertiary, malignant, and ulcerous ter- tiary periods respectively, and of hered- itary syphilis, in which a single dose of ^'606'' may often practically have a life- saving effect. In far-advanced para- and meta-syphilitic diseases of the nervous and vascular systems, it is well, as Ehrlich recommends, to abstain from the adminis- tration of arsenobenzol in general. For, in the first place, opinions are in agreement that here one may expect the least success, and, especially in advanced cases, this drug may under some circumstances have a very toxic effect. Further, arsenobenzol should be employed if frequent relapses occur a short time after a mercurial cure. If regular cases of fresh syphilis of the primary and secondary 198 THE CHEMOTHERAPY OF SYPHILIS periods are treated with arsenobenzol, some- what from the standpoint of being able to exercise a preventative or arresting effect respectively, as in early treatment, then, as is advised by Hoffmann, Neisser, Wein- traub, and others, it will be necessary, under all circumstances, to follow this up with a few drastic mercurial treatments. For it is not merely the manifest pheno- mena of syphilis we are treating, and of which respectively we wish to effect the disappearance. Even if these had healed up a short time after the beginning of the specific cure, we continued the treat- ment for a certain time. Indeed, we repeated whole cures even if the patients were free from symptoms, '' as '' (I quote from the words of W. Fischer) '' experience has taught us to regard prolonged mercurial therapy as a certain prophylaxis against further relapses and deleterious secondary diseases." Whether we may hope for the fulfilment of these expectations with arsenic prepara- tions also, and especially with Ehrlich's 199 THE THERAPY OF SYPHILIS arsenobenzol, remains to be seen from the experience of many years. In considering whether we should employ arsenobenzol in the treatment of primary and secondary syphilis, we must further be influenced by the question whether we have actually in the Ehrlich-Hata prepara- tion one which is superior to mercury, and is at the same time less toxic. We know that certain cases of the primary and secondary periods, such as large markedly indurated primary affections, severe glandular swell- ings, papulous exanthemata, and anal and genital papules, are less accessible to the new preparation than to the usual mercurial therapy. Further, most of the failures and relapses respectively, which have been ob- served up to the present, have been especi- ally in the early secondary period. With a few injections, however, of one of the usual mercurial preparations, we mostly attain the same object. Further, these have not such unpleasant, and indeed toxic, secondary effects, as may sometimes, under 200 THE CHEMOTHERAPY OF SYPHILIS some circumstances^ follow an injection of arsenobenzol. In any case, patients who have been treated with arsenobenzol in the early period of syphilis must be kept under careful supervision, even after the dis- appearance of the manifest symptoms. The present condition of their disease must be explained to them — i.e., the possibility of the appearance of relapses and the power of transmitting infection in the latent period — and above all they must be warned not to marry too soon or incautiously, or again resume sexual intercourse. I have already mentioned in discussing relapses that, in consequence of the extremely favourable first reports of the Ehrlich-Hata '* 606/' the idea has penetrated into all lay circles, '' Cure of syphilis at one stroke,'' and an explanation without reserve is imperative in the interest of universal welfare. Now, as regards the contra-indications to treatment with arsenobenzol, in the first 201 THE THERAPY OF SYPHILIS place, advanced diseases of the nervous and vascular symptoms belong here. Com- pletely compensated heart troubles, accord- ing to Grassmann, do not require to be excluded from Ehrlich - Hata treatment without further question. Naturally, great caution is necessary when other organic diseases are already present, especially of the kidneys, even when it is a question of direct syphilitic diseases of these organs. As I have already mentioned, arsenobenzol should not be applied without hesitation to diseases of the optic nerves, even if these rest on a syphilitic basis, having regard to the nature of this preparation. Further questions, such as whether we know the highest innocuous dose for the individual injections properly, whether and within what intervals of time the injec- tions should be repeated, and to what total dose we dare go without injuring the organism, are, as I also mentioned above, not yet fully explained at the present time. 202 THE CHEMOTHERAPY OF SYPHILIS Various authors repeat the injections in the event of the action being unsatisfactory, or in relapses, once to twice within shorter or longer intervals, generally in somewhat smaller doses than at the first injection. Up to the present, no specially toxic secondary effects have been observed with these repeated injections, but the cause of the disease has not always disappeared altogether. In the occasional repetition of the injections, the practitioner must exer- cise great caution, and must always take into consideration that if there is any deposit of arsenic present — such as are formed by intramuscular and subcutaneous injections, and can persist for a fairly long time — a cumulative arsenic action may easily be set up. Von Raven cautions practitioners regarding the frequent repe- tition of small doses, especially of arseno- phenylglycin, which is so closely related to arsenobenzol, because this may bring about hypersensibility, and have a toxic effect. Whether, however, the repeated injection of 203 THE THERAPY OF SYPHILIS arsenobenzol, as of atoxyl, may give rise to serious injury, especially of the optic nerves, is, in my opinion, not yet sufficiently deter- mined to permit of a general repetition of the Ehrlich-Hata drug. At the conclusion of my work, I must not neglect to express my sincerest thanks to my highly - esteemed chief. Privy Counsellor Uhlenhuth, Director of the Im- perial Health Bureau, and to my much- respected colleague. Dr. Arndt, First Assist- ant of the Imperial University Polyclinique for Skin and Venereal Diseases, Berlin, for their kind assistance. 204 LITERATURE^ Alt : " Tentative Treatment of Paralytics with Arsenophenylglycin." Mimchener Med. Wochen- schr., 1909, No. 29, p. 1457. " The Newest EhrHch-Hata Preparation for SyphiHs." Ibid., 1910, No. 11, p. 561. " On the Technique of the Treatment with the Ehrhch-Hata Syphilitic Drug." Ibid., 1910, No. 34, p. 1774. Berliner Klin. Wochenschr., 1910, No. 27, p. 1293. Ibid., 1910, No. 40, p. 1857. " The Significance of the Newest Treatment of Syphilis for Public Hygiene." Zeitschr. f. Medi- zinalbeamte, 1910, No. 14. Remarks made during discussion at the Eighty- Second Meeting of German Natural Philosophers at Konigsberg. Deulsche Med. Wochenschr., 1910, No. 41, p. 1896. AssMY : "On the Technique of Intravenous Hata Injections." Med. Klin., 1910, No. 48, p. 1898. Basch : Budapesti Orvosi Ujsdg, 1910, No. 37. Berliner Med. Gesellschaft, Therap. d. Gegenw., 1910, No. 7. 1 Up to the beginning of December, 191 o. 205 THE THERAPY OF SYPHILIS Bertarelli, Pasini, Botelli : Giornale italiano delle malattie veneree e delta pelle, 1910, No. 4. Blaschko : Report of the German Society for the Combating of Venereal Diseases, i9io,viii,,No.4. " Critical Observations on the Ehrlich-Hata Treatment." Berliner Klin. Wvchenschr., 1910, No. 35, p. 1611. Blumenthal : Med. Woche., 1902, No. 15. Med. Klin., 1907, No. 12. AND Jacobi, Therapeut. Monatshefte, July, 1907, and Deutsche Med. Wochenschr., 1907, No. 26. BiRiNGER : Therapeut. Monatshefte, August, 1903. BoHAC AND SoBOTKA ! *' On Undesirable Secondary Effects after the Employment of Dioxydiamido- arsenobenzol ('606' Ehrlich-Hata"). Wiener Klin. Wochenschr., 1910, No. 30, p. 1102. " Appendix to the Communication on Undesirable Secondary Effects after the Employ- ment of Dioxydiamidoarsenobenzol (' 606 ' Ehrlich-Hata"), Ibid., 1910, No. 31. *' Remarks on Ehrlich's Reply, ' On Vesi- cular Disturbances after the Employment of the Preparation " 606 " ' in No. 30 of this Journal." Ibid., 1910, No. 34, p. 1224. Bornemann: Miinchener Med. Wochenschr., 1905, No. 22. Brandle and Clingestein : "Results up till now with EhrHch '606.' " Med. Klin., 1910, No. 34, p. 1332. Breinl and Todd : Brit. Med. Journ., 1907, i. 19. Bressler : " The Treatment of Syphilis with the Ehrlich-Hata Drug (Dioxydiamidoarsenobenzol)." First to Third Editions, Halle-am-Saale. 