it produces an acute disease of a relapsing type and is THE USE OF ARSPHENAMIN IN self-limiting. Spironema morsus muris {Spirochaeta morsus- NONSYPHILITIC DISEASES - muris), the organism of rat-bite fever, produces a local MATHEW A. REASONER, M.D. lesion at the point of entrance and passes through the Major, Medical Corps, U. S. Army lymph nodes and invades the blood stream and tissues. AND It produces an acute disease of a relapsing type and is HENRY J. NICHOLS, M.D. self-limiting. Major, Medical Corps, U. S. Army Treponemp. pertenue, Castellani, 1905 {Spirochaeta WASHINGTON, D. C. pertenuis), begins its invasion by a local lesion, invades the blood stream, then localizes and produces surface It has been shown by Bronfenbrenner and Noguchi,1 and occasionally deep lesions. It also and may spread by Akatsu,2 Akatsu and Noguchi3 that the spiro- autoinoculation. It is self-limiting. Yaws is not a chetes, especially those parasitic to the higher animals, congenital disease. have many characteristics to a greater or less degree Treponema pallidum, Schaudinn, 1905, {Spirochaeta in common. This is noted in their to be morphology, pallida), produces at first a local lesion, invades the motility, cultural peculiarities and methods of growth, blood stream and involves all tissues and may be trans¬ their reaction to certain compounds especially those mitted to the next generation. The disease does not sometimes known as spirocheticides, and their thermal tend toward recovery. death point. While between some of the various spe- In considering the effect of arsphenamin in non- cies of spirochetes there is quite a little difference in syphilitic disease, it should be remembered that the morphology, there seems to be a sufficient number of original work which led to the production of ars¬ characteristics in common to justify our placing them in phenamin was done not only with Treponema pallidum a single group. but also with Spironema recurrentis of relapsing The following examples will serve to illustrate grada- fever, Spironema gallinarum of a disease in fowls and tions in pathogenicity: Treponema pertenue of yaws. Ehrlich and Hata's a free first monograph on salvarsan is called "The Experi¬ Spirochaeta plicatilis, Ehrenberg, 1833, living mental organism found in stagnant water. Chemotherapy of Spirilloses (Syphilis, Relaps¬ Cristispira balbiana, Certes, 1882 (Spirochaeta bal- ing Fever, Chicken Spirillosis and Yaws)."4 The favorable action of is to be con¬ bianii), has developed parasitic properties for a cold arsphenamin blooded animal and is found in the of sidered as a group effect due to a chemical affinity crystalline style between the and the vital structure of the oyster. drug the organ¬ ism. It was dentium, Koch, 1887 den- logical to expect that other affinities, to a Treponema (Spirochaeta greater or less would be found others is a found com¬ degree, among tium), ordinarily saprophytic organism of the and in the normal human mouth. It invade spirochetes that when present, they could be monly may demonstrated Erom the but its exact rôle in such invasion is not therapeutically. beginning, damaged tissue, the action of as known. therefore, arsphenamin was studied a effect on diseases rather R. 1906 group spirochetal than from Spironema vincenti, Blanchard, (Spirochaeta the of alone. It has been in is the cause of local lesions on the standpoint syphillis given vincenti), probable almost every pathologic condition to which human flesh human mucous membrane, and it invades the underly¬ is heir, but for effect, its tissues but is not believed to invade the specific proper therapeutic ing regularly field would seem to be limited among dis¬ blood stream. nonsyphilitic eases to those caused and in a few 1874 by spirochetes Spironema recurrentis, Lebert, (Spiroschaudin- instances in lesser degree to certain protozoal and nia recurrentis, Spirochaeta recurrentis), invades the bacterial infections. Favorable results had also been human blood stream but does not local produce lesions, observed in one disease of unknown etiology, in rat- bite fever. the cause the was Read before the joint meeting of the Section on Pharmacology Later, of disease found and Therapeutics and the Section on Dermatology at the Seventy-First to be a An should not be made Annual Session of the American Medical Association, New Orleans, spirochete. attempt April, 1920. to carry the group effect too far as there are appar¬ Because of lack of space, this article is abbreviated in The Journal. some diseases, such as Weil's disease The complete article appears in the Transactions of the Section and in ently spirochetal the author's reprints. A copy of the latter will be sent by the author and yellow fever, in which arsphenamin has no benefi¬ en receipt of a stamped addressed envelop. cial effect. 1. Bronfenbrenner and Noguchi: J. Pharmacol. & Exper. Therap. 4: 333 (March) 1913. 2. Akatsu: Arb. a. d. k. Gsndhtsamte 25: 494, 1907. 4. Ehrlich and Hata: The Experimental Chemotherapy of Spirilloses, 3. Akatsu and Noguchi: J. Exper. Med. 25: 363 (March) 1917. Berlin, Julius Springer, 1910.

