„iMinnfnni HX641 18355 RC201 .B17 The treatment of syp RECAP ! : **' m Columbia Unttiergi \7 ^cJjool of Bental anb (J^ral burger? jeieference l^i&rarp \ % Digitized by the Internet Archive in 2010 with funding from Open Knowledge Commons http://www.archive.org/details/treatmentofsyphiOObake THE TREATMENT OF SYPHILIS ^ "*T^ .. o ■ THE MACMILLAN COMPANY NEW YORK • BOSTON • CHICAGO • DALLAS ATLANTA • SAN FRANCISCO MACMILLAN & CO., Limited LONDON ■ BOMBAY • CALCUTTA MELBOURNE THE MACMILLAN CO. OF CANADA, Ltd. TORONTO THE TREATMENT OF SYPHILIS BY H. SHERIDAN BAKETEL, A.M., M.D. FELLOW OF THE AMERICAN COLLEGE OF PHYSICIANS; LT. COLONEL, MEDICAL RESERVE CORPS, UNITED STATES ARMY; PROFESSOR OF PREVENTIVE MEDICINE AND HY- GIENE AND LECTURER ON GENITO-URINARY DISEASES AND SYPHILIS IN THE LONG ISLAND COLLEGE HOSPITAL, BROOKLYN; ATTENDING SYPHILOLO- GIST AND CHIEF OF CLINICS, VOLUNTEER HOSPITAL, NEW YORK; GENITO-URINARY SURGEON TO THE HOUSE OF RELIEF OF THE NEW YORK HOSPITAL; MEDICAL DIEIECTOR OF THE H. A. METZ LABORATORIES; MEMBER OF THE AMERICAN UROLOGICAL ASSOCIATION, ETC. Nrai f nrk THE MACMILLAN COMPANY 1920 All nghts reserved Copyright, ig2o By the MACMILLAN COMPANY Set up and electrotyped. Published March, 1920. TO MY BELOVED FATHER, THE REVEREND OLIVER SHERMAN BAKETEL, D.D. WHOSE SAINTLY LIPE HAS BEEN AN ABHUNG SOURCE OF ADMZRATION, EN- COURAGEBtENT AND DEVOTION, THIS BOOK IS AFFECTIONATELY DEDICATED PREFACE To be successful in the treatment of syphilis, the physician must be the master of intravenous medication, for resultful treatment of lues is dependent to a very great extent on the ad- ministration of arsphenamine or neoarsphenamine. The existing textbooks covering the field of syphilis, while strong in diagnosis and prognosis, are weak in that part of treat- ment which concerns the actual introduction of arsenical prod- ucts into the system. They advise their employment but fail to give the readers in minutiae the various steps by which a suc- cessful administration is accomplished. This fact is the raison d'etre of this book. It is not a volume for the skilled syphilographer, who has a technic which is entirely satisfactory to himself, but rather is intended for those physicians who have not heretofore employed the intravenous method of injection or those whose acquaintance therewith is limited. To some the elaborate detail of description as to the preparation and injection of salvarsan may appear elementary, but in that very fact Ues its strength. A wide ex- perience in the treatment of lues with the arsenicals and a com- prehensive knowledge of this field of medical practice has dem- onstrated that many physicians are lacking in information as to the "whys, wheres and hows" of intravenous medication. It is for this great body of medical men who desire to treat intelli- gently and skillfully the luetic cases which come to their atten- tion that this book has been v/ritten. The author has drawn not only upon his own knowledge in its preparation but has also consulted the leading authorities on the disease. Credit has been given so far as known and we are in- debted to many syphilographers and professional friends for advice and help. Particular gratitude is expressed to Dr. John A. Fordyce and to Dr. Henry H. Morton for valuable suggestions and assistance. viii PREFACE as well as to Dr. Chester N. Myers, U. S. Public Health Service, and Dr. A. E. Sherndal for collaboration in the preparation of the chemistry of the arsenicals. In carrying out the professional work on which the contents of this book are based, aU brands of arsphenamine and neoar- sphenamine have been utiHzed, including the German, American, EngUsh and Canadian, but the majority of the cases have been treated with salvarsan and neosalvarsan which seem to be the counterparts of the original products. H. S. B. 1 6 Fifth Avenue, New York. CONTENTS CHAPTER I PAGE The Part of the Wassermann and Lange's Chloride of Gold Tests est the Diagnosis and Control of the Various Forms of Luetic Infection , i CHAPTER n Antiluetic Agents lo CHAPTER m The History and Chemistry of Arsphenamtne ii CHAPTER IV The Chemotherapy of Arsenic Compounds 25 CHAPTER V Indications, Contraindications and Efficiency of Arsphenamine 30 CHAPTER VI A Plan for Antiluetic Treatment 37 CHAPTER VII The Technic of Arsphenamine Administration 42 CHAPTER Vni The Technic of Neoarsphenamine Administration 69 CHAPTER IX The Methods of Employing the Mercurials and Iodides 77 CHAPTER X Reactions and Accidents Following the Use of Arsphenamine . . 88 X CONTENTS CHAPTER XI PAGE The Wassermann Reaction and the Effects of Treatment Thereon 105 CHAPTER XII The Treatment of Syphilis of the Central Nervous System. ... 114 CHAPTER XIII The Treatment of Congenital, Malignant and Visceral Syphilis 139 CHAPTER XIV Syphilitic Re-infection 150 CHAPTER XV The Cure of Syphilis 152 LIST OF ILLUSTRATIONS The Intravenous Injection of Arsphenajune: The apparatus necessary, for articles on pages 42-43 Facing p. 42 Distilling Apparatus: A simple type for physicians who have no gas, electricity or running water " "45 Distilling Apparatus: A simple and inexpensive water still for physicians who have laboratories " " 46 Apparatus for Holding Normal Sodium Hydrgxid Solution " " 49 The Intravenous Injection of Arsphenamtne: The patient, by twisting his shirt sleeve with the left hand, makes a very satisfactory tourniquet " "52 The Intravenous Injection of Arsphenamine: The introduction of the Fordyce needle into the vein " "54 The Intravenous Injection of Arsphenamine: The needle having been introduced into the vein, etc " " S6 The Intravenous Injection of Neoarsphenamene " "73 The Intravenous Injection of Neoarsphenamine: Tourniquet has been removed and the concentrated solu- tion is being introduced into the vein, etc " "74 The Intravenous Injection of Neoarsphenamine: The injection having been satisfactorily completed, etc " "76 Syringe and Needle for Intramuscular Mercurial In- jection " " 80 The Intramuscular Injection of Mercury " "82 The Intramuscular Injection of Mercury: After the area has been sterilized with alcohol or iodin, etc. . " " 84 The Intramuscular Injection of Mercury: After the mercury has been slowly deposited in the mus- cles, etc " " 86 THE TREATMENT OF SYPHILIS THE TREATMENT OF SYPHILIS CHAPTER I THE PART OF THE WASSERMANN AND LANGE's CHLORIDE OF GOLD TESTS IN THE DMGNOSIS AND CONTROL OE THE VARIOUS FORMS OF LUETIC INFECTION The Wassermann Reaction. — It is incomprehensible to think of treating a case of syphilis without the frequent utilization of the Wassermann test. While this test has been decried by certain individuals and while every careful observer will admit that it is not an infalHble test, it would be out of the question in our opinion to treat lues successfully without its employment. Throughout the pages of this book we show in the discussion of various matters of technic the occasion for employing the Wassermann reaction, because so far as we are able to determine it is an agent for the perfection of accuracy in diagnosis which is without an equal in the light of our present knowledge. Not only does it assist us diagnostically, but it also enables us to arrive more definitely at a prognosis. It would be out of place in a treatise of this sort to go into the technic of the Wassermann reactions but, in view of its very great importance, it seems advisable to discuss a few of the terms that are being used in connection with the Wassermann. Re- produced herewith are extracts written by Drs. 0. S. Hillman and A. M. Burgess for Mallory and Wright's excellent work on Pathological Technique. (W. B. Saunders Co., Philadelphia, 1918.) Complement (Alexine). — "This is a substance which is found in all fresh sera; its activity is destroyed by exposure to heat at 55° or 56° C. for half an hour. Serum treated in this way is said to be inactivated, and can be reactivated by the addition of 2 THE TREATMENT OF SYPHILIS another serum containing active complement. The sera of various animals differ in their complementary activity and also in their fixability, which is another characteristic that is possessed by complement. Anti-complementary action is a property which develops in a serum on standing or which may be present to a certain degree at the time the serum is drawn. In selecting a serum for the Wassermann reaction it is best to choose one which has the greatest degree of activity and fixabiHty. It has been found that guinea-pig serum fulfills these demands probably better than the serum of any other species. " Amboceptor. — This is a specific reaction product, which may be present in any normal serum, and which can be pro- duced in the serum of an animal by repeated injections (immuni- zation) of cells or substances (erythrocytes, serum, egg-albumin, etc.), for which it has no natural amboceptor. Amboceptors that are normally present in serum are called natural ambocep- tors ; those which are produced as the result of artificial immuniza- tion are called immune amboceptors. Amboceptors are classi- fied according to the particular substances employed in their production; for example, hemolytic amboceptors (also called hemolysins) are those that are produced by the injection of red blood-corpuscles into an animal; bacteriolytic amboceptors (bacteriolysins) are produced by the injection of bacterial ex- tracts. An amboceptor is specifically defined by prefixing the term ' anti ' to the name of the particular species employed in its production; for instance, when sheep's erythrocytes are the immunizing agent, the amboceptor is designated as an anti- sheep hemolytic amboceptor. "Complement and amboceptor are the two factors necessary in the production of serum hemolysis. This can be demon- strated by a simple experiment, as follows : immunize a rabbit to human red blood-corpuscles by means of repeated injections, thereby producing in the rabbit serum an anti-human hemolytic amboceptor. If serum from such a rabbit is brought into con- tact with a suspension of washed human red blood-corpuscles, dissolution of the corpuscles or hemolysis will take place; if, how- ever, the rabbit serum be heated to 56° C. for one-half hour (in- WASSERMANN AND LANGE'S TESTS 3 activated), and then corpuscles added, no hemolysis will occur. Finally, if normal human serum or normal guinea-pig serum be added to the mixture, hemolysis will go on as before. These three factors which enter into this reaction, namely, the com- plement, the hemolytic amboceptor, and the red blood-corpus- cles, constitute what is called, for the sake of brevity, the hemo- lytic system. "The function of the amboceptor in the above reaction of hemolysis is to sensitize or prepare the erythrocytes for the action of the complement; the latter than has the power of causing dissolution of the red cells, resulting in a clear red fluid. Neither amboceptor nor complement acting alone can produce this re- sult. For complete hemolysis a definite ratio must exist be- tween the various factors — amboceptor, complement, and ery- throcytes. The requisite strength and proportion of these three can readily be estimated by titration. " Antigens and Antibodies. — Antigens are substances which, when injected into a suitable animal, are capable of producing in that animal substances called antibodies, the latter thus being specific reaction products. Erythrocytes, bacteria, and pro- teins are examples of antigens. Under antibodies are included hemolytic and bacteriolytic amboceptors, agglutinins, and pre- cipitins. Antibodies are also found in the serum of patients suffering from infections with microorganisms. In typhoid fever, for instance, an antibody is developed in the patient's serum as a result of the action of the typhoid bacillus upon the immunizing mechanism of the body. "Generally speaking, it may be stated that antigens and anti- bodies bear a specific relationship toward one another; for in- stance, the hemolytic amboceptor produced by injecting a rabbit with sheep's red blood-corpuscles acts with these corpuscles only and with no others. The agglutination of t3^hoid bacUH by the serum of the typhoid patient is also an example of this intimate connection between antigen and antibody; this fact is made practical use of in the Widal reaction for the determination of the t3^hoid agglutinin (antibody). The phenomenon of precipi- tation is another instance of the visible and direct action between 4 THE TREATMENT OF SYPHILIS antigen and antibody. Both agglutination and precipitation are dual mechanisms requiring no intermediate agent to com- plete the reaction. "In syphilis an antibody is supposed to be developed in the patient's serum, probably through the action of the treponema pallidum. It seems to be doubtful, so far as we know at present, whether the antibody in sj^hiHs is actually specific or not. How- ever, from a practical standpoint it may be said that it is the presence or absence of this so-called syphilitic antibody that we seek to demonstrate in the serum diagnosis of the disease. " Complement Fixation. — As stated above, antigen and anti- body unite with one another specifically, and, when united, ac- quire the property of fixing or absorbing complement. This fact can be best illustrated by the interaction of two sets of antigen-antibody combination. Take, for example, a suspension of typhoid bacilli (antigen) and bring it into contact with typhoid serum (antibody) ; if complement is now added, bacteriolysis will result. That complement has been fixed or absorbed by this antigen-antibody combination is evidenced by the fact that if red blood-corpuscles and their specific amboceptor (another antigen-antibody combination) be added later, no hemolysis will occur; complement, in other words, is not available for hemolysis on account of being fixed by the first antigen-antibody combination. This is the well-known phenomenon of comple- ment fixation or deviation of Bordet and Gengou, upon which the Wassermann reaction and its various modifications are based. The so-called syphilitic antibody present in a patient's serum when brought into contact with an antigen is capable of fixing complement. This reaction is indicated by absence of hemolysis when the other two factors of the hemolytic system are added. "When the reaction was first introduced, it was thought that the antigen used in the diagnosis of syphilis was specific, as it was then made from the liver of a syphilitic fetus. This was the nearest approach obtainable to actual extracts of the causative agent, namely, treponema pallidum. It has been conclusively proved that this original antigen is not specific, as it has been WASSERMANN AND LANGE'S TESTS 5 found that extracts of normal livers, as well as other organs, and also certain lecithin preparations will fix complement in contact with not only luetic sera but also sera from patients infected with leprosy, yaws, sleeping-sickness, and malaria. The variabil- ity in the statistics of different writers is probably due to the variety of antigens employed, and at present this appears to be the principal limitation to the specificity of the reaction. "The aqueous extract of the liver of a syphilitic fetus, which is used as an antigen in the original Wassermann reaction, is not employed in the following methods on account of its instability, and, incidentally, on account of the frequent difficulty of ob- taining syphilitic fetuses. The modifications of the original test which have been devised depend, for the most part, on varia- tions in the source of the antigen and in the employment of a different hemolytic system. "Probably the most important modification is that of Noguchi, in which an antihuman hemolytic system is substituted for the antisheep and the acetone-insoluble fraction of an alcoholic extract of a normal organ (heart, liver, or kidney) is used as antigen. Plain alcoholic extracts of normal organs and of livers and spleens of syphilitic fetuses have been used by many workers in the Wassermann reaction, but at the present time the best antigen seems to be an alcoholic extract of human heart muscle saturated with cholesterin. On account of its stability for long periods, this antigen is particularly valuable, especially when reactions are done at infrequent intervals. "For purposes of distinction the two following methods will be designated as the Wassermann and Noguchi reactions respec- tively, although, strictly speaking, the name Wassermann should be applied to the original method of doing the reaction — that is, with the aqueous extract of a liver of a syphilitic fetus. "In the Wassermann reaction the patient's serum is inacti- vated in order to destroy the native complement, which is pres- ent, as a rule, in an appreciable amount. Complement of known strength necessary for the reaction is supplied by fresh guinea- pig serum. In the Noguchi reaction an antihuman hemolytic system is employed, as Noguchi maintains that, owing to the 6 THE TREATMENT OF SYPHILIS presence in human serum of varying amounts of natural am- boceptor for sheep's corpuscles, many positive reactions are rendered negative in the Wassermaim test on account of an in- crease in the total amount of amboceptor present, thus disturbing the proper proportion between amboceptor and complement necessary for complete fixation. It is not necessary to inactivate the patient's serum in the Noguchi reaction, as the human com- plement is only very slightly hemolytic for corpuscles of the same species, and also because the amount of complement present is practically negligible, owing to the small quantity of patient's serum used for the test." Dr. Archibald McNeil, director of laboratories of the National Pathological Laboratories, differs from the statement above that cholesterinated antigen is the best and most reliable one to employ. Such an antigen may at times give positive results in cases free from luetic infection, and, for this reason. Dr. McNeil