206 LITERATURE Breuning : Derm. Zentralhl., x., No. 5. Citron, H., and Mulzer, P : " On the Preparation of Ready-Made Solutions of Dioxydiamidoarseno- benzol (Ehrlich-Hata '606')." Med. Klin., 1910, No. 39, p. 1531. Darrier : La Clinique ophthalmologtque, 1907, No. 3. Dobrovits : "On the Curative Effect of EhrHch ' 606 ' on the Infant through the Mother." Wiener Med. Wochenschr., 1910, No. 38, p. 2209. Ibid., 1910, No. 40. DoNAGH, Mo : Lancet, ii.. No. 10, 1910. Dorr : Wiener Klin. Wochenschr., 1910, No. 26, p. 987. DuHOT : Annales de la Poly clinique centrale, Brussels^ 1910, Nos. 5 and 6. " 606." PubHshed by the Brussels Central Polyclinique. " Unexpected Results in an Infant with Heredi- tary SyphiHs after treating the Mother with '606.''' Mi4,nchener Med. Wochenschr., 1910, No. 35, p. 1825. Ehrlich : "On the Present Position of Chemo- therapy.'' Berichteder Chem. Gesellsch., xlii., No i. " Chemotherapy of Infectious Diseases." Zeitschr. f. drztl. Fortbildung, 1909, vol. vi.. No. 23, p. 721. " Chemotherapeutical Trypanosome Studies." Berliner Klin. Wochenschr., 1907, Nos. 9-12. " On Vesicular Disturbances after the Em- ployment of the Preparation ' 606.' Reply to the Article," etc. Wiener Klin. Wochenschr., 1910, No. 31, p. 1132. Med. Klin., 1910, No. 34, p. 1322. 207 THE THERAPY OF SYPHILIS Ehrlich: "Does the Intravenous Injection of *6o6' present any Special Dangers ?" Munchenev Med. Wochenschr., 1910, No. 35, p. 1826. " Chemotherapy of Infectious Diseases.'* Zeitschr. f. cirztl. Foribildung, vol. vi., No. 23, p. 721. AND Bertheim : Pharm. Ztg., 1907, May i. Berichte der Deutsch. Chem. Gesellschafi, xl., 3293. AND Rata : " The Experimental Chemotherapy of Spirilloses." Published by Julius Springer, Berlin, 1910. English Translation, Rebman Limited, 1911. Ehrmann : " Some Remarks on the Action of the New EhrHch Preparation ' 606.' " Wiener Med. Klin., 1910, No. 38, p. 2202. Eitner, E. : " Collection of Illustrative Cases of Ehrlich ' 606.' " Wiener Klin. Wochenschr., 1910, No. 34, p. 1233. " Vesicular Disturbances and Other Secondary Effects after an Injection of Ehrlich ' 606.' " MUnchener Med. Wochenschr., 1910, No. 45, p. 2345. Emery : " The Preparation ' 606.' " Paris, 1910, No. 37. "The Treatment of Syphilis with the Ehrlich Preparation ' 606.' " Proceedings of the Eighty- Second Meeting of German Natural Philosophers and Physicians at Konigsberg, on September 20, 1910. Deutsche Med. Wochenschr., 1910, No. 41. Fauser : Med. Korrespondenzbl. d. WiirlL cirztl. Landesvereins, July, 1910. 208 LITERATURE Favento : Milnchener Med. Wochenschr, 1910, No. 40, p. 2080. Finger : Arztl. Reform-Ztg., 1910, No. 14. " The Newest Stimulants in the Domain of Syphilidology." Wiener Klin. Wochenschr., 1908, No. I, p. I. " The Treatment of SyphiHs with Ehrlich's Arsenobenzol." Ibid., 1910, No. 47, p. 1667. Fischer, W. : "On the Ehrlich Treatment of Syphilis." Therapie d. Gegehwart, September, 1910, No. 9. "Contributions to the Treatment of Syphilis with Ehrlich-Hata ' 606.' " Med. Klin., 1910, No. 45. AND HOPPE : " The Behaviour of the Ehrlich- Hata Preparation in the Human Body." Milnch- ener Med. Wochenschr., 1910, No. 29, p. 1531. Fleckseder : Wiener Klin. Wochenschr., 1910, No. 36, p. 1279. FoRBAT : Ibid., 1910, No. 40. Frankel and Grouven : " Practice with the Ehrlich Drug ' 606.' " Milnchener Med. Wochenschr., 1910, No. 34, p. 1771. FuLD : Semaine Medicale, 1910, No. 38. Furth : " Practice with Ehrlich ' 606.' " Wiener Klin. Wochenschr., 1910, No. 43, p. 1524. Galewsky : Reference, Med. Klin., 1910, No. 47, p. 1877. Gennerich : "On the Treatment of Syphilis with Ehrlich * 606.' " Berliner Klin. Wochenschr., 1910, No. 38, p. 1785. " Observations as to Place of Application and Dosage with Ehrhch's Treatment." Ihid., 1910, No. 46, p. 2o8q. 209 o THE THERAPY OF SYPHILIS Gennerich: ''On the Treatment of Syphilis with EhrHch ' 606.' " Berliner Klin. Wochenschr., 1910, No. 1735. Gerber : " On the Effect of the Ehrhch-Hata Drug ' 606 ' on Spirochaetes of the Mouth." Deutsche Med, Wochenschr., 1910, No. 46, p. 2144. G:^RONNE AND HuGGENBERG : Reports from the Wiesbaden Medical Society. Berliner Klin. Wochenschr., 1910, No. 28. Glaser: "Ehrlich'6o6.'" Editions 1-3, Vienna, 1910. Glaubermann : Berliner Klin. Wochenschr., 1907, No. 36. Gluck : " a Short Account of 109 Cases of Syphilis treated with '606/ " Miinchener Med. Wochen- schr., 1910, No. 31, p. 1638. GouRWiTSCH and Bormann : "The Ehrlich-Hata Preparation ' 606.' " Deutsche Med. Wochen- schr., 1910, No. 38, p. 1750. Grassmann : " Which Heart Diseases form a Special Contra-indication to the Employment of Ehrlich- Hata * 606 ' ?" Miinchener Med. Wochenschr., 1910, No. 42, p. 2178. Greven : Ibid., 1910, No. 40. Gr6sz : " Arsenobenzol (Ehrlich ' 606 ') in Syphilitic Diseases of the Eyes." Deutsche Med. Wochen- schr., 1910, No. 37, p. 1693. Gruter : " Arsenobenzol in External Diseases of the Eyes." Ibid., 1909, No. 10, p. 444. Hallo peau : Bulletin general de Therapeutique, June 23, 1907. AND BouDET : Bulletin de Dermatologie et de Syphiligraphie, 1907, No. 6. 210 LITERATURE Hallopeau: La CUnique, September 6, 1907 "On an Abortive Treatment of Syphilis in Thirty Days." Bulletin de VAcademie de Mede- cine, Third Series, vol. Ixiii., p. 482. Hamel, H. : " The Treatment of Syphihde by Means of Local Mercurial Injections." Annales de Derm, et de Syph., May, 1908. Hecker : " Estimation of the Efficacy of Ehrhch- Hata ' 606.' " Deutsche Med. Wochenschr igio No. 46, p. 2143. ' ' Heinrich : " Some Noteworthy Cases of Arsacetin Treatment, with Historic and Critical Remarks." Therap. Monatsh., 1910, November number Henius : Inaugural Dissertation. Giessen, 1902 Hermann : " Some Remarks on the Effect of the New Ehrlich Preparation ' 606.' " Wiener Med Wochenschr., 1910, No. ^S, p. 2202. Herxheimer : " Arsenobenzol and Syphilis." Deut. Med. Wochenschr., 1910, No. 33, p. 1517. G., AND Reinke, F. : " On the Influence of the EhrHch-Hata Drug on the Spirochetes m Congenital Syphilis." AND ScHONNEFELD, Med. Klin., 1910, No. 36, p. 1400. Heuber : Therap. Monatsch., 1910, No. 8. Heuck : Berliner Klin. Wochenschr'., 1907, No. 35 Heymann: Deutsche Med. Wochenschr iqqq No. 50. > /p \f> Hoche : Munchener Med. Wochenschr. 1905 No 14 Hoffmann, E. : " Appendix to the Work of Schaudinn and E. Hoffmann on Spirochceta pallida," etc. Berliner Klin. Wochenschr., 1905, No. 23. 211 THE THERAPY OF SYPHILIS Hoffmann, E. : *' Upon the Presence of Spirochsetes in Ulcerous Carcinoma." Berliner Klin. Woch- enschr., 1905, No. 28, p. 880. " Further Communications on the Presence of Spirochceta pallida in SyphiHs." Ibid., 1905, No. 32. " Spirochceta pallida in a Macaque inoculated with Blood." lUd., 1905, p. 46. " Further Communications on the Spirochceta pallida, with Demonstration." Derm. Zeitschr., 1905. " On the Spirochceta pallida." Deutsche Med. Wochenschr., No. 43, p. 1710. " The iEtiology of Syphilis," Julius Springer, Berlin, 1906. " Atlas of Etiological and Experimental SyphiUtic Research." Julius Springer, Berlin, 1908. AND Blumenthal : " Estimate of Sero-diagnosis in Syphilis." Derm. Zeitschr., 1908, p. 23. "The .Etiology of Syphilis." Published by Julius Springer, BerUn, 1910. "The Treatment of Syphilis with the New Ehrlich-Hata Arsenic Preparation." Med. Klin., 1910, No. 33, p. 1291. Hollander : Society of Internal Medicine (Meeting of July I, 1907). Reference in Berliner Klin, Wochenschr., 1907, No. 30, p. 974. HtJGEL AND RuETE : Milnchener Klin. Wochenschr., 1910, No. 39. Igerheimer : Berliner Klin. Wochenschr., 1910, No. 33. ai2 LITERATURE Isaac, B. : " Results with the EhrHch Preparation * 606 ' (Dioxydiamidoarsenobenzol)." Berliner Klin. Wochenschr., 1910, No. 33, p. 1528. IVERSEN : " On the Effect of Ehrlich's New Arsenic Preparation (' 606 ') in Relapsing Fever." Mtinchener Med. Wochenschr., 1910, No. 15, P- 777- " On the Treatment of Syphilis with Ehrlich's Preparation ' 606.' " Ibid., 1910, No. 33, p. 1723. Jaraux : Presse Med. Beige, 1910, No. 37. Johnston, A. : " Intravenous Injection of Soamin in Cerebrospinal Meningitis." Brit. Med. Jo urn., 1910, vol. i., p. 193. JuNKERMANN : Med. Klin., 1910, No. 35. " On the Technique of Treatment with the Ehrlich Preparation ' 606/ " Ibid., 1910, No. 40, p. 1572. JuTOCH, Mc : Lancet, ii., No. 10, 1910. JvANYi : Wiener Med. Wochenschr.; 19 10, No. 36. Kalb : " On the Action of Ehrlich's Arsenobenzol on Syphilis of Children, with Special Reference to Congenital Syphilis." Ibid., 1910, No. 39, p. 1378. Klemperer : " On the Treatment of Pernicious Anaemia." Berliner Klin. Wochenschr., 1908, No. 52, p. 2293. KowALEWSKi : " Neuritis Optica as a Relapse after Ehrlich-Hata (' 606 ')." Ibid., 1910, No. 47, p. 2141. Kren : " On the Treatment of Syphilis with Ehr- lich's Remedy." Wiener Klin. Wochenschr., 1910, No. 45, p. 1596. 