Downloaded From: http://jama.jamanetwork.com/ by a Northeastern University Libraries User on 05/26/2015 CONSIDERATION OF SPECIAL SPIROCHETAL of 10 per cent, arsphenamin in glycerin. This form of DISEASES treatment is probably more essential in military than Vincent's is a form of in civil practice. Ordinarily, this treatment will suffice ; Angina.—Vincent's angina it if have ulcération of the mucous membrane by a but if fails to control the disease, the lesions produced become it spirochete known as Spironema vincenti (possibly extensive or if serious complications exist, is neo- Spironema buccalis, which has for some reason advisable to give intravenous injections of in become pathogenic), in connection with a fusiform arsphenamin medium-sized dosage. bacillus. The relationship of these two organisms to Pulmonary Spirochetosis; Fetid Spirillar Bronchitis ; the disease has not been entirely worked out, as some Pidmonary Gangrene.—From a number of widely sepa¬ observers attribute the lesions to the fusiform bacillus, rated sources, different observers have described a form Tunnicliff,5 however, an excellent of a of spirochetal lung involvement. From Uganda, Tay¬ gives description 13 phase of the pathology, showing the zone of spirochetes lor describes a condition with pneumonic symptoms in advance of the fusiform bacilli in the affected tissue. and termination by crisis. Loygue, Bonnet and Peyre 14 This disease is ordinarily located in the pharynx, but found many organisms in fourteen of twenty-seven may occasionally involve other portions of the body. grave cases of influenza and in four fatal cases. In In civil practice it is not a very common disease, it one case the spirochetes were also found in the urine. is generally susceptible to treatment with local anti¬ Ribeyro15 describes a prolonged case in Peru. A septics and rarely assumes epidemic form. In the mili¬ series of cases was reported from Egypt by Farrah.16 tary service, conditions are different and this disease Castellani1T found two types of spirochetal pulmonary must receive serious consideration as a cause of con¬ involvement in soldiers of the Italian army, the one siderable invalidism and occasional deaths. Bouty ' lasting only several weeks and appearing as an acute states that Vincent's angina forms from 2 to 3 per bronchitis ; the other as a chronic bronchopneumonia of cent, of throat troubles in the French army in peace months' or years' duration or becoming malignant with times. Recent statistics in a British in France irregular fever, emaciation and death. hospital 18 hemoptysis, show the proportion to be as high as 23 per cent. Violle described a mild type with good prognosis. Campbell and Dyas 7 give a very adequate description Nolf and Spehl19 described a condition which they met of the epidemic among the English soldiers at Bram- during the war, similar to a baronchitis or a broncho¬ and detail the different and forms pneumonia, and always characterized by a fetid breath. shott, England, types 20 of manifestations. They note that syphilitics seem The causative organism is described by Nolf and to react worse to this affection. They advise that in seems very similar to what Noguchi has termed Trep¬ mild cases, any of the numerous recommended applica¬ onema macrodentium. It is also to be found in pul¬ tions will about a cure, but con¬ monary gangrene, which may be a termination of this frequently bring they 20 sider the most useful remedy to be arsenic in the form condition. Nolf states that arsphenamin exercises of arsphenamin or neo-arsphenamin, as a local appli¬ a decidedly curative effect if given early. If delayed, cation. the prognosis is not so favorable, or it may be necessary Tixer and Tobe8 discuss the disease as found to administer repeated doses over a period of several among the French soldiers. They advise various local weeks. In such a case it will be noted that, coincident applications, giving first place to neo-arsphenamin. with the treatment, there is a diminution of the spiro¬ They advise the intravenous administration of neo- chetes and a disappearance of the fetid odor of the arsphenamin when the lesions of stomatitis or angina breath. are particularly extensive or when they are accom¬ Pyorrhea alveolaris.—Little is known of the etiology panied by complications. Bouty ° describes the serious of the several conditions resulting in this disease. In results which may follow the appearance of Vincent's some cases, arsphenamin has a decided effect (which angina in the military service. He recommends the use many not be permanent,) and in others, no results are of neo-arsphenamin either in solution or powder noticeable. Where improvement is shown, the spiro¬ applied locally to the affected portion. Renon and Des- chetes are probably responsible, either primarily or bouis * report a series of cases treated in this same secondarily. the manner, with very satisfactory results. Niglot and Relapsing Fevers.