believes that the plain alcoholic antigen is much safer and gives results that coincide more closely with clinical findings than does the cholesterinated antigen. The latter undoubtedly gives positive results in a number of latent and treated cases of lues in which the plain alcoholic extract antigen gives negative re- sults. Dr. McNeil feels it would be better to obtain negative re- sults in a positive case of lues than positive results in negative cases, especially as it is generally understood by the medical profession that a negative result does not exclude the possibility of luetic infection. Very few practitioners are qualified by experience to make the Wassermann test, and those who are interested in it and desire the exact technic are referred to Mallory and Wright's book. Lange's Colloidal Gold Test They will find therein also a good description of Lange's col- loidal gold test of the cerebrospinal fluid in syphilis. This test is easily and quickly made. "It consists, " says Dr. John A. Fordyce (Am. Jour. Med. Sci., October, 1916) " of a series of color changes which occur so characteristically and constantly that they may WASSERMANN AND LANGE'S TESTS 7 be said to be specific. It is performed with ten dilutions of spinal fluid in geometrical progression from i to 10 to i to 5120. The color change depends on the amount of colloidal gold precipi- tated and varies from the negative salmon red through red blue, Klac or blue, blue gray or gray, and colorless. These changes may be plotted in curves or are arbitrarily expressed from zero to five. A negative colloidal gold would show no change and would therefore be expressed as 0000000000. In tabes and cere- brospinal syphiHs the reaction occurs in the lower dilutions with the intensity of the change in the third and fourth or fourth and fifth tubes. The term 'luetic zone' or 'luetic curve' is used to describe this reaction. The reading would be as follows: 1 133 200000 or 1223320000. In meningitis of non-syphilitic origin the maximum change occurs beyond the syphilitic zone — that is, in the higher dilutions — while in paresis precipitation of the colloidal gold occurs regularly in the first four to eight tubes with decolorization or a turbidity, and the reading represented as 5555431000 or as many fives as there are decolorized tubes. To this zonal change Miller and Levy applied the term ' paretic curve.' A properly standardized — that is, a neutral solution of colloidal gold — shows either no change at all with a normal spinal fluid or produces a slight variation with a bluish nuance in the first four or five tubes which is negligible. Some cases may even give a change to a frank red blue in the first four tubes, so that the reading would be iiiioooooo, but with aU the other laboratory findings negative it has been shown this had no diagnostic import. "It may be said," continues Fordyce, " that, as a rule, there is a parallelism between the other positive findings in the fluid and a positive gold reaction. The significance of any one of the in- dividual abnormahties must be appreciated before a proper in- terpretation can be placed upon the laboratory findings. We know that a lymphocytosis alone is not pathognomonic of syphilis as a mild grade is met with in other affections of the central nervous system and that the cell count cannot be relied upon to differentiate between tabes, cerebrospinal S3rphilis, and general paresis, as an equally high pleocytosis may be met with in any of 8 THE TREATMENT OF SYPHILIS these conditions. So too the presence of globulin alone indicates organic disease of the brain or cord, but does not separate sjTphilitic from non-syphilitic disease. " More positive information is derived from the complement- fixation test, as a positive Wassermann occurs only in lues. How- ever, his test by itself does jiot supply a differential diagnosis as fixation to 0.2 c. c. or lower is met with not only, in paresis but in some cases of progressive tabes 3-nd cerebrospinal syphilis. On the other hand, with a distinctly syphilitic process, as in cerebral endarteritis, abortive or stationary forms of tabes, and some types of cerebrospinal syphilis, the Wassermann may be completely negative. In the last-named cases a supplementary gold test is of value in demonstrating the luetic nature of the condition. Its greatest value and by far most prominent role, however, is in distinguishing between paresis and the conditions which simulate it as well as its prognostic significance in tabetics who show no mental impairment but give a paretic curve. Since the application of the gold sol test a number of patients in whom no cerebral involvement was suspected have given the curve characteristic of paresis." Clinical Application of the Wassermann Reaction This subject is so succinctly set forth by Dr. Henry H. Morton of Brooklyn in his admirable book {Genito-Urinary Diseases 6° Syphilis, p. 739, 1918, C. V. Mosby Co., St. Louis), that it is presented here in Mo: ''The diagnostic value of the Wassermaim test depends upon the fact that the antibody contained in the serum causing the reaction is specific, occurring only in the serum of luetics. Ex- cept in rare instances this has been found to be true. Positive reactions have been obtained in frambesia, relapsing fever, trypanosome infections, and tubercular leprosy. It is also found positive after veronal, morphin, scopolamin, ether narcosis (Wolfsohn), and frequently in sera obtained just before or after death. Therefore, while it is true that a positive reaction is ob- tained in a few diseases and conditions other than sjrphilis, the WASSERMANN AND LANGE'S TESTS 9 differential diagnosis between syphilis and those diseases should not be difficult, at least in this country, and the reaction may be said to be practically specific. "A negative reaction, on the other hand, can not be accepted as proof that the disease does not exist, as negative findings have been obtained in a small percentage of active cases of syphilis. If, however, a negative reaction is repeatedly obtained after several trials made at intervals, it is almost positive proof that the disease is not present. The reaction appears from two to four weeks after the appearance of the initial lesion, and persists throughout all stages of the disease unless influenced by treat- ment. A positive reaction has been obtained forty or fifty years after infection. Quite often a positive reaction may be obtained before the appearance of secondary symptoms. In the active stages of the disease 95 per cent of cases give a positive Wasser- mann reaction and at least 75 per cent of tertiary cases. In latent cases of the disease, while the continued existence of the spirochetse renders the patients liable to outbreaks of symptoms at any time, nevertheless, the organism is often in a dormant state, which makes the appearance of symptoms less likely. In these latent cases a positive reaction is obtained in 50 per cent of the cases. It is in this class of cases that the Was- sermann reaction is of special value as these patients are often apparently healthy and may give no history of ever having had the disease. Oftentimes a negative reaction in these latent cases may be transformed into a positive reaction by the administra- tion of a short course of mercury or salvarsan." CHAPTER II ANTI LUETIC AGENTS In the constitutional treatment of S3^hilis dependence is placed mainly on three drugs, arsenic, mercury, and iodin in the form of the iodides. The preparations mostly used are: Arsenic Mercury Given by Intravenous, or Intramuscular, or Subcutaneous Injection or by rectum Given oraUy Arsphenamine Neoarsphenamine Protiodid Bichiorid Mercury with chalk Biniodid Calomel Blue Mass Iodides By Fumigation Calomel Inhalation ' By 1 Inunction Oleate — lo per cent Unguentum hydrarg)^! - Bichiorid By Hypodermic Injection in Gluteal Soluble Succinimid Biniodid Benzoate Muscles Insoluble Salicylate Calomel Gray oil Given Potassium ioc lid By Hypodermic Injection By Enema or Sodium iodid Ammonium i( Ddid Intravenously ^ Strontium ioc lid CHAPTER III THE HISTORY AND CHEMISTRY OF ARSPHENAMINE Before the knowledge of chemotherapy had reached its present stage, arsenic compounds had been used haphazardly for the cure or alleviation of syphilis and other protozoal diseases for many years, probably just as long as mercury. At first only inorganic arsenic derivatives were known, but with the exten- sion in the field of preparative organic chemistry which occurred early in the 19th century, some organic combinations of arsenic became known which were used to some extent in therapy. The recent development in the use of arsenic compounds in medicine received its original impetus in the discovery of the curative action of atoxyl ^ on sleeping-sickness. The chemical struc- ture of this substance, which was obtained by the action of arsenic acid on aniline, was first correctly explained in 1907, when Ehrlich demonstrated that it was the sodium salt of para-amido-phenyl arsinic acid.^ The possibility of subject- ing this substance to the chemical transformations character- istic of benzol derivatives was thus opened, and from then on attention was chiefly centered on such aromatic organic arsenic derivatives because of their comparatively low toxicity and apparent curative properties. In addition to atoxyl, "Hec- tine," a benzene sulfonate of atoxyl,^ NaO\ 0=A < > -NHSQ2C6H6 HO/ *'Arsacetin," an acetyl atoxyl,^ NaO\ O = As < > -NHC0CH3 HO/ 5 and "Asiphyl, " a mercury salt,' [NH2-C6H4-AsO(OH).0]2Hg were proposed as therapeutic agents. 12 THE TREATMENT OF SYPHILIS Aflanity between Certain Living Cells and Chemical Sub- stances. — The haphazard method of using these compounds stopped with the development of a definite theory of specific affinity between certain living cells and certain chemical sub- stances, and its practical application to internal antisepsis for the cure of trypanosome and spirochsetal diseases. Binz and Schuiz ^ had found that arsenic acid was reduced in animal tissues to arsenious acid. It had also been noted that cacodylic acid was reduced in the organism. Ehrlich concluded from this that the arsenic compounds which had been used hitherto, and which were all derivatives of pentavalent arsenic, did not exercise an action on the parasites until after they had been reduced by the organism to the trivalent form. Investigation along this hne led to the greatest advance in the preparation of therapeutically valuable substances. It was found that by reducing the pentavalent compounds of arsenic to the trivalent form an enormous increase in the power to destroy the parasites which cause disease was developed. For example, para-oxy-phenyl arsinic acid does not kill try- panosomes in dilutions as strong as i or 2%, whereas if reduced to the corresponding trivalent arsenic compound, para-oxy- phenylarsenoxide, it kills trypanosomes quickly in dilutions of I to 10 million.^ Further investigation led Ehrlich to conclusions in regard to the mechanism of the action of these drugs on the parasites, which form the basis of the theory of arsenic chemotherapy as at present generally accepted. According to this theory the parasite possesses certain points of attack, termed by Ehrlich " chemoceptors " which have a specific affinity for certain chem- ical groups, of which trivalent arsenic is one. Other groups, such as the amido (NH2), the hydroxyl (OH), appear to anchor them- selves to definite parasites and so exert on them the specific drug action. The Discovery of Salvarsan By a combination of work in chemical synthesis and biological examination along the lines of this theory, covering many years^ HISTORY AND CHEMISTRY OF ARSPHENAMINE 13 Ehrlich and his co-workers arrived at a substance which has pro- duced very remarkable therapeutic results. It was originally im- ported under the name "Salvarsan" and its manufacture in this country by Federal license under the name " Arsphenamine " has become an important factor in the industry of synthetic drugs. Several milHon ampules of arsphenamine and its compounds have been manufactured and distributed in this country, and the Government's campaign against venereal disease in which arsenicals of this t3Ape will play an important part, has still further increased the necessity of production on a large scale. In the work which led to the preparation of salvarsan, the object sought after was a substance which would combine maximum toxicity to the disease-producing parasite with min- imum toxicity to the organism which harbored the parasite. The measure of the former is the curative dose, of the latter the tolerated dose. The success in attaining this object may be judged by a comparison of the ratio of curative to tolerated dose in some of the better known arsenicals: atoxyl 1:2, arsacetin 1 13, arsenophenyglycine i :2, salvarsan 1 158.^ Preparation of Arsphenamine The preparation of arsphenamine involves a number of chem- ical processes in a field which is comparatively complicated and requires a large amount of special knowledge. It is further complicated by the necessity of extra precautions on account of the great susceptibility of the final product to chemical and physical influences. A great variety of methods for its produc- tion have been proposed but as might be expected the number of processes used for practical purposes is comparatively limited. The first step in the synthesis of the aromatic organic arsenic compounds is the introduction of arsenic into the benzene nu- cleus. The methods which have been applied commercially for this purpose are probably limited to three. I. The Bechamp condensation, melting arsenic acid with aniline to produce arsanilic acid,^ or with phenol to produce para-oxy-phenyl arsinic acid.^° The best yields are obtained 14 THE TREATMENT OF SYPHILIS in the aniline melt. The process must be carefully regulated as to proportions of reagents and temperature, in order to obtain the best results. With high temperatures and an excess of aniline, the tendency to the formation of secondary arsanilic acid is increased. With phenol the condensation appears to give less satisfactory yields, although as a step in the preparation of arsphenamine it has the advantage of leading more directly to the goal. 2. The arseniation of dimethylaniline with arsenic trichloride, leading to N-dimethyl arsanilic acid. This process appears to be used in connection with French patents for the manufacture of arsphenamine.^^ 3. Bart's reaction, coupling diazo compounds in alkaline solution with sodium arsenite. This method is capable of very wide appUcation and starting from para-amido-acetanilide has been appUed commercially to the production of arsanilic acid.-^^ From the arsinic acids produced by these methods a large number of derivatives can be obtained, by the usual chemical reactions on benzene compounds. The practical production on a large scale of some of these requires considerable elaboration. The Immediate Mother Substance of Arsphenamine The immediate mother substance of arsphenamine is 3-nitro- 4-hydroxy-phenylarsinic acid. A large number of procedures for the preparation of this substance have been proposed. One of the methods generally used starts from parahydroxy-phenyl arsinic acid, obtained by the action of arsenic acid on phenol, or by the diazotization and hydrolysis of arsanilic acid. This hydroxy acid is then nitrated at a low temperature to form the nitrohydroxy acid. Another method consists in combining ar- sanilic with oxalic acid, nitrating the resulting oxalyl compound, subsequent saponification and hydrolysis v/ith strong caustic potash leading to the nitro-hydroxy acid which is used for con- version into arsphenamine. The 3-nitro-4-hydroxy-phenyl arsinic acid used for the produc- tion of arsphenamine can and should be prepared in a high state HISTORY AND CHEMISTRY OF ARSPHENAMINE 15 of purity. Arsphenamine itself cannot be purified, consequently all possible extraneous material should be eliminated, previous to the final step in the manufacture. From 3-nitro-4-hydroxy-phenyl arsinic acid, the process of pre- paring arsphenamine consists in a reduction of the nitro to an amino group and a partial reduction of the arsenic acid group, forming a double bond between two molecules. The resulting insoluble arseno base is then isolated, converted into its soluble dihydrochloride, isolated by suitable precipitation, dried thor- oughly in a high vacuum, and packed in ampules in vacuum or inert gas. If the reduction is carried too far, highly toxic arsines may be formed, if the reduction is insufficient or improperly carried out, the nitro group may be left intact, or the arsenoxides formed. Several methods for the reduction and subsequent treatment have been proposed. The original scheme was a progressive reduction, first of the nitro group by means of sodium amalgam, then of the arsenic group by the action of sulfur dioxid in acid solution with potassium iodid as a catalyst. ^^ Kahn patented a procedure involving a complete reduction to the primary arsine, which was then added to a solution of the amino-phenyl- arsenoxid with which it combined forming the arseno base.^"* The reduction by means of phosphorous or hypophosphorous acid has also been described ^^ and the use of zinc dust, zinc chlorid and sulfurous acid has been subject of patents. ^^ For the practical purpose of large-scale production sodium hydrosulfite has probably been used exclusively, and under proper conditions has proven an ideal reagent, although it introduces the necessity of removing certain impurities from the crude arseno base. When this method is used the reduction takes place in one stage, and the arseno base, being insoluble in the medium, can be filtered directly. For the preparation of the dihydrochlorid, a method has been patented for the precipitation of a solution from hydrochloric acid.