213 THE THERAPY OF SYPHILIS Koch, R. : Deutsche Med. Wochenschr., 1906, No. 51 (Supplement). Ibid., 1907, No. 2. Kromayer : Biochimica e Therapia Sperimentale, ii., No. 5. Berliner Klin. Wochenschr., 1910, No. 27, p. 1294. " A Convenient, Painless Method of the EhrHch- Hata Injection." Ihid., No. 37, p. 1698. " Ehrlich-Hata ' 606 ' in Ambulant Practice." Ihid., 1910, No. 39, p. 1791. " Theoretical and Practical Considerations of Ehrlich-Hata ' 606.' " lUd., 1910, No. 34, p. 1585. Landsberger : Therapie der Gegenwart, 1907, No. 3. Lange : " On the Acquirement of the Wassermann Reaction in Cases of Syphilis treated with Ehr- lich's ' 606/ " {Berliner Klin. Wochenschr., 1910, No. 36, p. 1656. Lassar : Ihid., 1907, No. 22. Lesser, E. : " Textbook of Venereal Diseases." Tenth and Eleventh Editions. Published by Vogel. "Treatment of Syphilis in the Light of the Results of Recent Research." Society for In- ternal Medicine, Meeting of June 10, 1907. LoEB : " Experience with Ehrlich's Dioxydiamido- arsenobenzol (' 606 ')." Miinchener Med. Woch- enschr., 1910, No. 30, p. 1580. Malinowsky : Przeglad Chorob, 1910, No. 8. Maass : Berliner Klin. Wochenschr., 1907, No. 17. McDonagh: Lancet, ii., No. 10, 1910. Meirowsky : " The Effect of Ehrlich's Drug on the Syphilitic Process." Med. Klin., 1910, No. 42, p. 1653. 314 LITERATURE Meirowsky and Hartmann : " Influencing the Symptoms of a Hereditarily Syphilitic Infant through the Serum of Patients who had previously been treated with EhrUch's Arsenobenzol." Med. Klin., 1910, No. 40, p. 1572. Meltzer : New York Med. Journ., Ixxxii., No. 8. Metschnikoff and Roux : Annul, de V Institute Pas- teur, vol. xix., 1905. Mesnil and Nicolle : Ihid., 25, i., 1907. MiCHAELis, L. : Demonstration before the Berlin Clinical Society on June 22, 1910. Reference in Berliner Klin. Wochenschr., 1910, No. 28. " A Hundred and Ten Cases of Syphilis treated according to Ehrlich-Hata.'' Ihid., 1910, No. 37, p. 1695. " The Subcutaneous Administration of the Ehrhch-Hata Syphilitic Preparation." Ihid., 1910, No. 33, p. 1531. MiCHELi AND QuARELLi '. Corriere Sanitaria, 1910, No. 30. MiEKLEY : " On the Effect of Atoxylate of Mercury on Human Syphilis." Deutsche Med. Wochen- schr., 1909, No. 41. MiLiAN : Le proces medical, 1910, No. 35. Mondschein : Wiener Med. Wochenschr., 1910, No. 36. Moore, Nieren stein, and Todel : Biochemical Journal, 1907, ii., 324. Moses : Berliner Klin. Wochenschr., 1907, No. 38. MtJLLER : "On the Therapy of Primary Syphilitic Affection." Med. Klin., 1910, No. 48, p. 1899. MuLZER, P. : "On the Appearance of Spirochsetes in 215 THE THERAPY OF SYPHILIS Syphilitic and Other Infected Tissues." Berliner Klin. Wochenscher., 1905, No. 36, pp. 1144-1149. MuLZER, P. : " Collective Reference on the finding of Spirochaetes in Syphilis." Arch. /. Derm., 1906, vol. Ixxix., Nos. 2 and 3. " On the Technique and Practical Value of the Wassermann Reaction." Zeitschr.f. Immf., 1910, vol. v., Nos. 2 and 3. AND MiCHAELis : " Hereditary Syphilis and the Wassermann Reaction." Berliner Klin. Wochenschr., 1910, No. 30. See Citron. See Uhlenhuth. Neisser, a. : " Experimental Syphilitic Research from its Present Position." Julius Springer, publisher, Berlin. " On the Employment of Arsacetin (Ehrlich) in the Treatment of Syphilis." Deutsche Med, Wochenschr., 1908, No. 35, p. 1500. " On the New Ehrlich Drug." Open Letter to the Editor of the Deutschen Med. Wochenschr if t. Ibid., 1910, No. 26, p. 1212. AND KuzNiTZKi : " On the Significance of Ehr- lich's Arsenobenzol for the Treatment of Syphilis. ' ' Berliner Med. Wochenschr., 1910, No. 32, p. 1485. NocHT AND Werner : Deutsche Med. Wochenschr., 1910, No. 34. Nystrom : " EhrHch-Hata Mixture." Bjork and Borjesson, Stockholm, 1910. Oppenheim : " On the Mercury-Fast Qualities of the Spirochaetes of Syphilis, together with Remarks 316 LITERATURE on the Therapy with Ehrlich-Hata ' 606.' ' Wiener Klin. Wochenschr., 1910, No. 37, p. 1308. Pasini : " On a Simple and Practical Method of In- jecting the Ehrhch-Hata Preparation ' 606/ " Miinchener Med. Wochenschr., 1910, No. 47, p. 2461 Corriere sanitario, 1910, No. 30. Pick : Imperial Medical Society, Vienna. Reference Wiener Klin. Wochenschr., 1910, No. 26. " Report on the Results up to the Present of the Treatment of Syphilis with the Ehrhch-Hata Preparation (120 Cases)." Ibid., 1910, No. 33, p. 1193. Poll AND and Knaur : " Report of Fifty Cases of Syphilis treated with Ehrhch-Hata ' 606/ " Ihid., 1910, No. 43, p. 1521. Pritchard, R.: "A Case presenting the Early Symp- toms of General Paralysis with Recovery under Soamin." Brit. Med. Journ., 1910, vol. i., p. 192. RiEHL : " On the Treatment of Syphilis with Ehr- lich's Remedy." Wiener Klin. Wochenschr, y 1910, No. 45, p. 1594. Rosenthal : " On ' 606/ " Berliner Klin. Wochen- schr., 1910, No. 47, p. 2137. RuELE : Miinchener Med. Wochenschr., 1909, No. 14. Rumpel : Reference Med. Klin., 1910, No. 46, p. 1837. Salmon, Comptes Rendus Hebdom Soc. Biologie, March 22, 1907. Ihid., April 19, 1907. Salomon : " Treatise on the Treatment of Syphilis with Ehrhch-Hata * 606.' " Med. Klin., 1910, No. 42, p. 1652. 217 THE THERAPY OF SYPHILIS ScHANZ : " The Ehrlich Preparation ' 606 ' in Diseases of the Eyes." Munchener Med. Wochenschr., 1910, No. 45, p. 2344. ScHAUDiNN AND HOFFMANN, E. : "Current Report on the Presence of Spirochaetes in Infected SyphiHtic Tissue and in Papilloma." Arheiten aus dem Kaiserlichen Gesundheitsamte, April 10, 1905, vol, xxii., No. 2, p. 527. ScHAUDiNN : "On the Spirochaetic Result in the Juices of the Lymphatic Glands of Syphilitics." Deutsche Med. Wochenschr., May 4, 1805, No. 18, pp. 711-714- Demonstration before the Berlin Medical Society, May 17, 1905. Berliner Klin. Wochen- schr., 1905, No. 12, p. 694. Conclusion of the Discussion at the Meeting of the Berlin Medical Society on May 24, 1905. Ibid., 1905, No. 23, p. 733. " On the Spirochceta pallida in Syphilis and the Difference of this Form compared to Other Kinds of this Genus." Ibid., May 29, 1905, No. 22, p. 673. " On the Knowledge of the Spirochceta pallida.*' Deutsche Med. Wochenschr., October 19, 1905, No. 42, p. 1665, and No. 43, p. 1728. " Reply to Attestation before us (Butschli's)." Ibid., 1906, No. 2, p. 71. Discussion Remarks, Fifteenth International Congress, Lisbon, April 19 to April 26, 1906. Reference Derm. Zeitschr., vol. xiii., No. 8, p. 573. ScHiLD : Berliner Klin. Wochenschr., 1902, No. 13. Derm. Zeitschr., 1903, x., No. i. 218 LITEKATURE ScHREiBER, E. : " On the Intravenous Injection of the Ehrhch Drug ' 606/ " Miinchener Med. Wochenschr, 1910, No. 39, p. 2026. AND HOPPE : " On the Treatment of S3^philis with the Newest EhrHch-Hata Arsenic Prepara- tion ' 606.' " Ibid., 1910, No. 27, p. 1430. ScHWABE : " On the Effect of Ehrlich's Arsenobenzol on Psoriasis and Lichen Ruber Planus." Ibid., 1910, No. 36, p. 1877. Schwartz and Flemming : "On the Behaviour of the EhrHch-Hata Preparation, Arsenophenyl- glycin, of Iodide of Potassium, and of SubHmate, to the Wassermann Reaction." Ibid., 1910, No. 37, p. 1933, Seligmann and Croner : Deutsche Med. Wochenschr,, June 20, 1907. Sellei : " The CHnical Action of Ehrhch's Diamido- arsenobenzol (' 606 ')." Miinchener Med. Woch- enschr., 1910, No. 39, p. 2031. SiESKiND : " Comprehensive Report of 375 Cases treated with the EhrHch-Hata Preparation." Ibid., 1910, No. 39, p. 2027. Spatz, a. : " Current Reports on SyphiHtic Cases treated with the ' Therapia steriHsans magna ' (EhrHch-Hata Preparation)." Wiener Med. Wochenschr., 1910, No. 17. Spiethoff : Miinchener Med. Wochenschr., 1910, No. 35, p. 1822. Strauss : " Early Treatment of the Primary Syphi- Htic Affection with Mercurial AppHcations and Cauterization." Derm. Zentralbl., November, 1906. 219 THE THERAPY OF SYPHILIS Taege : " On the Successful Treatment of a Syphi- litic Infant by treating its Nursing Mother with ' 606.' " Milnchener Med. Wochenschr., 19 10, No. 33, p. 1725. '* Experiences and Observations with the Ehr- lich-Hata Preparation ' 606 ' in the Treatment of Syphilis." Ibid., 1910, No. 42, p. 2180. Thalmann : " Syphilis and its Treatment in the Light of Recent Researches/' April, 1906. ToMASCZEWSKi I " Report given before the Charite Medical Society on June 2, 1910." Berliner Klin. Wochenschr., 1910, No. 33, p. 1553. ToRDAY : *' Report on the Ehrlich-Hata Treatment." Wiener Klin. Wochenschr., 1910, No. 39, p. 1381. Treupel : " Experiences and Considerations with the New Ehrlich-Hata Drug in Syphilitic and Meta - Syphilitic Diseases." Deutsche Med. Wochenschr., 1910, No. 30, p. 1393. " Further Experiences with Ehrlich-Hata In- jections in Syphilitic and Meta-Syphilitic Diseases." Ibid., No. 36, p. 1787. Truffi : Biochimica e Therapia Sperimentale, ii., No. 5. Uhlenhuth : Discourse at the Colonial Congress, 1910. Gross and Bickel : Researches as to the Effect of Atoxyl on Trypanosomes and Spirochaetes." Deutsche Med. Wochenschr., 1907, No. 4. Discussion Remarks, Berlin Medical Society, February 13, 1907. Berliner Klin. Wochenschr., 1907, No. 12, p. 349. 