—All reports available from 10 those Levy report six cases treated with local applications who have used arsphenamin and neo-arsphenamin of neo-arsphenamin in powder, directly to the lesions. in the treatment of the various types of relapsing fever lx have been The results were prompt and satisfactory. Rolleston favorable. describes the satisfactory results obtained from the use Among those recommending unqualifiedly the use of in are a in and arsphenamin relapsing fever the following: of glycerin swab dipped arsphenamin powder 24 to the lesion. Greene 12 describes the Stitt,21 Manson,22 Robledo,23 Jarno and Iversen.2S applied directly 26 excellent results obtained from both Manson and Thornton present a summation of the arsphenamin by results local applications and by intravenous injections. obtained from novarsenobillon, neosalvarsan, that Summing up the foregoing, it is probable among 13. Taylor, J. A.: Ann. Trop. Med. 8: No. 1 (April 20) 1914. the best results are obtained the 14. Loygue, Bonnet and Peyre: Bull. et m\l=e'\m. Soc. m\l=e'\d. d. h\l=o^\p. local applications, by de Par. 42: (No. 29) 1918. use of neo-arsphenamin applied in powder form or with 15. Ribeyro: Cronica med. Lima 35: No. 665, 1918. 16. Farrah: Lancet 2: 608 (Oct. 4) 1919. a local twice glycerin swab, or by applications, daily, 17. Castellani: Presse m\l=e'\d., 377, 1917. 18. Violle: Rev. g\l=e'\n.de clin. et de th\l=e'\rap.32: 144, 1918. 5. Tunnicliff: J. Infect. Dis. 25:132 (August) 1919. 19. Nolf and Spehl: Arch. m\l=e'\d. belges 71: 1, 1918. 6. Bouty: Brit. M. J. 2: 686 (Nov. 24) 1917. 20. Nolf: Arch. Int. Med. 25: 429 (April 15) 1920. 7. Campbell, A. R., and Dyas, A. D.: Epidemic Ulceromembranous 21. Stitt: Diagnostics and Treatment of Tropical Diseases, Ed. 3, Stomatitis (Vincent's Angina) Affecting Troops, J. A. M. A. 68: 1596 Philadelphia, P. Blakiston's Son & Co., 1919, p. 86. (June 2) 1917. 22. Manson: Tropical Diseases, Ed. 6, New York, William Wood & 8. Tixier and Tobe: Progr\l=e`\s m\l=e'\d. Third Series 33: 245, 1918. Co., 1919, p. 243. and Soc. de Par. 23. Rev. med. 9. Renon Desbouis: Bull. et m\l=e'\m. m\l=e'\d.d. h\l=o^\p. Robledo: de de Bogot\l=a'\ 37: (Jan.-March) 1919 . 26: 247, 1913. 24. Iversen: Russkivy Vrach 15: 505. 10. Niglot and Levy: Lyon m\l=e'\d. 122: 1181, 1914. 25. Jarno. Wien. klin. Wchnschr. 28: (April 22) 1915. 11. Rolleston: Proc. Roy. Soc. 1: (Oct. 10) 1912. 26. Manson and Thornton: J. Royal Army M. C. 33: No. 2 12. Greene: Northwest Med. 4: 50, 1914. (August) 1919; ibid. 33: No. 3 (September) 1919.

Downloaded From: http://jama.jamanetwork.com/ by a Northeastern University Libraries User on 05/26/2015 luargol, galyl and salvarsan in the African type of and about 0.2 micron in width. It tapers gradually fever : toward the finely pointed ends, either one or both of 1. Give arsphenamin or one of its substitutes. which are curved for purposes of propulsion when the 2. Of these, novarsenobillon, 0.9 gm., gave most satisfactory organism is in motion. It is tightly wound at short and results. regular intervals of about 0.5 micron to each section. 3. Give it on the first attack of fever and, failing this, wait Experimental work carried out by Inada and his until the first relapse, and give it then on rise of temperature. associates indicates that it is for Leptospira 4. Administer it on the rise of and possible always temperature to the unin¬ never in the apyrexial period. icterohaemorrhagiae penetrate apparently skin of the within a of five 5. Should a further the dose as before jured guinea-pig period relapse occur, repeat be on the rise of temperature. minutes. It may therefore possible for the organ¬ 6. If such a course is followed, we are of the opinion that ism to be transmitted through direct contact with the we have means at our disposal whereby an attack of relapsing excreta of an affected person. This disease is more fever in the African native can be cured. important from the military view than from the stand¬ of the civilian the From the available and it would point physician. During year 1915, reports opinions, cases of infectious were observed the seem that is the and jaundice among neo-arsphenamin drug of election soldiers. Stokes and 33 demonstrated the will serve as a in all of English Ryle specific types relapsing fever. in the blood and urine of affected soldiers. Rat-Bite Fever.