^^ The generally used procedure consists in dissolving the base in methyl-alcoholic hydrochloric acid and precipitation of the dihydrochloride by means of ether, ^^ i6 ■ THE TREATMENT OF SYPHILIS In the final steps of the manufacture of arsphenamine it is important to exclude atmospheric oxygen. In the reduction by sodium hydrosulfite, this is taken care of by the sulfur-dioxid formed by the oxidation of the hydrosulfite. During the filtra- tion of the base, the preparation of the dihydrochlorid and its final isolation, air should be replaced by carbon dioxid or other inert gas. To insure a product of maximum stabihty, it must be carefully dried in high vacuum, and all subsequent operations conducted in an atmosphere of inert gas. There appears to be some doubt as to whether such careful precautions are reaUy necessary and it is possible that a pure arsphenamine, particularly after moisture and solvents have been removed, is a very much more stable substance than ap- pears from some of the hterature on the subject. There is no doubt, however, that in view of the nature of the material and the use to which it is put, the best method of procedure is to adopt every possible precaution in the manufacture, even at the risk of overdoing it. Explanatory Diagrammatic Outline The large number of proposed chemical procedures for the preparation of arsphenamine and its intermediates is outlined in the following charts, which show the chemical relationship of the various substances to the final product, arsphenamine. § Z 2 Ky^ _Z - ~ *E 0*i ■ ->< M ^ I td o«i r-** * 4.Z L.. O^jO O'l I I I I o e ■T"T ^ HISTORY AND CHEMISTRY OF ARSPHENAMINE 19 It would appear that every conceivable avenue of approach has been utilized for the preparation of arsphenamine. It is probable, however that only a few of these proposed methods have been applied to practical production of the material. The value of any single method can only be judged by extensive study and application to the production of material which is satisfactory chemically, therapeutically and economically. The considerable physical and chemical variations in different brands of arsphenamine as now obtainable, indicate that the processes used by different manufacturers vary to some extent either in principle or method of manipulation. Color and solubil- ity in solvents, particularly in methyl alcohol, and the ease v/ith which the material forms aqueous solutions differ decidedly with different brands. The arsenic content varies from about 29 to about 33 per cent. Since the theoretical arsenic content of pure arsphenamine is 34.2 per cent, these figures represent great variations in purity and may affect the dosages used in biological tests and clinical practice by as much as 10 per cent. The im- purities which produce this low arsenic content as far as at present known consist of moisture, various amounts of solvents, inorganic material, and sulfur. These variations in the product no doubt have an important bearing on variations in clinical results and the advantages of standardizing the preparation are obvious. The Manufacture of Arsphenamine At the present time most American manufacturers produce arsphenamine in comparatively small batches, of 500 or 1,000 grams, and a recently pubhshed English monograph on organic arsenicals notes with apparent satisfaction that batches of 1,500 grams are being produced. For quantity production this small scale involves the employment of many assistants, working in shifts, and an obvious possibility of insufficient control resulting in a lack of uniformity in the product. By calling to aid the mechanical means well known to the chemical engineer, so as to insure absolute and constant control throughout the process,, it has been found possible to produce salvarsan in batches of over 20 THE TREATMENT OF SYPHILIS 7,000 ampules at a time. Careful comparisons have shown that the material manufactured on this scale is as good or better than can be obtained from small laboratory batches in which identical raw materials are used. The capacity of a plant operating on this basis is about 14,000 ampules of 0.6 gram every 14 to 16 hours. This large-scale production also has the advantage of insuring the absolute identity of a large amount of material, from which data can be obtained in regard to the influence of technic and personal factors on the results obtained from the administration. At the same time it gives the practitioner complete assurance as to the uniformity of a product should he desire to use many doses of one batch on a series of patients for purposes of comparative study. The product is uniform chem- ically, toxicologically and therapeutically. It is identical in every respect with the original preparation upon which the therapeutic reputation of the drug was established. It is tol- erated by test animals in doses of 120 mg. and higher pro kilo body weight which represents a very low toxicity as compared with other drugs used in a similar manner. A criticism of arsphenamine may be made on the ground of inconvenience in administration. The product occurs in the form of its dihydrochloride, which should be readily soluble in water of ordinary temperature. This solution is not suitable for injection, however, until the hydrochloric acid has been neu- tralized and the arsphenamine then further converted into its di-sodium salt. The addition of the improper amount of alkali for this purpose, either too much or too little, produces solutions which may give trouble in injection. If the arsphenamine requires hot or boiling v/ater to form the solution, the preliminary preparation of the intravenous solution becomes still more com- plicated, and more possibilities of affecting the proper action of the drug are introduced. The Evolution of Neoarsphenamine With the idea of simplifying the technic of administration, modifications prepared from arsphenamine have been intro- duced which dissolve readily in water, forming solutions wliich HISTORY AND CHEMISTRY OF ARSPHENAMINE 21 are ready for injection without further manipulation. Of these, neoarsphenamine is coming largely into favor, since in addition to its convenient administration it is also less toxic than arsphen- amine. This substance is prepared from arsphenamine by com- bination with sodium formaldehyde sulfoxylate. It occurs in the form of its yellow sodium salt, readily soluble in water with slightly alkaline reaction. This product is being manufactured on a large scale in the United States and a very extended use in clinical practice has given satisfactory results. The dry sodium salt of arsphenamine has also been proposed as a more convenient form for administration. This dissolves readily in water forming a solution which corresponds exactly to that obtained in the preparation of a properly alkalinized ar- sphenamine solution. It has been manufactured in this country, but does not appear to have come into any extended use. A number of other arsenicals have been proposed as substitutes for or as improvements on arsphenamine. Since arsphenamine is a patented product and can only be manufactured under license, it is obvious that many attempts to introduce competitive products will be made. So far, no other arsenical has shown advantages which would enable it to replace or compete with arsphenamine to any marked degree. The Precursors of Arsphenamine During the work which culminated in the preparation of ars- phenamine, a very large number of other arsenicals were syn- thesized and studied, some of which were for a time used in therapy. They may be considered as the precursors of arsphe- namine, and the results of their use indicated the lines along which improvements might be effected. As already noted, atoxyl was the first of the extensively used aromatic organic arsenicals. This was replaced later by its acetic acid derivative under the name of arsacetine. After EhrHch took up the study of these arsenicals and dis- covered the decided increase in trypanocidal efficiency caused by their reduction to the trivalent arseno compounds, phenyl- 22 THE TREATMENT OF SYPHILIS glycine-arsinic acid was introduced as No. 418 in his experi- mental series. Its sodium salt, under the name "spirarsyl" con- stituted an important advance over atoxyl and its immediate derivatives, and was the most successful remedy among the arsenicals which preceded salvarsan. It was later replaced by salvarsan, No. 606, of Ehrhch's series, which represents the culminating point of this line of research. Attempts to simpHfy its use in therapeutics led to the introduc- tion of neosalvarsan and salvarsan sodium which have already been described. The former is numbered 914 in Ehrhch's series. Working along the same line and with a similar object in view, Mouneyrat prepared a phosphamic acid derivative of arsphen- amine which was marketed under the name "Galyl" No. 11 16, and subsequently a complex disulfonamide of arsphenamine appeared under the name "Ludyl," No. 1151 of Mouneyrat's series. These preparations both belong to the neoarsphena- mine type of arsphenamine derivatives, intended to produce neutral or feebly alkaline solutions ready for injection without preUminary manipulation. Other Arsphenamine Derivatives Another type of arsphenamine derivatives which have received considerable attention are the co-ordination compounds with various metals. This interaction, discovered during Ehrhch's researches on salvarsan, appears to be a general one with organic arsenical compounds, although on account of their therapeutic importance it is chiefly the co-ordination compounds of arsphena- mine which have been studied. Danysz prepared co-ordination compounds of arsphenamine with silver salts, and introduced "Luargol" in which the action of the drug is reinforced by silver bromide and antimony oxide. A large number of other co-ordination compounds of arsphena- mine and neoarsphenamine have been studied, in which salts of mercury, silver, gold, copper and platinum are in combination, but the preparations mentioned above are the only ones which have been used therapeutically to any extent. The same applies HISTORY AND CHEMISTRY OF ARSPHENAMINE 23 to other modifications of the molecule, in which the various char- acteristic groups have been substituted or rearranged with a view to modifying or improving the therapeutic action. It is not many years ago that the chemistry of the organic arsenic compounds occupied only a very modest place in chemical literature, but in recent years, the interest in their therapeutic application has developed a voluminous record of research and experiment along these lines, and several monographs on or- ganic arsenicals have been published. The chemical structure of the arsenicals mentioned above is shown in the following cut, and also some of the modifications of arsphenamine which have been patented with the object of introduction as arsphenamine substitutes. They will indicate some of the lines along which attempts are being made to improve or replace the products which are now in use. Spirarsyl — sodium arsenophenylglycinate No. 418 in Ehrich's series NHCHaCOONa NHCH2C00Na C6H4 — As = As — C6H4 Galyl — dihydroxy-arsenobenzene-phosphamic acid No. 1 1 16 of Mouneyrat's series HO.CeHg— As = As— CeHg.OH NH^-_^,,^NH P.O(OH) LuDYL — benzene-disulphamino-bis-amino-dihydroxy arseno benzene No. 1151 of Mouneyrat's series /SO2NH CeHaCOH)— As = As— C6H3(OH)(NH2) C6H4^ SO2NH CgHsCOH)— As = As— CeHaCOH) (NH2) 24 THE TREATMENT OF SYPHILIS LuARGOL. — diamino-dihydroxy arseno benzene-silver-bromide-antimonyl- sulfate. No. I02 of Danysz series [(NH2)(OH)C6H3— As = As— C6H3(OH)(NH2)]2 Ag Br. SbO. (H2S04)2 Typical co-ordination compound; AS Me X Me denotes metal || X " halogen AS Me X BIBLIOGRAPHY 1. Thomas and Breinl, about 1902. 2. EhrHch and Bertheim, Ber. (1907) 40-3292. 3. Balzer and Moimeyxat, Progres Medical (1909, No. 27); French Patent 401586 (1908). 4. U. S. P. 907016 (1908). 5. May, Baker and Bates, Eng. Pat. 8959 and 24428 (1908); Fr. Pat. 396i92;D. R. P. 237787. 6. Ber. 12, 2200; 14, 2400. 7. Ber. 42, 28. 8. EhrHch and Hata, Experimental Chemotherapy of SpiriUoses, London 1911. 9. O. and K. Adler, Ber. 41, 932 (1908); Kober, J. A. C. S. (1919) 451. 10. Mouneyrat, Eng. Pat. 3087 (1908). Conant, J. A. C. S. (1919) 431. 11. Poulenc and Oechslin, Fr. Pat. 449373, 451078, 474056. 12. Bart, D. R. P. 250264, Eng. Pat. 568 (1911). 13. EhrHch and Bertheim, U. S. P. 986148. Benda and " Ber. 41, 1657 (1908). EhrHch and " Ber. 45, 761 (1912). 14. D. R. P. 251571, 254187. 15. D. R. P. 271894, 206456. 16. Poulenc, Eng. Pat. 21421 (1914). 17. See 15, and also D. R. P. 216270, 235430, 269886, 269887, Kober J. A. C. S. (1919) 442. 18. Morgan, Organic Compounds of Arsenic and Antimony (1918), p. 226. 19. D. R. P. 206057; U. S. Pat. 888321 and 907016 (1908). EhrHch, Ber. 42, 36 (1909). 20. Eng. Pat. 3087, and 9234 (1915). 21. Morgan, Organic Arsenic Compounds, p. 256. 22. Danysz, Compt. Rend. (1914) 159, 452. CHAPTER IV THE CHEMOTHERAPY OF ARSENIC COMPOUNDS The selective action of a compound for certain cells depends on the coming together of a particular group in the molecule into some sort of chemical connection with the cell substance. In 1898, Ehrlich (Deut. med. Woch., page 1052) advocated the theory that the selective action of a compound for certain cells must be based upon the penetrability of the drug. This difference of affinity determined whether the drug had greater power to de- stroy the parasite or to combine with the protoplasm of the host. In the one case it is known as a parasitropic and in the other an organotropic substance. After many years of investigation of arsenic compounds, the field of arsenic therapy was divided into two sections. One was devoted to the study of arsenic in the pentavalent form, the other, to arsenic in the trivalent form. There are at least three weU-defined qualifications that a prep- aration must possess and they are summed up as follows: — 1. The compound must be non-irritant and capable of re- maining in perfect solution at the temperature and the alkalinity of the tissues. 2. It must act quickly on the parasites before they can acquire a tolerance to the drug. 3. When the parasites have been expelled from the blood by therapeutic doses, there must be no recurrence in a majority of cases within some fixed time, which will depend to some extent on the particular host and the strain of parasites. Pentavalent Arsenic Compounds Along these lines of research much work has been carried out and certain arsenic compounds have been selected as partially fulfilling these requirements. In chemical language we have two groups of arsenic compounds, inorganic and organic. For use 26 THE TREATMENT OF SYPHn.IS in the present instance, only the organic compounds will be considered. We will deal first with the pentavalent arsenic preparations and then discuss the trivalent arsenic compounds. Arsenic has had some reputation in the treatment of protozoal diseases since the time of Fallopius. The compounds containing arsenic in the pentavalent condition are: — /OH /CHs OH OH = As— OH = As— CH3 = As ONa As = \0H \ONa /\| /\ ONa Arsenic acid Sodium cacodylate V \X NH2 NHCOCH3 Sodium arsanilate Sodium acetyl arsanilate (atoxyl, soamin) (arsacetui) Biological examination shows that all of these products are comparatively nontoxic when introduced into the animal system until changes take place that liberate arsenic. The arsenic in these compounds is liberated very slowly in the system, thus pro- ducing the ordinary therapeutic effects of the element. The chief objection to this class of compounds is found in the fact that they are excreted readily and generally in an unchanged form. This means that relatively large doses must be adminis- tered to gain beneficial results, while on the other hand the kid- neys and liver are suffering from a tremendous oversupply of arsenic. Another objection is found in the fact that treatment with this class of compounds is followed by degeneration of the optic nerve and optic atrophy. These as well as the therapeutic action are mainly due to the reduction products which are formed in the organism. Pentavalent arsenic probably produces cumulative effects after repeated doses. Atoxyl was found to be very efficient in tr3rpanosomiasis but also it was found that in vitro there was little activity for the reason that there was no reduction of the arsenic to the trivalent condition. Rohl, and Friedberger {Zeit- schrif. Imunitdts forschung u. exp. Ther., Vol, I, 1909) Berl. klin, Woch. 1909, No. II, Berl. klin, Woch., 1908, No. j8, Therap. Mon- CHEMOTHERAPY OF ARSENIC COMPOUNDS 27 ats, May, 191 1) state that the curative action probably depends on the transformation of the organic pentavalent arsenic com- pounds into trivalent preparations which are directly toxic to protozoa in the same maimer that arsenic pentoxid is partly reduced in the organism to arsenious acid. (Binz and Schulz, Archiv.f. exp. Path u. Fharm., Vol. II, page 200, 1879.) Furthermore, pentavalent compounds cause disturbances of the digestive system and nephritis as well as toxic effects on the general nervous system. When these compounds are admin- istered continuously characteristic symptoms of arsenic poison- ing are manifested. The pentavalent organic arsenic compounds do not produce any effect on trypanosomes in vitro whereas trivalent compounds, either organic or inorganic, show consider- able activity. This difference of therapeutic action is probably due to the variability of chemical activity. It seems to be a well established fact that all arsenical combi- nations, which are capable of reacting chemically, are phar- macologically active, producing effects which in the last analysis are due to the action of the anions, AsOg or ASO4. The action further might be explained in terms of energy changes in which the valency of the element changes from pentavalent to triva- lent. A similar theory is foimd in the case of dyes in which there