220 LITERATURE Uhlenhuth : Discussion remarks, Berlin Army ]\Iedical Society, March 21, 1907. Society's Minutes. ■ AND Gross : " Researches as to the Effect of Atox}^ on Spirillosis of Fowls." Arbeit en aiis dem Kaiserlichen Gesundheiisamte, vol. xxvii., No. 2, 1907. Discussion Remarks, Berlin Medical Society, May 15, 1907. Berliner Klin. Wochenschr., 1907, No. 22. Hoffmann and Roscher : " Researches as to the Action of Atoxyl on Syphilis." Deutsche Med. Wochenschr., 1907, No. 22. Discussion Remarks, Society for Internal Medi- cine, June 24, 1907. Ibid., 1907, No. 30. Hoffmann and Weidanz : " On the Preventive Effect of Atoxyl on Syphihs induced Experiment- ally in Apes and Rabbits." Ibid., 1907, No. 39. AND Weidanz : " Researches as to the Preven- tive Action of Atoxyl in comparison to Mercury in Experimental Syphilis of Rabbits." Ibid., 1908, No. 20. — — AND Manteufel : " Chemo therapeutical Ex- periments with Some of the New Atoxylic Preparations in Spirochaetic Diseases, with Especial Reference to Experimental Syphilis." Zeitschr.f. Immf., 1908, vol. i., No. i. " On the Effect of Atoxylate of Mercury in Spirochaetic Diseases, especially in Experi- mental SyphiUs." Med. Klin., 1908, No. 43. AND MuLZER : Demonstration before the Berlin Medical Society on December 8, 1909. Berliner Klin. Wochenschr., 1909, No. 51. 221 THE THERAPY OF SYPHILIS Uhlenhuth and Mulzer : Demonstration before the Berlin Medical Society on January 12, 1910. Berliner Klin. Wochenschr., 1910, No. 4. " The Experimental Bases of Chemo- therapeutical Researches with the New Arsenic Preparations in Spirochaete Diseases, with Special Reference to the Treatment of SyphiHs." Deutsche Med. Wochenschr., 1910, No. 27. Discussion Remarks on Wechselmann's Discourse, Microscopic Society, May 20, 1910. Reference in ZentralhL /. Bakter., Supplement to Part I., vol. xlvii. Discussion Remarks on the Treatment of Syphilis with the Ehrlich Preparation ' 606.' Natural Philosophers, Konigsberg, September 21, 1910. Deutsche Med. Wochenschr., 1910, No. 41. Discussion Remarks on Roscher's Discourse to the BerHn Army Medical Society at the Meeting of November 21, 1910. Inquiry into the Effect of Ehrlich's Arsenobenzol in Syphilis. Berliner Med. Klin., 1910, Nos. 36, 37> 38, 39. 41. 43, 46. VoLK : Wiener Med. Wochenschr., 1910, No. 35. Wassermann, a., and Bruck : " Is the Complement Formation on the Arise of Specific Deposit a Phenomenon which is dependent on the Pre- cipitation, or the Effect of Amboceptors ?" Med. Klin., 1905, p. 1409. Munchener Med. Wochenschr., 1906, No. 49. Neisser, a., and Bruck, C. : '* A Sero-Diag- nostic Reaction in Syphilis." Deutsche Med. Wochenschr., 1906, No. 19, p. 755. 222 LITERATURE Wassermann, a., and Schucht : " Further Report on the Proof of Specific SyphiUtic Substance through the Anchoring of the Complement." Zeitschr. f. Hygiene und Infektionskrankheiten, 1906, p. 451. AND Plaut : "On SyphiHtic Antibodies and Cerebrospinal Fluid in Paralysis." Deutsche Med. Wochenschr., 1906, No. 44, p. 1768. " On the Development and Present Position of the Sero-diagnosis in Syphilis." Berliner Klin. Wochenschr., 1907, Nos. 50 and 51. " The Sero-diagnosis of Syphilis and its Signi- ficance in Medical Practice." Congress for In- ternal Medicine, Vienna, 1908. Miinchener Klin. Wochenschr., 1908, pp. 388 and 745. M., AND Meier, Gg. : " On the CUnical Value of the Serum Reaction," Deutsche Med. Wochen- schr., 1907, No. 32. Wechselmann : "On the Treatment of Syphilis with Dioxydiamidoarsenobenzol." Berliner Klin. Wochenschr., 1910, No. 27, p. 1292. Discourse given before the Berlin Medical Society at the Meeting of June 22, 1910. Derm. Zeitschr., 1910, xvii.. No. 7. Deutsche Med. Wochenschr., 1910, No. 32, p. 1478. " On Local and General Hyperaesthesia on the Employment of Dioxydiamidoarsenobenzol (Ehrlich *6o6')." Berliner Klin. Wochenschr., 1910, No. 47, p. 2133. AND Lange : " On the Technique of Injection of Dioxydiamidoarsenobenzol." Deutsche Med. Wochenschr., p. 1395, No. 30. 223 THE THERAPY OF SYPHILIS Wechselmann and Seeligsohn ; "On the Effect of DioxydiamidoarsenobenzolontheEye." Deutsche Med. Wochenschr., 1910, No. 47, p. 2189. Weintraub : " Experience with the EhrUch-Hata . SyphiUtic Remedy ' 606.' " Med. Klin., 1910, No. 43, p. 1683. Werner, H. : " The EhrUch-Hata Drug ' 606 ' in Malaria." Deutsche Med. Wochenschr., No. 39, p. 1792. WiCHECKiEWicz : Przeglad LekarsM, 1910, No, 39. Von Zeissl: Wiener Med. Wochenschr., 1903, No. 17. Ihid., 1907, No. 24. Ihid., 1907, No. 33. Ihid., 1910, No. 32. Ihid., 1910, No. 34. " Report on the Treatment of the First Hundred Cases with Ehrlich ' 606.' " Ihid., 1910, No. 38, p. 2203. Zernik : " Patent Charter for the Ehrhch-Hata Preparation * 606.' " Deutsche Med, Wochenschr., 1910, No. 37, p. 1716. ZiELER : " Experience with Ehrhch-Hata ' 606.' " Ihid., 1910, No. 44, p. 2040. " Development and Results of the Modern Arsenic Therapy in Syphilis." Miinchener Med. Wochenschr., 1910, No. 47, p. 2461. 224 INDEX Abdominal pain, 28 Abducens paralysis, 135, 186 Abortion after injection, 190 Absence of visual disturb- ances, 124 of patellar reflex, 179 Accelerationof pulse, 176, 188 Accommodation, paresis of, 123 Acetic acid, 58, 6j, 86 glacial, 60 solution, 63 Acetyl combination, 29 Acid, acetic. See Acetic acid carbonic, 64 para - amino - phenyl- arsenic, 12 solutions, 69, 81, 190, 192, 193 warning against in- jection of, 190 sulphanilic, 12 Acquired specific disease, 155 Action, indurating, 90 organotropic, 195 parasitotropic, 40 and secondary effects of "606," so toxic, 182 Acute nephritis, 191 syphilitic nephritis, 126 Adeps lanae anhydricum, 68 Administration of atoxylate of mercury, 34 Adults, fatal cases in, 191 Advance in therapy of syphilis, 196 Advanced nervous disease, 202 paralysis, 131 vascular disease, 202 Affections, gangrenous, 83 indurated primary, 200 of nervous system, 194 primary, 2, 4, 5, 92-98, 144, 153.154, 155, 156, 157, 159, 169 Affinity, neurotropic, 165 Air bubbles, 72 Albumin, 177, 179 Albuminuria, 35, 177 Alcohol, ethyl, 59 methyl, 54. S 6, 57 Alkali, 62 Alkaline reaction, 59 solutions, 51, S3, S4. 67, 81. 155 Alt's method, 52, S3 Alypin, 85 Amaurosis, 124, 125 Amyloid, chronic, 126 Anaemia, 191, 192 Anaesthetic, 85 Anal papules, 90, 103, 159, 200 Anamnesis, 9 Angina, 99 specific, 90, 98, I S3 225 THE THERAPY OF SYPHILIS Angina syphilitica, 22 Animal experiments, 4, 7, 34, 106 Animals, observations on, 48, 49, 68 Aniscoria, 186 Annular syphilides, 22 Antitoxines, 136 Anti-syphilitic action of atoxyl, 49 treatment, 8 Anus, 115, 157 Apes, syphilis of, 4, 20, 47 inoculation of, 48 Aphasia, auditory, 192 Apoplectic attacks, 193 Application, intramuscular, 81 subcutaneous, 81, 83 Arsacetin, 27-29, 40, 195 and blindness, 29 and deafness, 29 description of, 27 toxic action of, on optic nerve, 28 Arsenic, 138 Arsenic acid anilin, 12 action, cumulative, 203 deposit, 203 Arsenic-fast residue, 39 Arsenic intoxication, 192 neuritis, 189 preparations, 33, ly, 122, 199 residue, quinquevalent, 40 trivalent, 40 secretion of, 87 Arsenical preparations, in- jections of, 6 rheumatism, 178 Arsenicism, 189 Arsenobenzol, 48, 6^, 105, 106, 108, 109, no, 113, 116, 117, 118, 119, 120, 122, 123, 125, 126, 127, Arsenobenzol — continued : 128, 129, 130, 131, 132, 133, 134, 135, 136, 144, 146, 149, 150, 156, 157, 158, 160, 161, 162, 164, 165, 168, 170, 171, 173, 174, 178, 184, 185, 187, 190, 195, 196, 199, 200, 201, 202, 203, 204 arresting effect of, 199 best effects of, 121, 122 effect on organism, 86- 89 expectations of, 91 first report of, 89 neurotropic action of, 185 prophylactic power of, 48 therapeutic action of, 91, 92 toxic effect of, 195 value of, 197 when and how to use, 197 Arsenophenylglycin, 40-44, 46, 128, 203 chemical constitution of, 41 Arterio-sclerosis, 191, 192 Arteritis obliterans, 118 Assimilation, 86 Association of Internal Medi- cine, 30 Atonic ulcers, 160 Atoxyl, 6, 12-26, ij, 39, 40, 48, 49, 89, 112, 122, 125, 180, 195, 204 anti-syphilitic action of, 49 constitution of , 12, 13 effect of, 21-26 in human syphilis, 2 1 and mercury in syphilis, 30 226 INDEX Atoxyl, secondary effects of, 49. 125 spirillicide, action of, 49 in spirillosis of fowls, 18 and sublimate, continued application of, 29 toxic doses of, 23 toxicity of, 26 in trypanosome diseases, 30 Atoxylate of mercury, 29-37, 48, 89 administration of, 34 and rats, 3 1 secondary effects of, 34. 35 Atoxylic blindness, phases of, 25 resistance, 2$ Atrophy of optic nerve, 28, 39. 