is a certain chromophore group in addition to an anchoring group or salt-forming group. This group is one in which nitro- gen is involved and is well illustrated by the azo group — N = N — . Why Pentavalent Compounds are Unsatisfactory In conclusion the pentavalent arsenic compounds are unsatis- factory, due to the rapid excretion of the product and to the fact that the anatomic changes show degeneration of the optic nerve and retinal ganglia as well as the cerebral cell injury. Further- more the curative dose is so close to the toxic dose that it ren- ders most of these products dangerous, i. e., the ratio of the cura- tive dose to the tolerated dose is a small fraction. With a large dose for curative purposes it means an increased effort on the part of the kidneys and liver to withstand this attack. It should not be inferred that this class of compounds do not have any 28 THE TREATMENT OF SYPHILIS therapeutic action but it is a fact that in most cases they are less satisfactory than the compounds containing trivalent arsenic. Trivalent Arsenic Compounds The trivalent compounds of arsenic are many in number but only a few has been of practical use inasmuch as the adaptabihty of many of them has not been entirely satisfactory. From this large number a few have been selected because the ratio between the etiotropic efficiency and the toxicity has been more favor- able. In the case of salvarsan this ratio, according to the Hata method, was i : 58. Two products of this type have been used very extensively during the past ten years. However, this is no indication that other useful products cannot be obtained. A few structural formulas will indicate the organic preparations that illustrate trivalent arsenic in combination with ring compounds. OH OH OH As = As = As = /\ OH /\ OH /^ OH \y \y NO2 \y NO2 NH2 HH2 OH Arsanilic acid. Nitro arsanilic Nitro-oxy phenyl pentavalent acid, pentavalent arsinic acid, pentavalent As = As = As /\ /\ /\ \y NH2 \/ NH2 \X NH2 OH 01 I OH Amino oxy phenyl arsenoxide. Sa ivarsan base Twice as curative as salvarsan Tr ivalent arsenic 6 times as toxic. Triv rale nt arsenic As = As As = As \J NH2HCI 'vJ NH2HCI \J NH2 \y NH2 OH OH ONa ONa Salvarsan sodium As = As OH OH Salvarsan S/ NH2 \/NHCHOHOSNa ONa ONa OH OH Neosalvarsan CHEMOTHERAPY OF ARSENIC COMPOUNDS 29 Trivalent Arsenic more Potent Therapeutically In the case of trivalent arsenic the effective dose can be in- troduced with much greater safety and, according to EhrHch, the more powerful therapeutic action is due to the radical con- taining the trivalent arsenic, the importance of which was ren- dered apparent in experiments with trypanosomes and also to the introduction of hydroxy radicals in the para position in the molecules, in which the amido radicals are in the ortho position, relatively to the hydroxy radicals. In the case of these double ring compounds, there is a double arsenic action due to the scis- sion of the salvarsan (or neosalvarsan) molecule betvv^een the two arsenic groups giving the action of two trivalent arsenic mole- cules. The chemical change which takes place in the blood is probably represented by the following formulas: (Ernest Sie- burg — Zeitschr. physiol. chem., Vol. 97, p. 53, 1916.) As = As ONa NH2 V NH2 Protein combination ONa OH As = As = /\ /\ OH \y NH2 \y NH2 OP [ OH Amino oxy phenyl 2 amino 3 oxy arsenoxide phenyl arsenic acid \ 3 oxyl phenyl arsinic acid NH2 /\ or NH2 V OH OH amino phenols CHAPTER V INDICATIONS, CONTRAINDICATIONS AND EFFICIENCY OF AR- SPHENAMINE Particular Indications for Arsphenamine Treatment It should not be accepted as a fixed rule that all cases of lues are to receive arsphenamine treatment. As elsewhere discussed, there are certain definite contraindications to the use of the arsenical preparations. It is generally accepted, however, that particular indications for the use of arsphenamine can be laid down and it is, therefore, advised that the product be utilized in: 1. AU cases of early syphilis possessing distinctive symptoms. 2. In primary cases as an abortive agent. 3. In tertiary and latent cases with a positive Wassermaim. 4. In tabes and paresis, congenital syphilis, maUgnant syphilis, painful periostitis and gummata. 5. In cases in vv/^hich mercury cannot be used to advantage, when the patients become easily salivated or in which, after long continued mercurial treatment, the Wassermaim reaction re- mains positive. Contraindications to Arsenical Therapy Arsphenamine and neoarsphenamine cannot be used indis- criminately upon every luetic person. Therefore a careful physical examination of the patient is an important essential. If any of the following conditions exist these remedial agents should be withheld untU the offending obstacle has been re- moved if such is possible: Recent cases of myocarditis and valvular disease. Nephritis, not of syphilitic origin. Marked diabetes. Advanced tuberculosis. INDICATIONS, ETC., OF ARSPHENAMINE 31 Any diseases of the organs of the thoracic and abdominal cavities. Persons of very advanced years. Persons possessing an idiosyncrasy against arsenic. Following acute diseases, especially when depressing sequelae are present. Dr. H. H. Morton of Brooklyn suggests that salvarsan be used with extreme caution in brain syphilis, but directs attention to the fact that in acute optic neuritis, choroiditis and inter- stitial keratitis, it clears up the lesions with great rapidity. The urine of each patient should be examined before the administration of the drug and cases showing a renal involve- ment should be denied arsphenamine or it should be given in very small doses. After each injection of salvarsan and neosalvarsan the urine should also be examined, so that the physician, at all times, may be familiar with the condition of the kidneys. A trace of albumin and a few casts may be found in the urine the morning after an injection of salvarsan. This should not be considered a contraindication unless considerable albumin is present and the number of casts on the slide are in excess of ten. The Therapeutic Effects of Arsphenamine One injection of arsphenamine aids materially in rendering the patient non-infectious to those about him. The spirocheta palKda disappears from the chancre in from twelve to forty-eight hours after salvarsan injection and the lesion usually heals in from seven to ten days. Condylomata and mucous patches disappear within a few days after the injection, as do skin and bone gummata. Dr. H. H. Morton says the "effects of salvarsan in malignant syphilis are brilliant, especially in the cases which are refractory to mercury and iodides." Mortality in congenital S3rphiiis has been considerably lessened since arsphenamine treatment was instituted. Salvarsan reUeves the "lightning pains" of tabes, although 32 THE TREATMENT OF SYPHILIS it cannot restore the nerve tissue which has been destroyed. Tabetic and paretic patients are generally much improved by the use of salvarsan and in some cases the progress of the disease is arrested. The intraspinous use of arsphenamine in these cases is advo- cated by some and decried by others, but adherents of both intra- spinous and intravenous methods seem to be of the opinion that improvement usually follows the employment of arsphenamine. Arsphenamine's Therapeutic Efficiency The efficiency of arsphenamine as a curative agent in the treatment of lues has been so definitely established during the years of its employment that this subject needs only a passing word. The testimony of a few authorities will demonstrate to the casual reader the place the drug has made for itself in the world of therapy. Col. E. B. Vedder, U. S. Army {Syphilis and the Public Health j p. 259, 1918), says ''it has been sufficiently demonstrated that salvarsan is a specific in the treatment of syphilis, and while the fallacy of our original hopes of a ' therapia sterilizans magna ' is now apparent, this drug still remains the most potent remedy which we can command. Although it is still possible to treat syphilis by mercury alone or in combination with the iodides in the later stages of the disease, such treatment is distinctly inferior in its results to the proper combination of salvarsan and mercury." Dr. Loyd Thompson of Hot Springs {Syphilis^ p. 232, 1918) says "chancres, the syphilodermata, and the syphilomycoder- mata heal with startling rapidity, the treponemata sometimes disappearing from the lesions within twelve to twenty-four hours, while the symptoms of visceral syphilis and syphilis of the nervous system usually diminish and may disappear alto- gether following its (salvarsan's) use." Dr. Cole states in the Ohio State Medical Journal that "sal- varsan is the most powerful drug now^ at the physician's com- INDICATIONS, ETC., OF ARSPHENAMINE 33 mand in the treatment of syphilis and when wisely administered is practically free from all danger or marked unpleasantness." He adds that herein lies the great value of salvarsan (after an injection of salvarsan) that in twenty-four to forty-eight or seventy-two hours the acute, contagious lesions on any patient will be so changed that he will be no longer a direct menace to his friends and society. Cole believes that practically every case of cerebro-spinal syphilis with a high cell count in the spinal fluid will react well and quickly to salvarsan. He has seen "lightning pains" disappear after one or two injections — though this is not always true. Nine Indications for Salvarsan Dr. G. F. Lydston of Chicago states in the Medical Standard that he is convinced from careful observation that salvarsan is of great value in meeting the following indications : First. Prompt removal of genital lesions thus lessening: first, the danger of infecting others; second, the danger of detec- tion; third, local discomfort; fourth, the danger of serious com- plications. Second. The prevention or prompt removal of disfiguring skin lesions. Third. Precocious or malignant syphilis. Fourth. Cases resistant to mercury. Fifth. Early nerve, brain and visceral lesions, with the excep- tion of renal syphilis in which salvarsan is especially dangerous. Sixth. Cases of syphilitic cachexia or anemia, which often consist of a combiaation of overtreatment and syphilis. Seventh. Syphilis involving the organs of special sense, ex- cepting marked lesions involving the retina. The wisdom of employing salvarsan here is still subjudice. Eighth. Early tabes and, in some late cases, to relieve severe pain or involvement of the sphincters. Ninth. Infantile syphilis. In aU cases mercury should be regarded as still our sheet anchor in syphilis. 34 THE TREATMENT OF SYPHILIS Arsphenamine as a Prophylactic It is a matter of common belief that arsphenamine introduced into the system as soon as the initial lesion has manifested itself, or before, in the event the recipient feels he has been inoculated with the spirocheta palUda, will act as a prophylactic. Indeed the abiUty of arsphenamine to prevent syphihs from obtaining a foothold in the system has been exemplified in a great number of cases. One of the latest is the report by Dr. A. C. Magian (Bull, de I' Acad, de Med., Paris, May 20, 19 19) to the effect that on March 21, 1918, in the French Hospital at Man- chester he inoculated himself in the presence of twenty physicians with some of the serous fluid from a chancre. Less than an hour afterward he was given an injection of arsphenamine, 0.6 gram. None of the classical symptoms, either local or general, which would indicate syphilis, appeared, and although he had a Wassermann taken monthly for a year since that time it has been constantly negative and he has shown no indication what- ever of having the spirocheta pallida in his system. We have known cases in which the physician inadvertently pierced his skin with a needle which had been utilized for the in- jection of salvarsan. As a matter of precaution, the physician immediately had himself injected with salvarsan and no signs of lues ever developed. We are of the opinion that salvarsan used in this way will pre- vent syphilis. Arsphenamine as a Medicinal Agent in Other than Luetic Conditions Arsphenamine seems to be of value in conditions other than lues. In the tropics it is used as a more or less routine treatment in filaria, frambesia, malaria, recurrent fever, tick fever and marsh fever, and it has been recommended by some physicians in those conditions in which arsenic is indicated, such as psoriasis, leuko- derma, pemphigus, and the like. Vincent's angina, pyorrhea and " trench mouth " are also among the conditions in which arsphenamine has been employed. INDICATIONS, ETC., OF ARSPHENAMINE 35 No particular recommendation is made regarding the employ- ment of salvarsan in these diseases, as we have had no experience. We are of the opinion, however, that the use of arsphenamine will be much more general in the future as research evolves ways and means for its use. The great war has brought about an entire change in treating many conditions. One of the most unique has been described by Dr. A. Brechot, of the French Army {Paris Medicate, May 24, 1919). He employed neoarsphenamine intravenously for the purpose of preventing or curing septicemia, and as an adjuvant in furthering and hastening the healing of wounds. He found that in such conditions an intravenous injection of neoar- sphenamine, 0.3 gram, was followed by great improvement. According to the cases which he describes, the action of neoar- sphenamine became noticeable at least by the third day, and its effect was most beneficial in acute septicemias which were not complicated with marked local lesions. It was also of benefit in infected wounds in the soft parts which were of recent origin and which had become gangrenous. He did not obtain beneficial results when neoarsphenamine was em- ployed in conditions showing advanced suppuration or where there was an enormous amount of gangrene. The Comparative Use of Arsphenamine and Neoarsphenamine Each of these products has its ardent admirers among physi- cians. Some men insist that one, and others the other is the drug of choice. Personally, we believe that a great many things enter into the matter of a choice between salvarsan and neo- salvarsan. Some patients failing to improve with one, make marked improvement under the other, and, believing as we do that every case of syphilis must be individualized and treated according to the particular needs of the affected person, it is impossible to make an unqualified statement as to the value of one as compared with the other. Drs. Wm. B. Trimble and John J. Rothwell of New York (/. A. M. A., page 1984, 1916) made an interesting study based 36 THE TREATMENT OF SYPPIILIS on the treatment of no patients, and reached the conclusion that neosalvarsan is superior to saivarsan, being much easier of administration, less likely to cause severe reaction, and pro- ducing a greater percentage of negative results. Dr. OUver S. Ormsby of Chicago (/. A. M. A., page 949, 1917), says that saivarsan and neosalvarsan are the most eflfi.cient drugs yet discovered in the treatment of syphilis. As to a choice be- tween the two, Ormsby believes the extensive use of both pro- claims their efficiency, so that individual circumstances with the physician and patient must decide which is to be selected. He says the apparent preponderance of opinion that saivarsan is more eflScient is offset to a degree by the difficulties of its admin- istration and the more frequent reactions following its use. Research work and comparative tests will in the not distant future do much toward demonstrating the comparative value of the two drugs. It is admitted that from the standpoint of the general practi- tioner neoarsphenamine is the product of choice. CHAPTER VI A PLAN FOR ANTILUETIC TREATMENT Eternal vigilance is the price of freedom from the spirocheta pallida. Immediate, consistent, persistent and proper treatment is necessary to overcome the ravages of sj^hiHs. As soon as a diagnosis of lues is made, it is the duty of the physician to in- stitute treatment. We believe that the great majority of sores on the penis are likely to be chancres and we make it a rule to so regard aU sores that put in an appearance ten days or longer after exposure. It is far better to treat a chancroidal case as if it were specific than to "sHp up" on a case of chancre. It is well to bear in mind that many sores diagnosed as chancroids re- veal both Ducrey's bacillus and the spirocheta paUida and con- sequently demand antiluetic treatment. Dark field illmnination should be used on all penile sores as soon as seen, and little difficulty is experienced in demonstrating the presence of the spirochete if it is in the field. This is proof positive of the disease. In certain instances it is possible to abort syphilis by the most vigorous treatment. Some authorities advise the excision of the chancre as soon as it appears in the belief that, if taken in time, the spirochetes will not be able to penetrate the surrounding tissue, and we beheve it is better to be rid of the lesion if it is so situated that its re- moval will cause no deformity. Prompt Treatment Demanded As soon as the diagnosis has been made, it is our custom to give an intravenous injection of 0.3 gram salvarsan or 0.45 gram neosalvarsan, or in the case of a woman 0.2 gram salvarsan or 0.3 neosalvarsan. If well borne by the patient, 0.4 gram sal- varsan or 0.6 gram neosalvarsan is given five days later. 38 THE TREATMENT OF SYPHILIS Mercury, preferably one-fourth to one-half grain of the bi- chlorid in the form of a coUapsule, is given hypodermically in the buttock two days after the first injection of salvarsan or neosalvarsan and this is repeated three times a week for twelve weeks. If an insoluble mercury is desired we use the salicylate in collapsules of one grain weekly. Salvarsan or neosalvarsan is then administered at seven-day intervals until six more doses have been used, making the course number eight. When taken early, these cases show a negative Wassermann and it is our object to keep the reaction negative. One month after the last intramuscular injection of mercury a Wassermann is taken. If negative, another is taken one month later, and, if the result is the same, we wait two months before having another examination made. If still negative we have Wassermanns done bimonthly for two years, by which time, if the reaction continues negative, we feel that a cure has been effected. If, on the other hand, the first reaction shows positive, we repeat the course of salvarsan and mercury treatment and follow this up until a permanent negative is obtained. It is not always possible to see our patients at the time the in- itial lesion presents itself. Many of the cases of lues which appear in the physician's office are beyond the primary stage and abor- tion of the disease is out of the question. The Treatment of Longer Standing Cases It is necessary, in these, to institute intensive treatment, for it is on this rock that we must erect our therapeutic structure. Many a case has gone down before the gales of disease because the house of therapy was built upon the sands of infrequent and inconsistent treatment. As with the attempt to abort syphilis, we start the patient out with 0.3 gram salvarsan or 0.45 gram neosalvarsan (if a woman, the dose is respectively 0.2 gram salvarsan or 0.3 gram neosalvarsan). Two days later we inject hypodermically in the buttock a collapsule of ^ or 3^ grain mercuric bichlorid. Three A PLAN FOR ANTILUETIC TREATMENT 39 days later comes 0.4 gram salvarsan or 0.6 gram neosalvarsan. If all is well, salvarsan or neosalvarsan is continued at weekly intervals until eight injections have been given and mercury is given three times weekly at intervals for twelve weeks, unless the insoluble form is employed, in which case the injections are ad- ministered weekly. The kidneys must be watched for possible irritation. The action of the salvarsan kills most of the spiro- chetae palHdae, while the mercury destroys the spirillae which are to be found in organs beyond the reach of the arsenic. Four weeks after the last injection of mercury, a Wasser- mann is taken. If positive, the salvarsan-mercury course is re- peated and is so continued until a negative is obtained. If negative, the same routine obtains as in the abortive plan. When a case is taken early, one course of treatment is likely to result in a negative reaction, and the earlier we start intensive treatment the more likely are we to get negatives. Iodides Demanded in Tertiary and Latent Cases In tertiary and latent cases several courses of treatment may be necessary to reach the goal. Potassium iodid must not be forgotten in these cases, particularly if gummata or periosteal lesions or other manifestations of late syphilis are present. If the disease has affected the nervous system it is especially in- dicated. To be effective potassium iodid must be pushed in heavy doses. The drug should also be used in tertiary syphilis with a persistently positive reaction, without involvement of the central nervous system. Indeed there are cases, which, though apparently clinically cured, are serologically not cured, that is, they seem to be permanently positive. Such cases are termed ''Wassermann fast" and in the Hght of our present knowledge it seems impossible to change these positive cases to negative. If a patient shows a negative and later develops a positive, we have proof that he still has a focus of infection in his body and must be given another course of treatment. The provocative injection plays its part as related in the chap- ter entitled "Provocative Wassermann Reaction." 40 THE TREATMENT OF SYPHILIS We believe good treatment calls for the use of this procedure in early cases. If negative reactions result, we feel that we have reason to pronounce a cure. If spirochetae are still in the system, we should know it, and the provocative injection is the only agent, except time, which wiU make their presence known. In tertiary and latent cases a Wassermann of the spinal fluid must be made and the reaction of both blood and spinal fluid must be repeatedly negative before the case can be pronounced cured. Salvarsan and Mercury Necessary Dr. C. L. Barewald of Davenport, Iowa, in a paper read before the Scott County Medical Society, March 4, 1919, states that after using the various preparations on the market he found that salvarsan is by far the best, as it gives better results and more efficient elimination. He has given more than two thousand intravenous injections of salvarsan without experiencing any bad results. He emphasizes the fact that syphilis is not cured by salvarsan alone and that mercury must be included in the treatment. He gives salvarsan once a week for eight weeks and at the same time uses mercury, preferably by inunction. Intensive Salvarsan Treatment Dr. S. Politzer, of New York {Jour. Cut. Dis., Sept., 1916) is an advocate of the most intensive type of salvarsan treatment in acute cases. As soon as a positive diagnosis is made, he gives three injections of salvarsan in large doses at intervals of twenty- four hours, and follows this by a course of eight weekly injections of salicylate of mercury. If the treatment is begun after the appearance of the rash, this course of salvarsan and mercury- treatment is repeated after a pause of two months and again after a similar interval. After three courses within the first year, he suspends treatment if the Wassermann reaction is negative. If the treatment is begun a year or more after infection, treat- ment should be continued imtU negative, and two more addi- tional courses of treatment given, even though the reaction may be negative. A PLAN FOR ANTILUETIC TREATMENT 41 Dr. J. L. Murray of Toledo {Ohio State Med. Jour.) is an advocate of a similar method. His plan is to give a small dose of salvarsan on three successive days, followed by eight weekly injections of salicylate of mercury. In the secondary stage, Murray gives these intensive courses at intervals of three or four months regardless of the Wassermann reactioii. CHAPTER Vn THE TECHNIC OF ARSPHENAMTNE ADMINISTRA.TION The Intravenous Administration of Arsphenamine The fundamental principle of drug administration is based upon the proper usage of the remedial agents which are to be employed. Carelessness in technic or lack of necessary informa- tion regarding a drug has often seriously injured good prepara- tions. Three prime requisites stand out as necessary to the satisfac- tory administration of a drug: (i) knowledge of the drug and its properties; (2) a perfect understanding of the patient and his idiosyncrasies; (3) confidence and due precaution on the part of the administrator. In the injection of any drug by the intravenous method rigid asepsis is a most important factor. During the past two years over two million doses of arsphena- mine have been administered with varying degrees of success. After a careful study of the situation in hospital and private practice, we have evolved a method of administration, which provides safety and precaution in the highest degree for the physician and the patient. Preparation of the Drug The apparatus necessary for the administration of salvarsan includes : An adjustable bracket or stand, and a table for this stand to rest upon. Two glass cylinders of 250 c. c. capacity; one for holding the solution of salvarsan and the other, distilled water. Cd n !z; o S t c o u W r; p^ m Pi e < o o ;-i ^ cj o «) H X y ■ — ) 1— . rt 'Z M t) -1 n J^ W .^ > ^ f r^ Pi H rt y, m 1— 1 r. W CJ m *"• H -(-> rrt Ut rt a cu cj OJ J3 H TECHNIC OF ARSPHENAMINE ADMINISTRATION 43 Rubber tubing leading from each cylinder to a Morton three- way stopcock, on the end of which the needle is attached. Fordyce or other needles of fine, medium and large calibre, the size to be determined by the vein. 2 c. c. syringe and hypodermic needle for epinephrin. An abundant supply of freshly prepared double distilled and sterilized water, or 0.4 per cent sodium chlorid solution. A tourniquet of rubber tubing or a rubber catheter. A glass cylinder (250 c. c.) in which to mix the solution. Sterile gauze and sterile cotton. A glass funnel for filtering the solution. Tincture of iodin or alcohol. A bottle of freshly prepared C. P. sodium hydroxid — 15 per cent or normal sodium hydroxid — 4 per cent. A bottle of collodion for sealing the point of the puncture after administration. Lastly, the drug itself. Apparatus. — The mixing cylinder should be thoroughly washed with distilled water and drained for a few minutes, the stopper tied loosely to the neck of the cylinder and then the stopper and neck covered with a piece of gauze. The combination should be sterilized by dry heat and when cool, the stoppers inserted without removing the gauze. The gauze is tied around the upper part of the stopper so that it can be used as a protection to the stopper during its subsequent use in mixing. There is no objection to the method of boiling the cylinder for twenty minutes in the sterilizer except that it requires additional sterile distilled water for rinsing before use. All of the other apparatus should be sterilized just before using and extreme care should be exercised to avoid using the apparatus while it is still hot. The reason for this care is to avoid the decomposition of the salvarsan solution before it is used. It is a well-known chemical fact that too hot water is one of the chief factors in causing decomposition and subsequent re- actions. Just before using the apparatus, it should be rinsed out with sterile distilled water. 44 THE TREATMENT OF SYPHILIS DistiUed Water The water problem in the making of salvarsan solutions is a question of real importance to physicians, especially to those who have occasion to administer arsphenamine at infrequent intervals. It is at all times necessary to employ freshly distilled water and not that which may be several days or weeks old. It is absolutely imsafe to send to a neighboring town for distilled water or the 15 per cent sodium hydroxid, and by so doing the physician takes a considerable risk. It is a well-known fact that water contains many inorganic salts as well as much nitrogenous matter. To remove these impurities, the process of distillation is used but, through neg- lect, some of the water may be allowed to boil over into the side tube and thereby vitiate the efforts of purification. Water also contains volatile material of a gaseous nature and it is important to remove these impurities. Time and space do not permit a detailed discussion of a method which will yield what is known as "chemically pure" water or "conductivity water." However, a general method is presented for securing relatively large quan- tities of water suitable for intravenous use. Any suitable type of metal distilling apparatus provided with a block tin condenser will answer the purpose. A manufacturer of chemical apparatus can easily provide this type. In using it, care should be used in preventing the possibility of mechanical overflow. This provides a roughly distiUed water contaminated with volatile gases. This grade of distilled water should be used for obtaining sterile, freshly glass-distilled water. There are several ways of carrying out this procedure. The simplest technic is to place the water in any glass-distilling apparatus and add calcium oxid or alkaline permanganate to absorb carbon dioxid and destroy organic matter. The con- tents should be heated to boiling and the distillate collected in a flask suitable for later sterilization if the water is not to be used as soon as cool. A continuous distillation can be carried on by this method. Distilling Apparatus A simple type for physicians who have no gas, elec- tricity or running water, or who lack any one of these three conveniences. Description of this ap- paratus is found on page 45. TECHNIC OF ARSPHENAMINE ADMINISTRATION 45 A Simple Distilling Apparatus In case only a relatively small quantity is to be utilized, omit- ting the permanganate, it is well to distill off at least one fourth and discard it and to coUect the remainder for use. For the benefit of those who are limited in their facilities the apparatus shown in the accompanying picture is presented. This type of apparatus is designed for those who lack gas, electricity and running water or any one of the three conven- iences. It consists of an ordinary aspirating bottle which may be used as a source of water supply by putting ice into water and allowing the ice water to flow through the condenser as a means of cooling the water vapors. The rest of the apparatus con- sists of a pyrex distilling flask suitably connected to a glass condenser with a flask for collecting the water. The whole apparatus is held in place by a single iron stand with the necessary clamps and rings. The apparatus is cheap and very compact as well as usable. In fact it may be used by any physician who has need for distilled water and has gas and running water available. If the water is used within a half hour, it is sterile and suitable, otherwise it is necessary to boil the water before using and then cool it to room temperature (68-77° F.) before using it. Under no circumstances should hot water be used with sal- varsan or neosalvarsan. The Drug In manufacturing arsphenamine every care is used in protec- ting the drug from undue exposure to oxidation and moisture and it is reasonably safe to say that the product is very uniform in composition and therapeutic properties. Every ampule is carefully examined for any imperfection by the flotation method before it leaves the laboratory. During transportation accidents may happen to the glass container and in every instance the ampule should be placed in 95% alcohol for 20 minutes, to detect any imperfections such as a minute crack, which is invisible to the naked eye, and at the same time to sterilize the 46 THE TREATMENT OF SYPHILIS ampule. After examination the ampule is dried with a piece of sterile cotton or gauze. It is imperative that neither the contents of ampules that may have been damaged in transport, nor the remainder of previously opened ampules should be used, as this involves serious danger to the patient. While the ampule is in immersion, all the instruments and utensils which are being utilized in the administration should be boiled in distilled water. The Solution Before discussing this most important phase of the technic in arsphenamine administration, it may not be amiss to make reference to the fundamental principle of therapeutics. All therapeutic action is based upon the laws of chemical affinity which are in turn governed by the laws of chemical dynamics and equiHbrium. The demands on the drug are such that it is essen- tial the number of reactions should be reduced to a minimum. To meet these requirements it is necessary to foUow certain definite laws of chemistry. Some physicians insist on using the drug in concentrated solu- tions and pay little attention to alkalinization. Alkalinization and concentration are the two most important factors in preparing the solution for injection. It is a well-known fact that if solid sodium hydroxid is dropped into concentrated hydrochloric acid considerable heat is evolved, due to chemical action in forming the compound sodium chlorid. The same applies to arsphenamine when it is injected into the blood stream. A new compound is formed, one in which the proteins of the blood stream and the protozoa combine with the arsenical. The rapidity and amount of combination are the factors which determine whether there will be disturbances in the host. The cause of this chemical reaction is to be found in the fun- damental laws of energy changes. All of the energy changes are easily subdivided into intensity factors, and capacity factors. The intensity factor of any form of energy or change tends toward equalization of differences which condition develops when the Distilling Apparatus A simple and inexpensive water still for physicians who have laboratories in connection with their ofifices. TECHNIC OF ARSPHENAMINE ADMINISTRATION 47 rate of injection is very slow and the dilution is great. When two substances are brought together, the tendency to equalize the difference in concentration and tolerance is adjusted by the body. This can only be accomplished when the organism has an opportunity to meet these new conditions and establish an equilibrium where the drug changes into a soluble compound in the body, making due allowance for decomposition of the arsphenamine and the rate of elimination. To all those familiar with dynamics it will at once be observed that the "ideal" solution is the one which gives the most uniform results chemically, physically, and therapeutically. The con- centrated solutions should yield abnormal results unless the time factor is so carefully controlled that an ideal condition is obtained. Upon this scientific basis it is now suitable to prepare the solution. Preparation of the Solution A dilution of 100 mg. (o.i) to 25 c. c. of water is probably with- in the safe limits. The United States Army and the United States PubHc Health Service have recommended a dilution of 100 mg. in 30 c. c. of water. This is a most conservative recom- mendation in view of the fact that there may be other abnor- malities existing in the patients. It is also much better to err on the side of precaution and conservatism. The size of the dose recommended is generally conceded to be a 0.4 gram dose which should be given more frequently. This subject will be discussed at length in another chapter. The ampule of salvarsan should be opened by filing it in two or three places near the point where the body of the ampule joins the tip. A smart blow on the end of the ampule will break it off cleanly. About 50 c. c. of room temperature (68-77° F.) sterile, freshly distilled water should be