124 optical, 186 of papilla of optic nerve, 25 of visual nerves, 24 Attacks, apoplectic, 193 epileptic, 42, 188 gastric, 130 of perspiration, 193 Attenuated solutions (intra- venous injection), 56 Auditory aphasia, 192 nerves, 29, 195 organ, 187 Augmentation of diabetes, j 190 Author and Citron, method of, 6s, 64 Bandages, 86 Beads, glass, 53 Beard, papules in, 160 Behring's serum, 99 Benzine iodine, 72 Benzol nucleus, 1 5 Benzolsulph oneparamino- phenylarsenate of sodium, 37 Berkef eld's bougies, 14 Berlin Medical Society, 129, 133 Best effect of arsenobenzol, 121, 122 Bilateral specific iritis, 123 Bladder, paralvsis of, 181, 182, 188 Blaschko, method of, 62, 6^ Blindness, 24, 39 and arsacetin, 29 Blisters, pemphigous, 136, 138 Blood-corpuscles, 8/ red, 177 Blood-pressure, diminished, 176 disturbances of, 133 increased, 176 Bone disease, 103 Bonj'- processes, 1 16 Bruit, systolic, 176 Bubo, maxillar5^ 93 strumous, 97 Buccal mucous membrane, 156 Bulbar protuberance, 135 symptoms, 194 Bureau, Imperial Health, 16, 17, 29, 204 Buttocks, pain in, 81, 82 Cachexia, 194 Calcium carbonate, 64, 65 emulsion, 155 Calf of leg, 85 Calomel, 96, iii, 139 salve, 1 1 Cannula, Strauss, 79 Schreiber stopcock, 79 Carbonic acid, 64 Cardiac remedy, 133 227 THE THERAPY OF SYPHILIS Caries, 134 Cartilaginous primary forms, 93 Cases which failed to report themselves, 171 Catheter tap, Posner's, 78 Caustic soda, solution of, 50, 51. 52, 53. 54. 55. ^7> 182 Cauterisation, 6 Central nervous organs, in- jury to, 24 system, diseases of, 132 Cerebral syphilis, 116, 117, 118, 127 headache of, 105 Cervical spinal cord, 195 Chancre, 6, 22, 47, 92, 96, 108 Chancres mixtes, 97 CharitS Annates, 35 Charlottenberg United Chemi- cal Works, 30 Chemical constitution of arsenophenylglycin, 41 Chemical Institute, Virchow Hospital, 88 Chemotherapeutical experi- ments, 33 Chemotherapy of spirilloses, 33 of syphilis, 12-204 Chorioiditis, 186 Choroid, exudative processes of, 124 Choryza, 134 Chronic amyloid, 126 intermittent treatment of syphilis, 7 Cicatrix, 47, 1 1 1 Circulatory apparatus, dis- turbance of, 133 Citron and Author, method of, 63, 64 Cleansing process, 93 Cocaine, 85 Colonial Congress, 29, 42 Colonies, 18 Combined application of atoxyl and sublimate, 29 Compressed mono-sodium, 5 1 di-sodium, 51 Compression, 195 Condition of visual nerves, 125 Condylomata, 99, 10 1, 136 Congenital iritis, 1 74 specific disease of cornea, 124 syphilis, 109, 133, 155 Conjunctivitis, 174 Constipation, 179, 184 Constitution of atoxyl, 12, 13 Constriction, 130 Contraction of vessels of retina, 25 of visual field, 186 Contra-indications, 201 Cord, cervical spinal, 195 spinal, 194 Cornea, disease of, 20 congenital specific dis- ease of, 124 Corneal syphilis of rabbits, 31 Cortical softening, 194 Cranium, periostitic swelling of. 153 vault of, 116 Cubital vein, 52 Cumulative arsenic action, 203 Curative effect, momentary, 103 Cutaneous eruptions, 42 malignant syphilis, 116 Cutis, 170 desquamation of facial, 175 Cylinders, 177, 179 Cylinduria, 177 Cystitis, 194 228 INDEX Deafness and arsacetin, 29 labyrinth, 127 Death, 43 Deaths of syphilitic infants, 191 Decomposition, 182, 184 Degeneration, parenchyma- tosic, 193 Degenerative changes, 194 Deposit of arsenic, 203 Desquamation of facial cutis, 175 Destruction of spirochaetes, 174 Detrusor paralysis, 180, 188, 189 Deutschen Medizinischen Wochenschrift, 18 Deviation of course of disease 169 Diabetes, augmentation of, 190 Diagnosis and Wassermann reaction, 9 serum, 7 Diarrhoea, 178 Dichlorate, 65 Dichlorhydrate, 69 Difficulty in hearing, 187 Diffusion, 176 Di-hydrochloride of diamido- arsenobenzol, 54 Diminished blood-pressure, 176 Dioxydiamidoarsenobenzol, 44-204 formula, 45 Diphtheritic surfaces, 99 Disappearance of primary symptoms, 93, 94, 95 of reflexes, 181, 182, 183, 185 spirochaetes, 106, 107 Disease, advanced nervous, 202 of cornea, 20 Disease of intestinal tract, 176 kidney, 202 specific, 33, 163 vascular, 202 Diseased tissue, 3, 194 Diseases of central nervous system, 132 gummatous internal, 127 meta-syphilitic, 198 of mucous membrane, 99 optic nerve, 202 parasyphilitic, 132, 162, 198 of pharyngeal organs, 117 spirilla, 27 trypanosome, 15, 27, 39, 41 Disintegration of medullary sheath, 26 Di-sodium compound, 51 Distilled water, 54 Disturbances of blood-pres- sure, 133 of circulatory apparatus, 133 of heart's action, 176, 177 local, 81 optical, 38, 185 organic, 195 of speech, 192 of spinal cord, 180 vesical, 188 visual, 24, 25, 28 Dosage, 1 39-141 Dose of Hectine, 37 in intramuscular injec- tion of fowls, 46 in intramuscular injec- tion of apes, 47 in intravenous injection, 47 of apes, 47 of mercury, 5 Dosis efficiens tolerata, 41 229 THE THERAPY OF SYPHILIS Dosis maxima tolevata, 46 Dourine, 16, 29 Drastic mercurial treatment, 199 Drug exanthemata, 174 Dysarthria, 130 Dysphagia, 22 Dysphasia, 22 Dyspnoea, 190 Early stage of secondary syphilis, 98-110 treatment of syphilis, 5 Effect of arsenobenzol on primary, secondary, and tertiary syphilitic diseases, 89-139 arresting, 199 on heart's action, 69 preventative, 199 toxic, 203 Effects, secondary, -^6, 37, 38, 43, 172-195 Efflorescences, specific, 108, ISO Ehrlich drug and pregnant women, 190 " Ehrlich-Hata," 6, 44, 46, 93, 102, 107, 108, 112, 118, 121, 122, 123, 129, 135, 138, 139, 141, 153, 155, 158 " 606 " 50 injection, 127 preparation, 45 therapy, innocuousness of, 173 treatment, 147 Ehrlich and intramuscular injection, 80 and intravenous injec- tion, 80 Ehrlich's method, 5 5 Emaciation, 42, 43, 89 Embolic pneumonia, 190 Embolism, pulmonary, 190 Emulsion, 188 calcium carbonate, 155 Kromayer's, 65, 71 neutral, 72, 81, 82, 166, 190 Encapsulated foci, 166 Endotoxines, 135, 137, 174, 191. . Epicrisis, 196-204 Epilepsy, 43, 132 Epileptic attacks, 42, 188 Episcleritis, 123 Errors with regard to applica- tion of mercury, i Eruption, no of roseola, 3 Eruptions, cutaneous, 42 maculo-papulous, 90 Erythema, 174, 175 Eschar, necrotic, 114 Ethyl alcohol, 59 Eusemin, 85 Examination, microscopic, 194 Exanthem, 153, 155, 156, 159, 175 exsudativum multi- forme, 174 hsemorrhagic, 191 maculo-pustulous, 156 morbillous, 174 Exanthemata, 100, 10 1, 104, 105, 175, 200 drug, 174 haemorrhagic, 102 papulous, 34, 134 Exciter of syphilis, 2 Expectations from arseno- benzol, 91 Experimental injection of rats, mice, rabbits, etc., 15 Experiments on animals, 4, 7, 34, 45-50, 106 chemotherapeutical, 3 3 preliminary, 189 230 INDEX Exudative processes of choroid, 124 of retina, 124 Eye trouble, 165 affections, hereditary syphilitic, 123 Eyes, 185 Facial papule, 159 nerves, 195 paralysis, 118, 131, 151 Faeces, 87 Failures, 158 Fall of hair, 169 Fatal cases, 191, 192, i93 in adults, 191 of pemphigus neona- torum, 191 Fever, 83, 173, 174, i75. i/^, 191 First report of arsenobenzol, 89 Fistula, 156 Flatulence, 176 Florid specific symptoms, 147 syphilis, 44, 89, 168 Forms of application, 172 Fowler's solution, 14, 15 Fowls, spirillosis of, 17, 46, 48, 49, 106 Fresh syphilis, 198 Fuller's earth, 86 Fundus oculi, 25 Galloping syphilis, 35 Gangrenous affections, 83 Gastric attacks, 1 30 General infection, 3 reaction, 105 secondary effects, 172 treatment, when to begin it, 5 Genital papules, 159, 200 Giddiness, 28, 187 Glacial acetic acid, 60 Glands, lymphatic, 16 Glandular juices, 107 swellings, 94, 97, 200 Glass beads, 53 Gluteal muscles, 53, 83, 190 necrosis of, 192 region, 60, 65, 71, 72, 82 Gluteus, 190 Glycol, 54, 55 Gottingen Medical Society, Granulation, 33, 84 Grey oil, 37 Gumma, 113, 118, 120 laryngeal, 117 of tonsil, 114, 117 Gummata, 37, 113, ii4. ^S. 116 infectiousness of, 10 of larynx, 113 multiple, 114 subcutaneous, 113 1 Gummatous infiltrations, 22 internal diseases, 127 processes, 35, 117 syphilis, 116 ulcer, 114 wounds, 113 Haemorrhagic exanthem, 191 excrescences, 190 Hair, 87 fall of, 169 Hard palate, 115, 116 Hata injection, 186 powder, 63 Headache, 22, 28, 102, 103, 130. 135. 185, 187 of cerebral syphilis, 105 Hearing, 185 difficulty in, 187 improvement in, 128 Heart troubles, 202, Heart's activity, disturbance of, 176, 177 effect of, 69 Hectine, 37, 3 S 231 THE THERAPY OF SYPHILIS Hectine, dose of, 37 Hemianopsy, 188 Hemiplegia, 131 Hereditary syphilis, 133-139 164, 198 failure of " 606 " iri; 135 syphilitic eye affections, 123 Herxheimer reaction, 104, 105, 157 Hg, 93, 116, 121 salicylic injections, 66 Hoarseness, 99 Hollow needle, 52 Hot-air treatment, 6 water, 59 Human specific disease, S3 Hydrarg. atoxyl, 35 Hydrarg. sal, 1 1 1 Hydrargyrum oxycyana- tum, 6 Hydrochloride salt, 50 Hyperaesthesia, 43 "Hyperideal '606,' " 57, 140 Hyperleucocytosis, 86 Hyperplasia, 99, 100 Hypersensibility, 203 Hypertrophic papules, 103 Icterus, 127, 190 Ictus immunisotoricus , 166 Idiocy, 43 Immunity, 11, 18 Imperial Health Bureau. See Bureau Imperial University Poly- clinique for Skin and Venereal Diseases, 204 Impetiginous syphilide, 156 Impetigo capitis, 22, 169 Improvement in hearing, 128 Incipient diabetes, 127 Increase in weight, 88 Increased blood-pressure, 176 Indurated primary affections, 200 Indurating action, 90 Induration, syphilitic, 32 Indurations, 92, 93, 94 Infantile syphilis, 134 Infected tissues of primary and secondary periods, 105 of experimental syphilis, 106 Infection, general, 3 local, 174 spread while disease is latent, 172 transmission of, 201 Infections, 6 Infectiousness of gummata, 10 Infiltrated foci, 166 Infiltrations, 34, 83, 84, 85, 113, 134, 157, 166 gummatous, 22 nettlerash-like, 175 Influence of syphilitic re- search upon mercurial therapy, i-ii Influencing result of Wasser- mann reaction by arseno- benzol, 141-149 Inguinal gland, 157 Inhibition, involuntary, 184 voluntary, 184 Initial sores, 90 Injection, abortion after, 190 intragluteal, 134 intramuscular, 55, 58, 60, 69, 71-73, 82, 85. 87, 141, 163, 173, 203 intravenous, 57, 75-81, B>7, 88, 121, 140, 154, 167, 173, 176, 178, 192 pain of, 36, 85 repetition of, 203, 204 seat of, 65, 85, 86 subcutaneous, 60, 69, 73- 75, 88, 166, 174, 203 232 INDEX Injection, technique of, 71-81 Injections of arsenical pre- parations, 6 of mercurial prepara- tions, 6 Hg salicylic, 66 Injury, 204 to central nervous or- gans, 24 of optic nerve, 125 Innocuousness of Ehrlich- Hata therapy, 173 Inoculation of apes, 48 Intercostal neuralgia, 130 Internal organs, 109 syphilis of, 126-128 Interruption of vestibular nerves, 187 Interscapular region, 69 Intestinal tract, disease of 178 irritation of, 180 Intoxication, arsenical, 192 methylalcoholic, 182, 183 phenomena of , 28,43, i93 of sleeping sickness, Togo form, 43 of sleeping sickness. East Africa form, 43 Intragluteal injection, 134 region, 189 Intramuscular application 81, 82, 83 injection. See Injection of fowls, dose in, 46 Intravenous application, 81 82 injection. See Injection attenuated solu- tions, 56 Schreiber and Hobbe's method, 58 Schreiber's method, 75-78 Intravenous injection of fowls, 47 incorporation, 68, 69 Inunction cure, 138 treatment, 159 Involuntary inhibition, 184 Iodide of potassium, 112 Iodine, iii, 120 benzine, 72 therapy, 119, 197 tincture of, 72 I treatment, 115, 186 Iritis, 122, 123, 165 ' bilateral specific, 123 papulosa, 122 syphilitica, 23 Irritation of intestinal tract, 180 of sciatic nerve, 85 Iversen's method of intra- muscular injec- tion, 51 of intravenous inj ac- tion, 51, 52 Jarisch Herxheimer reaction, 104, 105 Joints, pain in, 174 Juices, glandular, 107 Keratitis parenchymatosa, 122, 123 Kidney disease, 202 Kidneys, ^y effect of Ehrlich drug on Knees, pam m, 188 Konigsberg Meeting of Natural Philosophers, 192 Kromayer's paraffin emulsion, 65-71 effect of, 70, 71 Labia, ulceration of, 90 Labyrinth deafness, 127 ^33 THE THERAPY OF SYPHILIS Late stage of secondary syphilis and tertiary syphi- lis, 110-119 Latent period, 201 specific disease, 157 stages, mercury in, 7 Laryngeal gumma, 117 Larynx, 115 tertiary syphilis of, 193 Lecithin, 86 Lecture to Magdeburg Medi- cal Society, 89 Leg, calf of, 85 ulcer of, 120 Legs : increased paralysis of, 188 ; pain in, 188 Lesions, primary syphilitic, 4 Lesser clinique, 20, 34, 35, 134. 182 Lesser's handle, 72 Leucocytes, 87 Leucocytosis, 86 Leucodevwia colli, 10 1 Levator palpebrse superioris, paralysis of, 185 Lightning pains, 129, 132 Lip, 155 papule of, 159 primary affection of, 93 Liquid paraffin, 66 Litmus-paper, 60 Liver, specific disease of, 127 tumour of, 60 Local disturbances, 81, 172 infection, 174 reaction, 105 secondary effects, 81 hocus minor is resistenticB, 165 Loss of power, 193 Luer syringe, 75 Lues cutanea maculosa, 134 praecox, 121 Lungs, 109 Lymphadenitis, 102, 107, 108, 109 Lymphatic glands, 16, 98, 156 Maculo - papulous eruptions, 90 exanthema, 22, 134, 156 Magdeburg Medical Society Lecture, 89 Magnesia usta, 133 Mai de caderas, 16 Malignant period, 198 syphilis, 23, 28, 35, 154, 158, 160, 163 and ulcerous tertiary forms respect- ively, 1 19-122 Manifest symptoms, 8, 171 syphilis, 196 mercury in, 7 Massage, 86 Maxillary bubo, 93 Medizinische Klinik, 135 inquiry of, 161 Medullary sheath, disintegra- tion of, 26 Mental disease, 43 Mercurial paraffin emulsion, 65 plaster, 6 preparations, 33 injections of, 6 therapy, 104, 119, 197, 200 influence of syphi- litic research upon, i-ii treatment, 115, 147, 148, 169, 186 Mercurialised animals, milk from, 139 Mercury, 28, 30, 112, 119, 120, 145, 196, 198, 200 and atoxyl, 30 atoxylate of. See Atoxy- late results of, 34 direct remedy in latent stages, 6 234 INDEX Mercury, direct remedy in manifest sy- philis, 7 in specific dis- ease, 7 doses of, 5 errors with regard to application of, i general treatment, when to begin, 2 salicylic acid, ij Meta-arsenic acid anilide, I2 Metamorphosis, regressive, 22 Meta- and para-syphilitic dis- eases, including tabes and paralysis, 128-133 Meta-s\philitic diseases, 198 Methaemoglobin formation, 88 Method, Alt's, 52, 53 Blaschko's, 62, 63 of A. Citron and the Author, 63, 64 Ehrlich's, 55 Iversen's, 51 of Michaelis, 58 of Schreiber and Hoppe, 56 of Spiethoff, 60, 61, 62 of Wechselmann, 54 and Lange, 59, 60 Methyl alcohol, 54, 56, 57, 182, 183, 184 alcoholic intoxication, 182, 183 iSIice, experimental infection of, 15 relapsing fever of, 19, 45 Microscopic examination, 194 Milk from mercurialised ani- mals, 139 Momentary curative effect, 103 Mono-dichlor hydrate, 8 1 -hydrochloride, 55 Mono-sodium compound, 5 i Morbillous exanthem, 174 Morphia, 85 Mucous membrane, buccal, 156 diseases of, 99 plaques, 98, 99 Multiple gummata, 114 MiXnchenev Medizin isch e Wochenschrift, 184 ^Muscles, bladder, weakness of, 130 gluteal. See Gluteal of swallowing, weak- ness of, 130 Myocarditis, 192 MjTcomatous tissue, -^■^ Xagana, 15 Narcotics, 86 Xaso-labial folds, 156 Natural Philosophers, Konigsberg 2\Ieeting of, 192 Nausea, 28, 176 Necessity for ophthalmo- logical examination, 125 Necrosis, 42, ^^x 84 of gluteal muscles, 192 Necrotic eschar, 1 14 Needle, hollow, 52 Negative phase, 148 reaction, 145, 146, 147, 151, 187 result, 141, 142, 143, 144, 167, 169 Nephritis, 28 acute, 191 sypnilitic, 126 Nerves, auditory, 29, 195 facial, 195 optic, 26, 123, 165, 204 diseases of, 202 phrenic, 194, 195 Nervous diseases, 140 symptoms, 180 system, 19S 235 THE THERAPY OF SYPHILIS N ettlerash-like infiltrations, 175 Neuralgia, intercostal, 130 Neuralgic pains, 85 Neurasthenics, 85 Neuritis, arsenic intoxica- tion, 189 optical, 123, 185, 186 specific, 165 Neuropathic aflfinity, 165 Neurotropic action of arseno- benzol, 185 Neutral emulsion, 58, 72, 81, 82, 166, 188 suspension, 59 Novocain, 85 Nucleus, benzol, 15 Nurse, wet, 137 Nursing mother and syphilitic infant, 136 Nutrient enema, 1 1 1 Nystagmus, 187 Observation period, 91, 168 extent of, 168 Observations on animals. See Animals Oculi fundus, 25 Oculomotoric paresis, 185 CEdema, 194 Olive oil, 36 Opacity, vitreous, 186 Ophthalmological examina- tion necessary, 125 Opisthotonus, 191 Opium, 86 Optic nerve. See Nerves atrophy of. See Atrophy toxic action of arsa- cetin on, 28 Optical atrophy, 186 disturbances. See Dis- turbances neuritis. See Neuritis Orchitis gummosa, 115 Organ, auditory, 187 Organic disturbances, 195 Organism, effect of arseno- benzol on, 86-89 Organotrophic, 40 action, 195 Organs, pharyngeal. 99 vital, 40 Os coccyx, pain in, 82 Ozaena syphilitica, 134 Pain, abdominal, 28 in buttocks, 81, 82 of injection, 36, 85 in joints, 174 in knees, 188 in legs, 188 lightning, 129, 132 neuralgic, 85 in OS coccyx, 82 of pressure, 86 at seat of injection, 183, 184 shooting, 28 Palate, 115 hard, 115, 116 soft, 115 Pallidas, 108 Palmar eminences, 157 Papilla of optic nerve, atrophy of, 25 Papules, 22, 90, loi, 107, 108, 115. 139, 155. 156, 157 anal. See Anal in beard, 160 facial, 159 genital. See Genital hypertropic, 103 of lip, 159 mucous, 159 of tonsil, 120 of vagina, 90 Papulous deposits, 161 exanthemata, 34 syphilide, 34, 134, 158, 159 236 INDEX Para-amino - phenyl - arsenic acid, 12 -arsanilic acid of sodium, 27 -arsonate Hg, 29 Paraffin emulsion, 190 Kromayer's, 65-71 mercurial, 65 liquid, 66 Paralysis, 17, 42, 128, 129, 132 abducens. See Ab- ducens advanced, 131 of bladder. See Bladder detrusor. See Detrusor of extensors, 189 facial. See Facial flabby, 118 of legs, 188 of levator palpebree su- per ioris, 185 of peroneus, 189 progressive, 128, 132 of rectus internus, 185 respiratory, 195 spinal, 129, 130 Paralytic patients, 143 Paraplegia, 131 Parasites, 18, 40, 105 Parasitotropic, 40 action, 41 Parasyphilitic diseases. See Diseases Parenchymatosic degenera- tion, 193 Paresis of accommodation, 123 oculo-motoric, 185 Paronychia, loi, 136 Parrot's pseudo-paralysis, 134 Patellar reflex, absence of, 179 Patients, paralytic, 143 specific, 143 . tabetic, 143 Pemphigoidal syphilide, 133 Pemphigous blisters. See Blisters Pemphigus neonatorum, 133, 134. 