poured in the mixing cylinder and the contents of 0.4 gram ampule lightly scattered on the surface of the liquid, using care in maintaining asepsis. The stopper should be placed in the flask and gentle agitation follow. The powder 48 THE TREATMENT OF SYPHILIS will dissolve readily in the cold water and when every particle is in solution alkali should be added at once, according to the table below. An ampule of 0.4 gram requires 3.36 c. c. normal sodium hy- droxide (4 per cent) or 16 drops of 15 per cent sodium hydroxide. It is imperative that the alkali be free from carbonates and gelatinous material. For this reason it is best to use freshly prepared alkali unless other proper precautions can be taken. Again the stopper should be inserted in the mixing cylinder, which should be inverted a couple of times, and then the volume increased to 100 or 120 c. c. After a gentle shaking, if the proper care has been exercised, the solution will be ready for intravenous administration. The salvarsan solution should be used immediately. In warm weather additional care should be used to avoid imusual tempera- tures. Table of Normal and 15 Per Cent Sodium Hydroxid Necessary c. c. of normal NaOH Drops (aver. = .07 c. c.) tn salt 15% NaOH required for disodium salt 4 8 12 16 20 24 28 32 36 40 The mechanism of the change taking place during the alkaliniza- tion is shown by the following table which indicates the most satisfactory form in which the drug should be given. Weight of drug required for dis .1 0.84 2 1.68 3 2.52 4 336 5 4.20 6 504 7 5-88 8 6.72 9 7 56 I 8.40 Apparatus for Holding Normal Sodium Hydroxid Solution The solution can be kept in the bottle indefinitely and, as it is measured out by a burette, absolute accuracy is certain, and perfect alkalinization is effected. The box holding the apparatus is shown with the sides and top turned back and the front cover removed. TECHNIC OF ARSPHENAMINE ADMINISTRATION 49 CHEMICAL TRANSFORMATION OF SALVARSAN INTO THE DISODIUM SALT Required for Intravenous Injection I SALVARSAN NH,HCl "Ns. ^y^HHjaCl OH 4^^ OH A Salvarsan as it appears on market n SALVARSAN BASE AS •— —" ^g^ OH y OH Sodium Chlorid Na CI is formed at this stage of alkalinization m MONO-SODIUM SALT OF SALVARSAN A3 DI-SODIUM SALT OF SALVARSAN SALVARSAN DI-HYDROCHLORIDE. Yellow Powder about Sl^^Arsoiic. Soluble in cold water.; Add to litmus. Solution not suitable for intraveno«s administration. U SALVARSAN BASE. Precipitated upon addition of 12 drops of 15% sodium hydroxide solution or 252 cc. of normal sodium hydroxide solution per 0.6 gram Salvarsan. Insoluble yellow precipitate. Causes reactions. Not suitable for intravenous administra* tion. m MoNo-ScH)iuM Salt of Salvarsan Formed upon addition of 18 drops of 15% sodium hydroxide solution or 3.78 cc. normal sodium hydroxide sdu- tion. JiM soluble in water. Clear yellow soludcm. Slightly alkcJine to litmus. Not suitable for intravenous a q C3 2i 1^ c rrl t rt ^ w [^ -c w QJ PL, -— ^ < P^ c «J o 4-1 y-\ XI aj X U M f^ ^ c o 1— 1 t2 O 3 ;S I? M O ^/J c > S ^ _g H fi OJ ?; rt J=! 1— 1 o U, ■55 Hi c OJ ^ -C *-f-* 1) -o rt 4J n r, 3 t/i TI -^ , H cr TECHNIC OF ARSPHENAMINE ADMINISTRATION 57 "The injection is made either by gravity or with a 30 c. c. piston syringe or by a syringe to which is attached a three-way stopcock and one rubber tube leading into the bottle containing the salvarsan, while the other leads to the needle in the patient's arm. Whatever the method employed, it is essential that the salvarsan be given slowly and that at least five and preferably ten minutes be taken for the injection of the 30 c. c. Therefore, the gravity method is the safest." The concentrated method of salvarsan introduction is doubt- less a safe one in the hands of so experienced and skillful an operator as Dr. Keyes, but for the average medical man, part of whose time must necessarily be given to other lines of medicine, we feel that the concentrated method is unsafe. Dr. Keyes' technic is presented to show that the concentration of the fluid is not regarded as dangerous by one of our most eminent col- leagues, but the earnest suggestion is made that men who have not had as much experience in the administration of salvarsan as Dr. Keyes do not emulate his example. Dr. Theodore H. Smith, of Detroit {Jour. Mich. State Med. Soc, April, 191 7) believes that concentrated solutions of sal- varsan are more effective than dilute ones in that the salvarsan in the concentrated solution is more slowly excreted, but he ad- mits that the one objection to this method is the urgent necessity of a perfect technic in the intravenous injection itself. He says that if the needle does not lie accurately within the vein, a small amount of the concentrated solution entering the perivascular tissue will produce results even more dangerous than with the more dilute solution. Injection of Salvarsan into the Superior Longitudinal Sinus One of the largest venous channels in the body is the longi- tudinal sinus lying at the posterior angle of the anterior fontanel. Through this medium salvarsan can be injected. It has been used for a number of years for the injection of saline solutions and for blood transfusion. Dr. Louis Fischer of New York, read a paper on "The Value of the Longitudinal Sinus in Transfusion and for Rapid Medica- 58 THE TREATMENT OF SYPHILIS tion" before the Section on Diseases of Children of the American Medical Association in June, 1918. He expressed himself as thoroughly convinced that the difficulty of entering a vein the size of the median basilic or even the femoral, in infancy, makes the longitudinal sinus the route of choice for the introduction of any medication into the system of an infant or for transfusion. Dr. Fischer has perfected a technic which physicians can well follow. He wraps the infant in a mummy bandage, well pinned, so that the arms and legs are confined, and places the child flat on its back. The head is steadied on both sides by an assistant while the needle is inserted into the sinus. He finds that he can enter through the anterior fontanel until the child has reached the end of its second year. As the sinus grows wider toward the back of the head, Fischer recommends the point of entrance to be as far posterior as possible. The needle is pushed through the posterior angle of the fon- tanel and directed downward and backward in a line with the sagittal suture. The sinus is very superficial and there is no need of entering deeper than i or 2 mm. For this purpose a sharp-pointed needle 3^ inch long of 20 or 22 gauge is best adapted. When the needle penetrates the sinus, resistance is lessened and the same sensation is observed as when a needle enters the dura mater in performing a lumbar puncture. In giving salvarsan by this method. Dr. Fischer advises that it be administered by gravity slowly. A cylinder from 30 to 100 c. c. capacity can be used. One end of a piece of rubber tubing is attached to the cylinder and the other end has a con- necting tip which fits into the needle. A stopcock should be at the end of the cylinder or near the end of the tubing. The needle is inserted into a small syringe attached. By a slight aspiration the physician can determine whether the sinus has been entered; if so, the syringe is detached and the apparatus, which has been filled and the air expelled, is connected. The child should be watched carefully and its color, pulse and respiration noted. Dr. Fischer is of the opinion that there is no danger of losing too much blood by the puncture, even though a large needle is used. TECHNIC OF ARSPHENAMINE ADMINISTRATION 59 Dr. Vincent of Boston warns against injecting too rapidly lest increase of intra-cranial pressure cause vomiting and dis- turbed respiration. These difficulties are soon overcome when the flow of blood has been temporarily checked. Air pressure in the tube must be released by detaching the syringe before the needle is withdrawn. Blood Precipitates Danysz and Fleig have written extensively about the forma- tion of precipitates when salvarsan is introduced into the blood by the intravenous route. The cause of many reactions has been traced to the use of acid and under-alkalinized solutions. Herring {Munch Med. Woch., Vol. 57, No. 50, 191 1) has shown that in rabbits the acid solution is twenty times as toxic and in dogs ten times as toxic as a properly alkalinized solution. When an acid solution is introduced into the blood stream a yellow, insoluble precipitate is formed and this prevents the flow of the blood through the capillaries. In this condition calcium and magnesium are precipitated as insoluble salts of salvarsan. The removal of these elements from the blood stream has a tendency to reduce the blood pressure and in the presence of the insoluble blood precipitate, it is practically impossible for the blood to circulate through the capillaries. If a properly alkalinized solution (disodium salt) is used, no fall in blood pressure is observed and, in addition, the formation of precipitates is almost entirely eliminated. If the monosodium salt is used, the carbonates, sulphates and alkaline phosphates cause a precipitation of the drug very easily on account of the hydrogen ion concentration, resulting from the chemical com- binations. An alkahne solution (many hydroxyl ions) tends to ehminate these conditions. The isolation and chemical analysis of these blood precipitates will be found in a recent U. S. Public Health report. The Intramuscular Administration of Arsphenamine The intramuscular method of injection was in the early days of salvarsan hailed as an easy and convenient manner of introducing 6o THE TREATMENT OF SYPHILIS the drug into the system. The pain attendant upon the injection proved to be a raison d'etre for discarding the method in favor of intravenous medication on the part of the great majority of salvarsan users. The intramusular method is still employed in such cases as present no suitable veins, and again by physicians who believe the results from the intramuscular method excel those from intravenous introduction. Col. Charles F. Craig, U. S. Army {The Wassermann Test, p. 1 80, 1 9 18) has demonstrated the truth of this assertion by a study of 500 cases, of which 209 were treated by the intramus- cular injection of the alkaline solution, 249 by the intravenous injection of the drug, and 42 by combined intramuscular and intravenous injections. This table illustrates the effect of the method of administra- tion upon the Wassermann reaction: Method of Total Cases Became Negative Remained Positive Administration Number % Number % Intramuscular. . . . Intravenous Combined 209 249 42 159 lOI 28 76.0 44-5 66.6 50 148 14 24 55-5 2,3-3, Totals 500 288 57.6 212 42.4 It will be observed, from a study of the table, that the effect of intramuscular injections of salvarsan upon the reaction is much more pronounced than other methods of administration. This method of administration has been almost abandoned by the profession, and in the army it has been entirely replaced by the intravenous method, owing to the pain and complications that follow the injections and the time lost in hospital. However, there is no question in Craig's opinion that the intramuscular method is infinitely more efficient in treatment than the in- travenous, as shown by the results upon the Wassermann test, for of the 209 cases so treated, most of them receiving but one injection of 0.6 gram salvarsan, 159, or 76 per cent became nega- TECHNIC OF ARSPHENAMINE ADMINISTRATION 6i tive, and fewer cases treated by the intramuscular method re- lapsed than when treated mtravenously. The figures given for the intravenous method are below what they should be for the reason that the majority of the cases studied only received one intravenous injection. Further observations upon this method of administration and its effect upon the Wassermann reaction have shown that with from three to five intravenous injections the results are as good as those obtained with the intramuscular injections, but the data here given are sufficient to show that the Wassermann reaction can be rendered negative by only one intravenous injection in at least 40 per cent of the cases. Intramuscular Method Superior to the Combined The effect upon the reaction of the combined intransmuscular and intravenous method of using salvarsan was determined in 42 cases, of which 66 per cent became negative, thus indicating that the results were not as good with the combined method as with the intramuscular method alone. However, this result was due to the fact that a number of the intramuscular cases had two or even three injections of salvarsan, and it is considered that one intramuscular injection of the drug is equal to at least three intravenous injections so far as the effect upon the Wassermann test is concerned. As should be expected, the effect of treatment with salvarsan upon the reaction increases with the number of doses of the drug that are administered, regardless of the method of administra- tion. Of 200 cases receiving one intramuscular injection of sal- varsan of 0.6 gm., 152, or 76 per cent became negative, while of 9 cases receiving two intramuscular injections, 7, or 77,7 per cent became negative. There is httle difference between these two groups of cases so far as the apparent effect upon the Wasser- mann test is concerned, but the number of cases receiving two intramuscular injections is too small to allow of our basing upon them any accurate statistics, as a large number of cases would undoubtedly give a higher percentage in this class of cases. Of the cases treated by the intravenous method, 177 were 62 THE TREATMENT OF SYPHILIS given one intravenous injection of 0.6 gm. of salvarsan, and 72, or 40.6 per cent became negative; 52 were given two intravenous injections of the same dose, of which 22, or 42.3 per cent became negative; while 10 cases were given three intravenous injections, of which 7, or 70 per cent became negative. There was but little difference in the percentage of negative results obtained in those given one and two intravenous injections; and it will be noted that two intravenous injections did not have as much effect upon the Wassermann reaction, as one intramuscular injection. The per- centage of negative results obtained with three intravenous in- jections, however, approaches closely to that obtained with one intramuscular injection, and justifies the assertion, based upon this obvious experience, that one intramuscular injection is equal, in its effect upon the Wassermann reaction, to three in- travenous injections of a salvarsan. Preparation of Arsphenamine for Intramuscular Use Several methods of preparing salvarsan for intramuscular in- jection are in vogue. EhrUch set forth the following method for the preparation of alkaline solutions for both intramuscular and intravenous in- jection: Ehrlich's Method "Into a narrow-necked, glass-stoppered, sterile, graduated glass cylinder of 300 c. c. capacity, 30 to 40 c. c. sterile freshly dis- tilled water of not more than room temperature are measured. The salvarsan, for example 0.5 gram, is sprinkled on the surface of the water and dissolved by vigorous agitation. To the solution, after it has become absolutely clear and no undissolved particles can be seen, 19 drops of 15% sodium hydroxid solution are added by means of a pipette, drop by drop. This causes a pre- cipitate which dissolves on shaking. The clear yellow solution is now filled up to 250 c. c. with sterile 0.5% saline solution pre- pared from chemically pure sodium chlorid and sterile Freshly distilled water. " Salvarsan solutions must always be freshly prepared. In the TECHNIC OF ARSPHENAMINE ADMINISTRATION 63 preparation of the alkaline solution it is imperative to observe that the salvarsan must be completely dissolved in distilled water {not saline solution), at ordinary temperature and that the solu- tion does not show any gelatinous particles whatever before the sodium hydroxid solution is added. The sodium hydroxid solution is not added gradually, but at once. The precipitate produced thereby must be completely dissolved prior to the further dilution of the alkaline concentrated salvarsan solution with 0.5% saline solution. The sodium chlorid must be chemically pure. Tap or spring water is imsuitable. Hot water must NOT be used in preparing the solution of salvarsan. Should the solution not be quite clear or become slightly turbid after a few minutes, a few more drops of sodium hydroxid solution should be added, a drop at a time and waiting 2 or 3 minutes after each drop to see if this quantity suffices to clear the solu- tion. Each 50 c. c. of this solution contains o. i gram salvarsan. "If no graduated glass cylinder is at hand, the concentrated salvarsan solution may be prepared in a small glass-stoppered flask, and after the addition of sodium hydroxid solution and complete clarification, poured into the saline solution. The solu- tion should be filtered if necessary. " Intramuscular Injections may be made with the alkaline solution as above described, but in this case only about 5 c. c. of fluid are required. For its preparation one proceeds by well triturating in a sterile mortar, for instance 0.5 gram salvarsan with 19 drops of 15% sodium hydroxid solution and then dilut- ing with distilled water to the desired volume. The injection is made into the upper exterior sections of the gluteal muscles. The injection should be made deeply but very slowly, so as not to cause hemorrhage. The neighborhood of the sciatic nerve must be carefully avoided. Intramuscular injections may also be made with simple triturations of salvarsan in fatty oils 1:10 (Oleum Amygdal. dulc, Oleimi Sesami, Oleum OHvae). "In all cases the area of the injection must be previously dis- infected with iodin-benzene or tincture of iodin. After intra- muscular appUcation the injected fluid should be distributed by massage. 