158 fatal cases of, 191 Penis, chancre on, 92 Period, early, 201 latent, 201 malignant, 198 primary, 198, 199, 200 secondary, 198, 199, 200 ulcerous tertiary, 198 Periostitic swelling of cra- nium, 153 Periostitis, 114, 116 Peroneus, paralysis of, 189 Perspiration, 87 Petri saucers, 66 Pharyngeal organs, 99 diseases of, 117 probes, 1 1 1 ulcer, 120 Pharyngo-laryngeal carci- noma, 192 Phases of atoxylic blindness, 25 Phenolphthaleln, 58, 59, 60, 61 Phenomena of intoxication. See Intoxication reactionary, 84, 174 retarded syphilitic, 114 tubero-serpiginous, 159 Phimoses, 95 Phrenic nerve. See Nerve Physiological salt solution, 52, 57 Pigment, 34, 90 Plaques, 22, 107 mucous, 98, 99 Plaques muqueuses, 161 Plaut-Vincent's angina, no Pneumonia, embolic, 190 Positive reaction, 145, 146, 147, 148, 149, 151 237 THE THERAPY OF SYPHILIS Positive result, 8, 141, 142, 143, 144, 167, 169 Posner's catheter tap, 78 Post-mortem, 191, 193 Potency, 89 Power, loss of, 193 Pregnant women and Ehrlich drug, 190 Preliminary experiments, 33 Preparations, arsenic. See Arsenic mercurial, 33 Preventative effect, 199 Primary affection. See Affections disappearance of. See Disappear- ance of lip, 93 reduction of, 93, 94, 95 inoculation of syphilis of rabbits, 5 period, 198, 199 and secondary periods, infected tissue in, 105 stage, 5 syphilis, 200 syphilitic lesions, 4 ulcer, 150 Processes, bony, 116 gummatous, 117 ulcerous, 113 Proctitis, 180 Progressive paralysis. See Paralysis Proliferation tissue, 93 Prophylactic, best, 86 power of arsenobenzol, 48 Prophylaxis, 6, 1 1 , 1 99 against relapses, 199 secondary diseases, 199 Prostitutes, 164 Prostration, 43 Protozoal diseases, atoxyl in, 16 Protuberance, bulbar, 135 Psoriasis palmaris, loi palmarum, 22 plantaris, 10 1 Pulmonary embolism, 190 syphilis, 126 Pulp, spleen - liver - bone- marrow, 4 Pulse, acceleration of. See Acceleration slowing of, 176 Puncture, seat of, 83 Pupils, reaction of, 186 retraction of, 186 Pure culture, 33 syphilis, 162 Quinquevalent arsenical residue, 40 Rabbits , corneal syphilis of , 3 1 experimental infection of, 15 syphilis of, 20, 33, 45, 46, 48 primary inocula- tion syphilis of, 5 Rats and atoxylate of mer- cury, 31 experimental infection of, 15 relapsing fever of, 19, 45 Reaction, alkaline, 59 general, 105 Jarisch-Herxheimer, 104 negative. See Negative phenomena, 84 of pupils, 186 serum, 8 specific, 33 Wassermann, 5, 7, 8, 35, 44, 79, 124, 141, 143, 144, 145, 146, 147. 151, 157. 164. 169, 187 238 INDEX Reactionary phenomena, 174 Record syringe, 63, 75 Rectum, tenesmus of, 179, 180 syphilis of, 127 Rectus internus, paralysis of, 185 Red blood-corpuscles, 177 Reduction of primary symp- toms. See Primary Reflexes, disappearance of. See Disappearance Region, gluteal. See Gluteal interscapular, 69 intragluteal, 189 Regressive metamorphosis, 22 Relapse, 147, 203 prophylaxis against, 199 Relapses, 121, 149-172 Relapsing fever, 30, 31, 49 of mice and rats, 1 9, 45 spirilla of, 46 Repetition of injection. See Injection Residue, arsenic-fast, 39 Resistance, atoxylic, 23 Respiratory paralysis, 195 Result, negative. See Nega- tive of Wassermann re- action, 9, 10 positive. See Positive Results of atoxylate of mer- cury, 34 Retarded syphilitic pheno- mena, 114 Retching, 176 Retention of urine, 179, 181, 183, 184. 188 Retina, contraction of vessels of, 25 exudative processes of, 124 Retraction of pupils, 186 Rhagades, 134 Rheumatism, arsenical, 178 Rigor, 173 Roseola, 22, 92, 100, 104, 153, 157, 169 eruption of, 3 urticarial, 157, 158 urticata, 100 Rupise syphiliticae, 10 1 Saddle-nose, 112 Salicylic acid mercury, 2)7 Saline solution, 61 Salt, hydrochloride, 50 Salts of sodium, 29 " Salvarsan," 50 Saucers, Petri, 66 Scarlatina, 175 Schreiber and Hoppe, method of, 56 Schreiber 's method of intra- venous injection, 75- stopcock cannula, 79 Sciatic nerve, 189 irritation of, 85 Sciatica, 85 Sclerosis, 94, 95, 96, 97 Sclerotic tissue, 32, 33 Scrotal tissue, 2)'!) ulcers, 32 Scrotum, syphiloma of, 33 Seat of injection. See In- jection pain at, 183, 184 of puncture, ^^ Secondary affections, 35 of atoxylate of mer- cury. 35 diseases, prophylaxis against, 199 effects. See Effects of atoxyl, 49, 125 local, 81 period, early, 200 239 THE THERAPY OF SYPHILIS Secondary period of syphilis, 37, 198, 199 phenomena, 155 symptoms, 2 syphilis, 154, 160, 165, 200 early stage of, 98- IIO Secretion of arsenic, 87 Septicaemia, 17 Septum, III Sero-diagnostic results, 143 reaction, 167 Serological examinations, 1 1 Serous fluid, 84 Serpigino-ulcerous syphilide, 115 Serum, 138 Behring's, 99 diagnosis, 7 reaction, 8 Shivering, 193 Shock, 194 Shooting pains, 28 Shoulder-blade, 60 Sickness, sleeping, 15, 16, 24, 42, 43 Side groupings, 45 " 606," 44, 45. 46, 49, SO, 65. 66, 67, 78, 94. 95, 105, 107, 108, 113, IIS, 116, 121, 122, 123, 124, 128, 129, 13s, 137, 138, 139. 142, 146, 149, IS3, ISS, 160, 164, 165, 170, 171, 173, 181, 190, 193, 196, 198, 201 (a), 60 (b), 60 action and secondary effects of, 50 " hyperideal," 57 intramuscular injection, SS solution of, 55 Skin, 87 Sleeping sickness. See Sick- ness Slowing of pulse, 176 Soamin, 38 Sodii />-aminophenylarsonas, 38 Sodium, salts of, 29 Softening, cortical, 194 Solution, acetic acid, 61 Solutions, acid. See Acid alkaline. See Alkaline attenuated, 56 of caustic soda. See Caustic Soda Fowler's, 14, 15 physiological salt, 57 saline, 61 of "606," 55 Sores, initial, 90 primary, 90 Specific angina. See Angina disease. See Disease acquired, 155 of liver, 127 mercury in, 7 efflorescences, 108, 150, 178 gravity, 178 meningitis, 117 neuritis, 165 patients, 143 reactions, $$ treatment, 2, 4, 171 and Wassermann reaction, 10 Speech, disturbances of, 192 Spiethoff's method. See Method Spinae iliacae anteriores supe- riores, 72 Spinal cord, 194 disturbances of, 180 paralysis. See Paralysis phenomena in tabes, 105 syphilis, 188 240 INDEX Spirilla, 47. 153 diseases, 27 of relapsing fever, 46 Spirillicide action of atoxyl 49 of " 606," 109, 1 10 Spirilloses, chemotherapy of, 33 Spirillosis of fowls. See Fowls atoxyl in, 18 dose of " 606 " in, 46 Spirit, 86 SpirochcBta gallinayum,iy, 19 pallida, 3, 5, t,^, 38, 104 Spirochastes, 6, 7, 17, 18, 19, 32, 33.47,48,68, 105,' 106, 122, 135, 136, ^37, 147, 148, 156, 157- 159, 166, 167, 191 destruction of , 174 disappearance of, 106, 107 Spirochjetic septicaemia of fowls, 3 1 Spirochaetosis of fowls, 3 1 Spleen -liver - bone - marrow pulp, 4 Stacre, primary, ; Sterile water, 56, 57 SUrilisatio magna, 196 Sterilise, 41 Stomatitis, 35 Strauss cannula, 79 Strumous bubo, 97 Subcutaneous cellular tissue, III gummata, 1 1 3 injection. See Injection method of, yT,, 74, 84 Sulcus CO yonarius, 156 Sulphanilic acid, 12 Suppuration, 84 Surfaces, diphtheritic, 99 Surra, 15, 16 Suspension, neutral, 59 of solutions which are ready for use, 50 Suspicious symptoms, 170 Swellings, glandular, 200 Symptoms, bulbar, 194 manifest, 8 nervous, 180 secondary, 2, 4 Synechia, 123 Syphilides, 100, 10 1, 102, 140 annular, 22 gummatous, 116 papulous. See Papulous pemphigoidal, 133 tuberculous, 22 tuberous, 114 Syphilidologists, 167 Syphilitic children, 145 disease, typical forms of, 4 diseases of the eyes, treatment with arseno- benzol, 122-126 induration, 32 infant and nursing- mother, 136 research, influence of upon mercurial therapy, i-ii triumph of, 1 1 sequelae, 131 tissues, 170 ulcers, 31 virus, 3, 4, 8, 165 Syphilis, i, 19, 20 advance in therapy of, 196 of apes. See Apes atoxyl in human, 2 1 and mercury in, 30 cerebral. See Cerebral chronic intermittent treatment of, 7 241 Q THE THERAPY OF SYPHILIS Syphilis, congenital. See Congenital cutaneous malignant, ii6 early treatment of, 5 exciter of, 2 florid. See Florid galloping, 35 gravis, ^6 hereditary, 133-139, 198 human, 33 infantile, 134 of internal organs, 126- 128 maligna, 36 malignant. See Malig- nant manifest, 196 primary, 200 pulmonary, 126 of rabbits. See Rabbits experimentally in- duced, 48 of rectum, 127 secondary. See Second- ary spinal, 188 tertiary, 28, 35, 37, 44, 109, 118, 154, 160 nasal, 113 testicular and cerebral, 115 therapy of, 34 ulcerosa praecox, 23 visceral, 127, 139 Syphiloma of scrotum, 33 Syringe, Liier, 75 Record, 63 System, nervous, 198 vascular, 198 Systolic bruit, 1 76 Tabes, 128, 129, 132, 194 spinal phenomena in, 105 Tabetic patients, 143 Tabo-paralysis, 129 Tachycardia, 176 Technique of injection, 71-81 Temperature, high, 175 Tenesmus, 178, 183 of rectum, 179, 180 Tertiary and malignant forms, 106 nasal syphilis, 113 period, 198 syphilis. See Syphilis of larynx, 193 ulcerous process, 153 ulcers, 22, 90, 115, 116, 118 Testicular and cerebral syphilis, 1 15 Therapeutic action of ar- senobenzol, 91, 92 Therapia sterilisans magna, 41. 43 Therapy, iodine, 119, 197 mercurial. See Mer- curial of syphilis, 34 Thigh, ulceration of, 113 Thirst, 178 Thrombo-phlebitis, ulcerous, 118 Thrombus, 190 Thymol acetin, 156 Tincture of iodine, 72 Tissue, diseased, 3, 194 myxomatous, 33 proliferation, 93 sclerotic, 32, 33 subcutaneous cellular, III Tongue, 153 Tonsil, gumma of, 114, 117 Tonsils, 99 Toxic action, 182 doses of atoxyl, 23 effect, 203 of arsenobenzol, 195 Toxicity of atoxyl, 26 Toxines, 105 242 INDEX Transmission of infection, 20I Treatment, anti-syphilitic, 8 drastic mercurial, 199 general, when to begin, 5 hot air, 6 iodine, 115, 1S6 mercurial. See Mer- curial specific. See Specific of s\^hilitic diseases of the ej-es with arseno- benzol, 122-126 Tremor, 193 Triumphs of sj-philitic re- search, 1 1 Trivalent arsenical residue, 40 Troubles, heart, 202 Trypanosome diseases. See Diseases atoxyl and mercury in, 30 Trj^anosomes, 16, 17 Tsetse fly, 16 Tubercle of lungs, 114, 115 Tuberculous syphilides, 22 Tubero - serpiginous phe- nomena, 159 Tuberous syphilides, 1 14 Tumour of liver, 160 T;^'pical forms of syphilitic disease, 4 Ulcer, pharyngeal, 120 of leg, 120 Ulcera dura, 94 Ulceration of thigh, 1 1 3 Ulcerations, 22, 117, 158 on labia, 90 Ulcerous, tertiary period, 196 thrombo-phlebitis, 118, 119 Llcers, 33, 37, m, 112, 113, 156 atonic, 160 Ulcers, scrotal, 31 syphilitic, 31 tertiary. See Tertiary Ulcum durum confunctivcs, 123 Ulcus molle, 97 United Chemical Works, Charlottenberg, 30 Urine, Sj, 88 diminution of, 177, 178 retention of. See Re- tention Urobilinuria, 87 Urticaria. 175 ; Urticarial roseola, 157, 158 i Uvula, 112, 11^ I Value of arsenobenzol, 197, i 19S of mercury, 2 ; Vascular system, 198 ; Vaseline oil, 68 I Vault of cranium, 116 Vein, cubital, 52 Vertigo, 176, 185, 187 Vesical disturbances, 188 Vesicles, 42 Vestibular nerves, interrup- tion of, 187 Virchow Hospital, Chemical Institute of, 88 Virus, 4 syphilitic. See S^'phi- litic Visceral SA-philis, 127, 139 Visual disturbances, 25, 28 absence of, 124 field, contraction of, 186 nerves, atrophy of, 24 condition of, 125 Vital organs, 40 Vitreous opacit}^ 186 Voluntary inhibition, 184 Vomer, 1 1 1 Vomiting, 28, 176 Vulva, 115 243 THE THERAPY OF SYPHILIS Warning against injection of acid solutions, 190 Wassermann reaction. See Reaction and diagnosis, 9 negative result of, 9, 10, 141, 142 positive result of, 5, 141, 142, 143, 157 and specific treat- ment, 10 Water, distilled, 54 Water, hot, 54 sterile, 56, 57 Weakness of muscles of swallowing, 130 of bladder, 1 30 Wechselmann's method, 54 and Lange, method of, 59, 60 Weight, increase in, 88 Wet nurse, syphilitic, 137 When and how to use arseno- benzol, 197 Wounds, gummatous, 113 244 AUTHORITIES REFERRED TO Alt, 43,45. 50, 52, 53,68, 69, 85, 87, 89, 90, 91, 92, 127, 129, 130, 140, 143, 176, 183, 190 Arndt, 204 Aschaffenburg, 116 Assmy. 78, 80 Auscherlick, 124, 145 Balzer, 21, 37 Bardachzi, 87 Bayet, 83, 119, 178 Behring, 99, 131, 188, igo Bergarth, 36 Bering, 144, 154, 159, 162, 177, 178 Bertheim, 12, 13, 45, 46 Bettmann, 162, 178 Bickel, 17, 18 Birch-Hirschfeld, 26 Blaschko, 36, 62, 74, 104, 168 Blumenfeld, 97, 99, 103 Blumenthal, 11, 15 Boas, II Boethke, 36 Bohac, 151, 179, 180, 181, 183, 188 Bonhoffer, 188 Borcher, 29 Brandenburg, 10 1 Brandle, 87, 100, 103, 120, 145. 152 Breinl, 15 Bressler, 112 Broden, 16 Browning, 27 Bruck, 1 1 Bruhns, loi, 103, 108, 145, 164 Buschke, 104, 165, 185, 189 Chrzelitzer, 94, 100, 104, 117, 163, 189 Citron, 70, 149 Clingestein, 87, 100, 103, 120, 145. 152 Cohn, 165 I Colle, II I Darier, 21, 23 j Dennecke, 96, 100, 153 I Dobrowicz, 137 I Dorr, 93, 100, 102, 120, 131, j 182 I Dreuw, 83, 164 i Duhot, 90, 127, 131, 137, 153, j 190 1 Ehler, 193, 196, 198, 199 I Ehrlich, 12, 13, 16, 23, 27, 29, 33. 34. 39, 40, 41. 43. 44, 45, 46, 49, 50, 55. 69, 80, 81, 91, 92, 104, 108, 114, 116, 117, 126, 128, 129. 137. I39> 140, 141, 146, 147, 148, 149, 151. 159, 166, 167, 168, 170, 177, 180-183, 184, 193 Eitner, 155, 161, 184 245 THE THERAPY OF SYPHILIS Fabry, 36 Fauser, 181 Fehr, 123 Feldmann, 29 Finger, 10, 11, 21, 175, 177, 182, 185, 186, 187, 190, 195 Fischer, W., 88, 121, 152, 159, 165, 185, 189, 199 Frankel, 67, 94, 99, loi, 102, 120, 127, 134, 143, 159, 174, 192 Friedlander, 117, 131, 155 Fiirb ringer, 72 Fiirth, 108 Gennerich, 95, 100, 118, 127, 142, 146, 154, 176 Gerber, 109 Geronne, 94, 95, 98, loi, 115, 127, 131, 144, 150, 159, 165, 173. ^7^< ^77' Gesser, 116 Glaubermann, 19 Gliick, 97, 99, 106, 113, 131, 144, 152, 159, 175, Grassmann, 202 Gross, Emil von, 18, 183 Grosz, 123 Grouven, 6y, 94, 99, loi, 108, 119, 120, 127, 134, 139, 143. 155. 162, 174, 192 Halberstadter, 96, 103, 145. 163 Hallopeau, 21, 38 Hammer, 29 Hartung, 159 Hata, 33, 45, 46, 47. 49, 106, 185, 186 Hauck, 21, 170, 181 Hecker, 108 Heinrich, 29 Hermann, 145 121, 163, 102, 153. 178 122, 190 102, 132, 159. 104, Herxheimer, 69, 94, 104, 109, 114, 120, 143, 154, 161, 175, 188, 191 Heuber, 88 Heymann, 28 Hoffmann, 4, 5, 6, 10, 20, 21, 102, 103, 104, 107, 119, 134, 151, 159, 176, 190, 192, 199 Hollander, 5 Hoppe, 50, 55, 56, 68,86,88, 142, 150, 190, 191 Hiibener, 17, 29 Hiiggenberg, 94, 98, loi, 102, 115, 150, 173, 178 Igersheimer, 124 Isaac, 98, loi, 115, 145 Iversen, 51, 69, 93, 94, 100, 107, 113, 140, 142, 148, 159, 173. 176, 178, 191 Jadassohn, 95, 161 Jakoby, 15 Jenssen, 28 Johnston, 39 Joseph, 155 Juliusberg, 93, loi, 119, 162 Junkermann, 67, 69, 72, 134 Kalb, 134, 138 Kaur, 188 Klausner, 87 Klemperer, 28 Knaur, 165 Koch, Robert, 16 Kopke, 16 Koster, 26 Kowalewski, 165 Kraus, 21 Kreibich, 21, 182 Kromayei, 65, 70, 73, 84, 100, 103, 113, 144, 152, 163. 176 Kusnitzki, 151 246 AUTHORITIES REFERRED TO Lambkin, 2)^, 39 Landsteiner, 10, 11 Lange, 59, 74, 87, 141 Lassar, 21 Ledermann, loi, 104, 114, 119, 131, 153, 163, 176 Lesser, E., 2, 21, 35, 36 Lesser, F., 126 Lilley, 130 Linser, 144, 154, 161, 181 Lipschiitz, loi, 102, 103, 104, 147, 159, 177 Loeb, 6y, 88, 145, 151, 190 McDonagh, 142, 162 Manteufel, 30 Marchoux, 17 Marenesco, 138 Meirowsky, 70, 115, 121, 127, 138 Mesnil, 16 Metschnikoff, 11 Michaelis, L., 11, 58, 59, 60, 69, 73, 74, 84, 95, 100, 112, 126, 131, 133, 143, 145, 162, 182 Miekley, 34, 35, 93, 94, 98, 99, 100, loi, 118, 119, 145, 155 Moore, 30 Moses, 21 Mouneyrat, 2,7 Mulzer, ^t, Nagelschmidt, 21 Neisser, A., 4, 7, 10, 11, 20, 27, 28, 38, 47, 68, 86, 93, 103, 104, 105, 132, 144, 148, 150, 151, 172, 173, 174, 176, 182, 199 Nicolle, 16 Nierenstein, 30 Oppenheim, 108 Orth, 192 Paderstein, 28 Passini, 67 Pflughoft, 29 Pick, 96, 120, 134, 142, 145, 177, 189 Pinkus, 94, 98, 159, 162, 178, 190 Plaut, 138 Pollack, 188 Polland, 165 Pritchard, 39 Profata, 1 1 Rapiport, 21 Raven, von, 43, 203 Raubitschek, 137 Ricord, 1 1 Rille, 96, 100, 154, 162, 174, 176, 181, 188, 190 Rodheim, 16 Roscher, 19, 21 Rouviere, 21 Roux, 1 1 Ruele, 29 Rumpel, no Saalfeld, E., 67, loi, 104, 163, 174 Sabotka, 151, 179, 180, 181, 183, 188 Salimpeni, 17 Salmon, 21, 27, 131, 140 Schanz, 24, 123 Schaudinn, 17 Scherber, 21 Scherschmidt, 42 Schindler, 96 Schlesinger, 133, 145, 174, 176, 177, 188 Scholtz, 106, 126, 138, 145, 159, 163 Schreiber, 50, 55, 56, 68, 75, 7^, 79, 80, 89, 93, loi, 106, 132, 140, 142, 150, 154, 163, 173, 175. 176, 190, 191 247 THE THERAPY OF SYPHILIS Schulz, 96, 97, 162, 178 Seeligsohn, 123 Sellei, 106, 182 Sieskind, 69, 74, 83, 84, 97, 100, 102, 103, 105, 106, 121, 122, 189 Solomon, 94 Sowade, 25, 27, 28 Spatz, 82, 94, 100, loi, 175, 178 Spiethoff, 60, 61, 68, j},, 95, 98, ICO, 102, 106, 113, 134, 143, 159, 174, 176, 161, 181 Stern, 96, 144, 155, 158, 159 Taege, 135, 136, 137, 160 Thalmann, 5 Thomas, W., 15, 16 Tomasczewski, 11, 47, 106 Torday, 130, 140, 145 Treupel, 87, 123, 131, 159, 162 Truffi, 104, 139 Uhlenhuth, 4, 11, 14, 16, \j . 18, 19, 20, 21, 24, 27, 29, 30, 32, i^, 34, 42, 45, 48 49, 106, 196, 204 Ulrich, 42 Volk, loi, 102, 103, 104, 147, 159. 177 Wassermann, 145, 146, 147 Weber, 117, 127, 142, 154 Wechselmann, 54, 59, 69, y-}), 74, 85, 88, 91, 92, 93, 100, loi, no, III, 112, 115, 123, 124, 125, 127, 130, 133, 13s, 141, 148, 149, 150, 152, 158, 162, 165, 166, 168, 171, 174 176, 1S8, 189, 190, 191 Weidanz, 20, 21 Weintraub, 78, 140, 199 Welander, 95, 10 1, 164 Woithe, 17, 29 Wolff, 152 Wolters, 104, 116, 127 Zeissl, von, 21, 93, 97, 116, 123, 131, 133, 139, 142, 164, 176 Zieler, -^j , 119 REBMAN LIMITED, 129, SHAFTESBURY AVENUE, LONDON, W.C. <^ ko\^ -L e><^ "^^vx ^\v^\^^^ ■'^'i^iEiiii^?'!;' iiiiipliliiiiflliiiiii^^^ "' "^'■^[.T:;;■•V^'■"■•*®^■'^■■'•'"■'■I^^^^ R|jj!;ii;-'!^:jl;*aJ.iiU>-|i^;i;^j;u,;j£i.;- -.; • : •-':'■