64 THE TREATMENT OF SYPHILIS "In sensitive persons the site of injection may be com- pletely anesthetized by a previous injection of 2 c. c. of a i% novocain solution. Hydropathic measures, as moist compresses, hip-baths, etc., or the appHcation of warm compresses, may be successfully employed to prevent afterpain. The internal ad- ministration of pyramidon has proved very efficacious." The Alt Method The Alt alkaline solution method is: "Ten c, c. of sterile dis- tilled water are placed in a beaker of about 50 c. c. capacity, the salvarsan added and triturated with a glass rod until com- pletely dissolved. Normal (4 per cent.) sodium hydroxid solu- tion is now added in the proportion of 0.5 c. c. to each o.i gram of the drug. The stirring is continued until a precipitate is formed and is partially redissolved. The alkali solution is now added drop by drop untU the opacity nearly clears. It is not desirable to permit the solution to become completely clear, as such a solution is more irritating to the tissues than the shghtly tubid solution. The total volume is now made up to 20 c. c." The Michaelis Method The neutral suspension of Michaelis is prepared as follows: "The salvarsan is dissolved in a solution prepared by adding 0.3 to 0.6 gram of sodium hydrochlorate to 16 c. c. of very hot sterile distiUed water in a wide-mouthed graduated cylinder. From 3 to 5 c. c. of normal sodium hydroxid solution are added and the mixture thoroughly stirred. Three drops of a 0.5 per cent, solution of phenolphthalein in 70 per cent, alcohol are added as an indicator, which causes a red color to develop. Then I per cent acetic acid solution is added, drop by drop, until the red color disappears. The salvarsan is precipitated as fine yellow floculi and finally a few drops of the normal sodium hydroxid solution are added to recolor slightly the phenolphthalein. The solution is then ready for injection." Oily Emulsions Oily emulsions are also employed intramuscularly to advan- tage. The firm of Hynson, Westcott & Dunning, of Baltimore, TECHNIC OF ARSPHENAMINE ADMINISTRATION 65 puts out ampules of salvarsan in oil ready for injection, which have met with favor at the hands of advocates of intramuscular medication. British Army Method Lt. Colonel L. W. Harrison, R. A. M. C, in charge of the Mili- tary Hospital, Rochester Row, England, reports favorably {Brit. M. /., May 5, 191 7) on the use of the intramuscular method of neosalvarsan administration. He used neosalvarsan dissolved in 10-15 minims of distilled water and injected into the gluteus medius muscle. This gave a fair amount of pain with some lame- ness after, but when accompanied by a hypodermic injection of morphin it proved as comfortable as any other method. He also utilized the same amount in deep subcutaneous injection, made under the fascia covering the gluteus medius muscle. This was less painful immediately afterward, but often caused the forma- tion of a tender lump on the site of the injection some days later. Another method was the intramuscular and deep cutaneous injections of neosalvarsan emulsified in creo. camph., melting point, 20° C. There was some pain for a few hours afterward but as a rule the patient would allow the site of the injection to be massaged vigorously the following days. The most useful method was the injection of six decigrams neosalvarsan dissolved in i c. c. of a 4 per cent, solution of sto- vain and made up to 2 c. c. with creo. camph., melting point, 15° C, or with camph. phenique. This was the most comfortable injection to use. It was made about a point three finger breadths below the crest of the ilium on a line joining the tuber ischii with the point on the crest of the ilium, which is perpendicularly above the great trochanter, when the patient is upright. As a result of these injections, Harrison feels that the intra- muscular or subcutaneous method is superior in immediate therapeutic effect to the intravenous, that the spirochetes dis- appear from syphiKtic lesions just as rapidly after the first in- tramuscular as after the first intravenous injection, and that the Wassermann reaction is more quickly influenced. 66 THE TREATMENT OF SYPHILIS An American Method Still another method which has been successfully utilized by some American physicians is to mix i oz. each of a 2 per cent novocain solution and chemically pure glycerin. To 4 c. c. of this combined mixture are added the contents of an ampule of neosalvarsan. They are thoroughly mixed together, antisepti- cally of course, and i c. c. is injected through each of four needles — two in each buttock. By the utilization of the four needles, there is not so much foreign substance in the given parts of the muscle and there seems to be less likelihood of trouble. The novocain anesthetizes the part for some time and takes away the initial sting of the injection. After Treatment In England and on the Continent it is the habit, after giving an intramuscular injection, to cover the surrounding parts with sterilized absorbent cotton fixed with elastic collodion. The patients were instructed to rest in bed for twenty-four hours and, according to various reports, the majority of them complained only of stiffness in the hip and thigh and occasionally of pain in the lower extremity. Some physicians also utilize a clay dressing, like antiphlogistine, in place of cotton. It is their custom to cover the entire gluteal surface with a thick layer of properly heated antiphlogistine and to cover this with gauze, and over that absorbent cotton. This application seems to work well following the intramuscular in- jection and, not only aids in the prevention of pain and to a con- siderable extent prevents any abscess formation, but enables the patient to attend to his ordinary affairs. Intramuscular Methods not Popular Notwithstanding the experience of Col. Harrison, as above recounted, the vast majority of practitioners seem to prefer the intravenous procedure of administering salvarsan and neosal- varsan. Their reasons are based upon the fact that the local disturbances, accompanied by pain and possible abscess, when TECHNIC OF ARSPHENAMINE ADMINISTRATION 67 the intramuscular method is employed, seem like a needless punishment of the patient. Moreover, the patients themselves demur and express a preference for any treatment which will eliminate the suffering so commonly accompanying the intra- muscular introduction of arsenical products. Administration of Arsphenamine by the Rectum More or less has appeared in the medical press concerning the introduction of salvarsan into the system by way of the large intestine. Various means have been advocated for the introduc- tion of salvarsan in this manner. This method is not advocated by medical writers except in children and adults whose veins are exceedingly difficult of entrance. We have employed it with success in different individuals, whose veins have not been utiliz- able. The patient has the usual pre-salvarsan preparation, so far as the gastrointestinal tract, etc., is concerned. In addition the lower bowel must be thoroughly cleansed by an enema. The patient is then placed on the table in the Sims or genupectoral position and a sterilized catheter is inserted into the rectum a distance of six inches. Our technic has been to slowly and carefully emulsify salvarsan in I ounce of olive oil by thoroughly stirring the powder into the oil with a glass rod. When this has been properly accomplished the oily emulsion is drawn up into a sterilized glass syringe and is forced through the catheter into the rectum. Another ounce of olive oil is then introduced in a similar way through the same catheter. The catheter is withdrawn and the patient is allowed to remain upon the table for one hour. If the injection is given at the home it is better to keep the patient in bed for several hours so as to prevent any escape of the salvarsan emulsion. It will be observed that arsphenamine employed in this manner is not alkalinized by sodium hydroxid but is put directly into the olive oil. Some physicians employ salvarsan for rectal injection by mak- ing an aqueous solution, but we prefer the oil on account of its blandness and because there is less opportunity of irritating the 68 THE TREATMENT OF SYPHILIS mucous membrane of the intestine. This method has been fol- lowed in giving weekly injections to patients and we have had no complaint of bowel irritability. When aqueous solutions are used sodium hydroxid is employed exactly as in making up a solution for intravenous injection. The amount of distilled water should be about 30 cubic centi- meters. Patients remaining in the genupectoral position any length of time complain of great weariness, so that after ten minutes we permit the patient to assume the Sims position. The physician must exercise care not to permit any escape of the injected contents. We have seen no occasion to utilize opium or any of its deriva- tives in this form. Some operators have added a little laudanum for its soothing effect, but our experience has not made this neces- sary. CHAPTER VIII THE TECHNIC OF NEOARSPHENAMINE ADMINISTRATION There are two methods of introducing neoarsphenamine into the system; one, the dilute, and the other, the concentrated. The preparation of the patient for either method is the same as that for arsphenamine, and every detail as set forth in the preceding pages, as to the physical condition of the patient, the gastro- intestinal toilet, and the urinary examination, should be carried out in its entirety. The choice of veins is the same. Dilute Intravenous Administration of Neoarsphenamine The apparatus necessary for the dilute administration of neosalvarsan is practically identical with that for salvarsan, with the exception that the use of sodium hydroxid is prohibited. The ampule of neosalvarsan should be immersed in 95 per cent alcohol for twenty minutes and all the instruments and utensils should be boiled in distilled water. When these latter are suffi- ciently cool, the amount of freshly distilled and sterilized water which is to be utilized for the injection should be run into the solution cylinder. The quantity of water differs with the amount of neosalvarsan to be utilized. This table will set forth the proper amounts : For Dosage I (0.15) use 25 c. c. " " 11(0.3) ' so c. c. " " 111(0.45) ' 75 c. c. " IV (0.6) ' 100 c. c. " " V(o.75) ' 125 c. c. " " VI (0,9) ' 150 c. c. This water must be room temperature and never hot, as hot water is likely to produce oxidation and give rise to reactions. 70 THE TREATMENT OF SYPHILIS The method of opening the neosalvarsan ampule is identical with that of salvarsan. The contents of the ampule should be scattered lightly over the surface of the water and the product will then very promptly go into solution. It is very seldom one finds occasion to agitate this solution, even in the slightest de- gree. The neosalvarsan solution is then filtered into the cylinder which is to be utilized for that purpose, and the freshly distilled and sterilized water as it is used in, the administration of salvar- san should be placed in the other cylinder. The technic for removal of the air and for preparing for the injection is identical with that already given for salvarsan, and practically every point brought out in the chapter on salvarsan can be duplicated in this connection. The Concentrated Intravenous Administration of Neoarsphena- mine One of the reasons for the widespread popularity of neo- arsphenamine is the ability of the physician to administer it in concentrated solution. The amount of fluid to be used seems to be a matter of opinion. Some employ only lo c. c. of water in giving 0.9 gram neosalvarsan and others employ solutions up to 50 c. c. The favorite quantity of solution is about 25 c. c. Two reasons are advanced for the use of the concentrated solution. The first, and doubtless the most general, is that it is "the lazy man's method." Some believe that as the necessary preparation for the injection is reduced to a minimum, such a small amount can be hurriedly injected. The second reason is that some physicians hesitate to intro- duce a large and what they deem an unnecessary quantity of fluid into the circulation. In the first instance it is doubtless true that there are prac- titioners who employ neosalvarsan on account of its ease of preparation. For some reason they feel that the addition of sodium hydroxid to the salvarsan solution requires a degree of skill or patience which they do not care to exercise. Again, some men are inclined to the newer product on account of the small TECHNIC OF NEOARSPHENAMINE ADMINISTRATION 71 amount of apparatus required for the injection. With others, time seems to be the deciding factor. They begrudge the few extra minutes demanded by the use of the gravity apparatus and consequently seek the quicker and more convenient way of utilizing the services of a Luer syringe. Reasoning of this nature is entirely wrong. The matter of time should not enter into the practice of medicine, especially when so grave a disease as lues is the enemy to be combatted. "The best is none too good" for the patient, and only the best method of giving a remedial agent should be considered. The relative value of salvarsan and neosalvarsan is con- sidered elsewhere and is not germane to the subject now under discussion, but we do most emphatically protest against the use of neosalvarsan or any other drug merely because it is easy of application. Time an Important Factor for Safety K upon due reflection and study of existing conditions the physician determines upon the use of neosalvarsan, he should bear in mind the strictures placed upon the rapid injection of the drug by Dr. George W. McCoy, U. S. P. H. S., and discussed at length in another chapter. He believes and rightfully, we feel, that two minutes should be given to the injection of each deci- gram of arsphenamine or twelve minutes to each maximum dose of 0.6 gram. As one and one-half decigrams of neoarsphenamine are equivalent to one decigram of arsphenamine, the natural assumption is that Dr. McCoy believes twelve minutes should be consumed in the injection of 0.9 gram neoarsphenamine. If his sensible and necessary injunctions are carried out the time factor will not enter into the consideration of the use of con- centrated solutions of neosalvarsan. Of the ease of preparation, owing to a lessened amount of apparatus, nothing need be said, for the fact remains that the method offers great convenience in this particular connection and we are heartily in sympathy with those who employ it on that account. 72 THE TREATMENT OF SYPHILIS The second reason, i. e., the amount of water put into the cir- culation, opens up a question concerning which there has been much discussion. Each school has arguments which appear to offer conclusive proof that it is correct in its deductions. We must admit with real frankness that long usage of both methods has not convinced us that either is wrong. We formerly employed 300 c. c. in administering 0.6 gram salvarsan. No untoward effects were observed from the use of so much fluid. Later, the amount was reduced to 250 c. c. and finally to 180, or 30 c. c. per decigram, and we have no present expectation of going below this amount in the administration of arsphenamine solutions. It must be admitted that in a few unguarded moments, sal- varsan has been injected by us for experimental purposes, in a concentration as low as 7 c. c. per decigram. Grave fears followed the use of this low concentration, and the patients were carefully observed for unpleasant symptoms, which, however, happily did not ensue. One swallow does not make a summer, but the experience has not been repeated lest some of the reactions we read about might fall to our lot. In the use of neosalvarsan we formerly used the gravity method, giving every decigram of neosalvarsan in 20 c. c. or 180 c. c. for a full dose. Added experience caused the amount to be lessened from time to time. When the use of a dilute solution of neosalvarsan is believed to be preferable, from 100 to 130 c. c. is deemed the proper amount. If it is felt the patient can or should have a smaller amoimt of water, a concentration ranging from 20 to 50 c. c. is given. Full blooded persons are generally picked for the greater concentration. As a rule, all things being equal, 25 c. c. is the average amount of fluid utilized. Danger of too Concentrated a Solution At the instigation of a colleague, who enthusiastically related marvelous serological results foUowing 0.9 gram neosalvarsan in 10 c. c. of water, this method was employed for several injections TECHNIC OF NEOARSPHENAMINE ADMINISTRATION 73 on four patients, all men in good general condition. After the injections each man complained that "the medicine is awfully strong," or "that shot had too much kick " or otherwise expressed his disapprobation of the method, not knowing of the undue concentration. They experienced dizziness and in some instances nausea, and one man felt an unpleasant tingling of the fingers. As these men had received three or more injections in concen- trations of 25 c. c. or greater, it was deemed advisable to abandon the use of the more concentrated solutions. It is worthy of note that the subsequent use of the usual concentration elicited no complaint from these patients, nor did they exhibit further dizziness, nausea, or other symptoms, during the remainder of their course of treatment. It is hardly necessary to give an abundance of evidence as to the value of the concentrated method, on account of its wide usage. It may not be amiss, however, to quote the experience of Favre and Massia (Press medicale) who successfully gave 3,150 injections in an average of 18 c. c. of water each. They employed a very fine needle, were able to enter small veins, and found that this high concentration showed no evidences of vein irrita- tion. Reactions were few and very mild in character. They be- lieve that the use of mercury with neosalvarsan lessens the prob- abiHty of reactions. We urgently advise the use of mercury with salvarsan and neosalvarsan in all cases where tolerated, not so much for its anti-anaphylactic as for its anti-luetic action. Technic of Concentrated Method In the utilization of this method, the patient is prepared as for the dilute injection of either salvarsan or neosalvarsan and, in- stead of using the apparatus for the dilute injection, a Luer syringe of from 25 to 50 c. c. capacity takes the place of the double glass cylinders, with the bracket, rubber tubing and three-way stopcock. The solution is made in a wide-mouthed glass graduate instead of in a tall, glass cylinder. After the ampule has been sufficiently immersed m alcohol, it is opened and the contents sprinkled on the surface of the 74 THE TREATMENT OF SYPHILIS freshly distilled water in the graduate. The amount of water depends on the ideas of the physician. Our practice is as a rule to give it in about 25 c. c. The neosalvarsan very speedily goes into solution. As the solution should be filtered, another glass graduate can be utilized for this purpose. As soon as this has been completed, the solution is drawn into the sterilized Luer syringe. The needle is then introduced. When the operator is certain that the needle is squarely within the vein, as indicated by the backward spurting of the blood, the syringe is attached to the needle and the contents very slowly injected. The same length of time should be consumed in administering the con- centrated solution as in the dilute. This means that the operator must push the piston of his syringe so slowly as to be almost imperceptible. The amount of time which Dr. McCoy recommends — twelve minutes for the full dose — shows that in giving a 25 c.c. con- centration not over 2 c.c. should be injected a minute. Subcutaneous Injection of Neoarsphenamine Neoarsphenamine can be injected subcutaneously without difficulty provided the operator has a very careful technic. The great desideratum is not to put it into the fatty tissues, into the fascia or into the muscles. One of the firmest advocates of the subcutaneous administra- tion of neosalvarsan is Dr. Joseph A. Thomas of Valdosta, Ga. He has used this method for six years, has given a very large number of injections in this manner and regards it very highly indeed. The preparation of the patient is looked upon as a very sacred trust by Dr. Thomas. He pays especial attention to the gastro-intestinal tract and insists that the diet on the day of administration be exceedingly simple and he particularly em- phasizes that no tomatoes should be ingested, as he has had cases of vomiting where this article of food has been taken, but he has never seen vomiting from any other cause. He is also particular about testing the secretions of the mouth. If he finds an acid condition he utilizes alkalis until the system O o 1 _c T3 ^ -a o '■% :3 ^ w o -o ■z o ^ < _c 3 s bC I—, p t3 o tS] o > 4-1 ^ -a aj 4-> tn H iz; 03 H cd 1— 1 T3 C/1 W > .ti S O B CTJ P 1-1 ^ O ^ en H o (U 1-1 ^ en +J TECHNIC OF NEOARSPHENAMINE ADMINISTRATION 75 becomes practically free from acidity. He believes this to be essential for the prevention of unpleasant after-effects, although in a letter to the author he says that he has not yet had any reactions. Dr. Thomas then examines the patient carefully for indications as to renal, cardiac or neurological disturbances. Those caused by syphilis do not form contraindications to the drug but, if present from other causes, he treats the cause before going further with neosalvarsan administration. Dr. Thomas' Technic For the employment of neosalvarsan subcutaneously, Dr. Thomas utilizes (i) a 10 c. c. Luer syringe mth a 20 gauge platinum needle; (2) a syringe with a small needle for the local anesthetic; (3) a glass graduate which will hold 20 c. c; and (4) freshly distilled, sterilized water. After the ampule of neosalvarsan has been thoroughly sterilized by immersion in alcohol, he opens it and dissolves the contents of the ampule in 10 c. c. of freshly distilled water at room tempera- ture. The patient is placed upon his abdomen and the skin at the angle of the scapula is painted with iodin around the point an inch or two in circumference. It is then anesthetized with a few drops of cocain. The neosalvarsan solution is drawn up into the Luer syringe and is injected UNDER the skin and not in it or in the fascia but in the connective tissue between the skin and the fascia. Dr. Thomas lays particular stress upon the importance of this point. The injection should be given very slowly. He advises that the operator make certain the needle is free and not in the skin by gently moving the needle from side to side. Upon the completion of the injection the site should be massaged thoroughly, so that there may be a wide-spread distribution of the solution under the skin. This massage prevents the formation of a lump. The point of entrance of the needle is covered with sterile gauze and adhesive. 76 THE TREATMENT OF SYPHILIS Dr. Thomas says that very little pain follows this method of administration and v/hen it is observed the pain will practically always be found to be intercostal and largely referred to the anterior aspect of the chest. The patients feel as if they had a pain over the heart, but the pain in Dr. Thomas' opinion, is of small consequence and it has been very seldom necessary for him to administer an opiate. The advantage of the subcutaneous administration of neosal- varsan over other methods is that it is unusually simple, is with- out danger, gives at least as good results as the others, and there is practically no after-pain and no detention from business. Dr. Thomas believes that the action of the drug is prolonged for about two weeks. He has injected several hundred patients in this manner and has never had any serious after-effects and only one of his patients has been compelled to go to bed. In this instance the temperature went to 105° F. This patient was in his secondaries with a malignant infection and the medical attendant feels that the cause of the rise in temperature was due to the liberation of many endotoxins following the administra- tion of the spirochetecide. < o en H =2 V ci O O M ^ .S c .2 o 1=1 -a CHAPTER IX THE METHODS OF EMPLOYING THE MERCURIALS AND IODIDES The Intramuscular Method of Injecting Mercury The intramuscular injection of the soluble or insoluble forms of mercury requires considerable care and should not be re- garded lightly. The favorite site for injection is about one inch from the crease of each buttock and the parts must be sterilized, prefera- bly with tincture of iodin. Platinum needles of 20 gauge are best adapted for this work, especially when soluble preparations are being used. The needles should be two inches long, so that the mercury can be deposited in the muscle and not in the fat or subcutaneous tissue. Careful examination of the needle should be made before each injection to ascertain any structural weakness. If a needle is broken off in the gluteal region the parts must immediately be laid wide open and the part extracted, for needles in that section of the body are rapid travelers. The needle must be thoroughly sterilized before use and after the injection the bore must be cleared of the detritus, lest some may be left in the bore and, having partially decomposed, be injected into the body at the time it is next employed. When any form of mercury is to be injected, we strongly recommend an all glass, 2 c. c. Luer syringe. In carrying out the operation of injection, after the site has been sterilized, we plunge the needle, minus the syringe, deeply into the muscle, with one short stab. This method causes the patient much less pain than slow penetration. If blood comes out of the shank of the needle, it should imme- diately be withdrawn, as a vessel has been entered. We have seen patients collapse after an injection of mercury when the 78 THE TREATMENT OF SYPHILIS syringe was attached to the needle and no precaution against the entrance of a blood vessel observed. If blood does not follow the introduction of the needle, the syringe should be attached and the contents of the barrel slowly injected. We heartily condemn imdue haste in making these injections as we believe much of the soreness following this form of medica- tion is due to too rapid introduction. After the mercury has been deposited in the muscle, the needle is withdrawn and the part slowly and thoroughly massaged under a piece of gauze. This acts to prevent the lumps which appear following gluteal injections, forming the so-called "cobble- stone " buttocks. As soon as bleeding stops, the point of entrance is sealed with collodion to prevent possible infection. The Inunction Method Many physicians beUeve the inunction method is the best, especially if the rubbing can be done by a person experienced in such work. This method has the advantages of causing no pain, of promptly and thoroughly saturating the body with the drug, and of non-interference with the digestive tract. Inunction is quite necessary in persons who are old or debilitated, or very fat, and in pregnant women, as these types cannot stand injections. The inimction has an added advantage in that it is stored up in the follicles of the skin and is eliminated through the urine long after the rubbings have been discontinued. The old-fashioned unguentum hydrargyrum is often used, but we prefer an ointment made as herein set forth, as it leaves no trace on the skin and is not unpleasant in odor: loo parts of mercury are mixed with 15 parts of anhydrous lanolin and 3 parts of olive oil. Carefully stir, adding the mer- cury in small quantities, but only when no more mercury pellets are visible. Then add a nearly cold mixture of 112 parts of lard and 70 parts of mutton tallow, this latter mixture having been prepared by melting together, and mix the whole carefully. The THE MERCURIALS AND IODIDES 79 resultant salve is of bluish-gray color and no mercury pellets should be visible to the naked eye. Anatomical Sites for Inunctions We suggest, if possible, inunctions just before retiring on seven successive days on these anatomical locations: ist day — Right and left calves. 2nd" Right thigh. 3rd " Left thigh. 4th " Abdomen. 5th " Chest. 6th " Right arm and forearm. 7th " Left arm and forearm. The rubbing should be continued for twenty minutes or until all the mercury has disappeared. After the inunction on the seventh day, the patient should take a hot, soapy bath and the following day commence another seven day series. The patient should wear woolen undergarments and change them only after the seventh day bath. The inunctions are continued as long as the case demands and each case must be individualized. Administration by the Mouth We mention this method only to condemn it and believe the physicians who pursue this line of treatment are following an ignis fatuus. Many a case of tabes and paresis has followed the use of mer- cury per OS, the patients meantime being sublimely unconscious of their ultimate fate. Continued use of mercury by this means impairs the power of the alimentary tract to absorb it and anemia, diarrhea and gen- eral debility often follow its continued use. Fumigation and Inhalation These methods are recommended when there are extensive ulcerating lesions, involving the deeper structures but are not 8o THE TREATMENT OF SYPHILIS suggested for ordinary cases. When indicated, however, these means are of real value. Intravenous Method This is not yet sufficiently perfected to permit of discussion of a helpful nature. We doubt not that eventually the intravenous route will form one of the standard methods. Form of Mercury to be Used The question arises as to whether one wiU use a soluble or in- soluble form of mercury. The insoluble in the form of the salicy- late is very popular, although, both calomel and gray oil have their ardent advocates. For example, Dr. J. A. Fordyce, if he em- ploys an insoluble form, utilizes gray oil *'in the form of mercurial cream, of which 5 minims represent i grain, in a series of ten or twelve injections, or salicylate of mercury 40 per cent suspension in doses of i to 3 grains, gradually increased, ten to twelve in- jections constituting a course." We have utilized this form of treatment with results not en- tirely satisfactory. Our dissatisfaction was largely due to the soreness which was likely to foUow the injections and particularly to the formation of lumps in the buttocks, the "cobble-stone" buttocks, in which condition mercury was found to be unab- sorbed, sometimes weeks after the original injection. We thereupon experimented with the succinimid, which is a soluble product. This was found to work well in clinics where the patients were men used to very heavy work and who were not easily affected or disturbed by localized soreness, but in private practice it proved to be altogether too painful, nor did the benzo- ate work to our satisfaction. The soluble mercury of choice we have found to be the bi- chlorid, which we ordinarily administer in the beginning of treatment in 3^ grain doses. If that is readily taken, the dose is increased to 3^ grain and then to i grain. Dr. Fordyce {Amer. Jour. Med. Sci., October, 1916) advised giving a soluble mercury intramuscularly every other day and quoted the bichlorid as his preference of the soluble forms, Iz: o H CJ w 1— > ;z; t— ( I-) < "S a t3 en q ;-l « o 3 « .s ^ 1— 1 F^ t) a o cfi o t3 T3 OJ OJ Q. u >% H ;3 ^ ;-< HH Ul ^ o « 'S) O CJ P^ cJ bio (J M C 1-1 ^ CI P en b 2; _fl ^ 1 * U3 . a en (U a> -a -C H H THE MERCURIALS AND IODIDES 8l giving from twenty to thirty injections either daily or every other day. A Convenient Means of Mercurial Administration One objection to the hypodermic use of mercury has hereto- fore been the frequent inability to obtain an absolutely certain dosage of mercury, especially where it has been put up in an oily suspension by the local pharmacist. Several years ago there came to our attention an ingenious method of holding insoluble or soluble mercurials in the form of coUapsule hypo-fills, which consist of bulbs made of gelatin holding an exact amount of the mercurials. By means of these coUapsules we carried on a long series of experiments utilizing the saUcylate, calomel, suc- cinimid, benzoate and bichlorid. The mercurial is held in a base containing neutral vegetable anhydrous fats and when intro- duced into the body breaks down in the form of alkaline pal- mitates and glycerin. The bichlorid is readily absorbed, the injection is followed by practically no pain and the "cobble- stone" buttock is something unknown. The great advantage of the use of collapsules is that the physi- cian is certain of exact dosage and he is also given a most con- venient method of administration. Our experience has been that the use of mercury in this form seems to increase the body weight and the arsphenamine is very materially aided. From the cut given herewith it will be observed that the gelatin top of the coUapsule is clipped off, and the contents squeezed into a 2 c. c. Luer syringe, which is warm from the previous sterilization, and it is, therefore, melted sufficiently to permit of immediate injection into the body. Advantages and Disadvantages of Soluble Mercury The great advantage of mercury in the treatment of S3^hilis is to have it as constantly in the system as possible. It might seem almost suicidal to advocate the use of bicholorid of mercury in from 3^ to i grain doses. This, however, is the dosage which Fordyce has employed in his clinics for a long time without any difficulty, and we have also utilized it to the very 82 THE TREATMENT OF SYPHILIS best advantage. It means, however, that the patient should come every other day for treatment and, while this can be accom- plished so far as the ordinary dispensary patient is concerned, it is often difficult for the private patient unless he be in a hospital. Another disadvantage of bichlorid is the possibility of a renal nephritis. We have never seen such a condition but the possibil- ity is ever present and must be most carefully considered. The use of bichlorid means that the urine must be constantly examined so that the condition of the kidneys can be at all times known to the physician. If the patient can come to the office every other day, or even twice a week, we recommend the bichlorid; if it is impossible and the patient can only be seen once a week, the salicylate is preferable. In some cases one grain of bichlorid injected once a week has been absorbed so slowly that we have been content to give weekly injections of one grain each. Iodides The employment of the iodides in the treatment of syphilis has undergone a very radical change since the introduction of salvarsan as an anti-luetic agent. It was formerly a part of the stock treatment of the syphilitic and after vigorous mercurial medication he was placed upon the iodides, preferably the iodid of potassium. Despite the fact that this drug disarranges the stomach of many patients, it was very generally utilized, al- though at times other preparations of iodin, such as salts of sodium, strontium, and ammonium, have been used. There are on the market a number of proprietary products containing iodides, which have been formulated in combinations, tending to eliminate the uncomfortable and unpleasant features caused by taking the raw iodides. Spirochetae not Affected by Iodin We have learned, however, that iodin has little or no effect upon the spirochetae. This was first brought to the attention of the profession by Colonel (then Captain) H. J. Nichols, U. S. Army {Journal of Experimental Medicine, p. 196, 191 1). 2 c ^ .2 12; -a 5 I— I -r- t5 ^ >» hH S O o *J >% 5 o c x (V( & G u (N M S XI P^ c o o :z: n ^ H O o w X a; 1— > o ^ o (J c3 3 PS J3 H < t) ^ tj -r; +-1 3 r/j _N bC ^ OJ 6 1— 1 "o f5 -C (73 OJ X -o fTi