—Rat-bite fever has been known in organism Ryle34 found the organism in rats captured in the Japan for many years, but only since Mayake's report in trenches where the cases of infectious jaundice had 1910 has attracted general attention. Cases have originated. been from 35 reported England, United States, Italy, East Kaneko and Ito some Africa and other countries. Inada, Ito, Hoki, performed experimental work on guinea-pigs to determine the Rat-bite fever should not be confused with strepto- effect of arsphenamin in this disease. This animal is thrix which be in the same infection, may conveyed not well to such work, as it has manner. It is caused unfortunately adapted by Spironema morsus-vnuris, weak resistance against arsenic. Their results were which is transmitted the bite of a 3e through rat, probably inconclusive. Stokes and report on the admin¬ as the result of abrasions or of the Ryle hemorrhages gums. istration of 0.3 gm. of in one case The a arsphenamin given spirochete lodges in the skin and, after varying without apparent effect. Stokes, Ryle and Tytler37 of a local lesion at period incubation, produces the state that "the treatment at present is purely sympto¬ site of It then the 38 injury. spreads through lymphatics matic." It was later shown Griffith and Inada, Ido and involvee the blood the skin and nervous by stream, and others,39 that there is a well-marked bacterial The is of an intermittent system. pyrexia type. and that serum treatment instituted in the Immunity develops and the disease is therefore self- immunity, early stages, or up to the fifth or sixth day, reduces the limiting. and duration of the disease and has a bene¬ to Stitt2T some success in treatment seems severity According ficial effect on the and to have followed the use of hemorrhages suppurative proc¬ arsphenamin. Bergamini28 esses. We must therefore conclude for the reports a case which was cured the intra¬ present apparently by that is not in a nor has venous administration of arsphenamin, after the failure arsphenamin any way specific, 29 it marked action on the course of the disease. of all other measures. Hata reports on the use of any Yellow 40 has demon¬ arsphenamin in eight cases of rat-bite fever. He used Fever.—Noguchi apparently strated that fever a intravenous injections of from 0.3 to 0.6 gm. of yellow is due to spirochete whose arsphenamin in adults. He concluded that the treat¬ morphology is very similar to that of Leptospira ment was the best available but in no way a specific for icterohaemorrhagiae. He has called this organism the disease. Tileston 30 reports two cases of rat-bite Leptospira icteroides. fever which had resisted other treatment but had The literature on the treatment of yellow fever with responded readily to 0.3 gm. of arsphenamin adminis¬ arsphenamin is scanty, and apparently little work has tered intravenously. Délai31 reports a case of rat-bite been done. Arago41 reviews the South American fever treated with one intravenous injection of 0.9 gm. reports and states that those who have tried it have of neo-arsphenamin. He felt that it hastened recovery. obtained good results. He advises that the first dose 32 Surveyor reports on the intravenous injection of 0.7 be given intravenously and in as large quantities as 0.9 gm. of neo-arsphenamin in a case of rat-bite fever, with gm. Noguchii2 states that arsphenamin in 1: 200,000 apparently good results. solution will, after two to three days' contact, destroy It is difficult to draw final conclusions as to the com¬ the organism of yellow fever in vitro but that experi¬ parative value of arsphenamin in this-disease, .until mental work with susceptible animals has failed to larger series of cases are reported on and more com¬ demonstrate that arsphenamin has any beneficial effect parisons obtained with other forms of treatment as on the course of the disease. While it is desirable to well as experimental work done with the lower animals have further reports of the treatment of the disease in the disease. we are susceptible to Meanwhile, justified man, yet even in the absence of such, we are justified in assuming that arsphenamin has a beneficial thera¬ in that fever is one of the effect. assuming yellow spirochetal peutic diseases not favorably influenced by arsphenamin or Weil's Disease.—Leptospira icterohaemorrhagiae neo-arsphenamin. (Spirochaeta icterohaemorrhagiae) is a very delicate and measures from 4 to 9 microns in 33. Stokes and Ryle: Jour. Royal Army M. C. XXVII, 1916. organism length 34. Ryle: Lancet 1: 142, 1917. 35. Inada, Ito, et al.: J. Exper. Med. 23: 377, 1916. 27. Stitt: Diagnostics and Treatment of Tropical Diseases, Ed. 3, 36. Stokes and Ryle: J. Royal Army M. C. XXVI, 1916. Philadelphia, P. Blakiston's Son & Co., 1919, p. 407. 37. Stokes, Ryle and Tytler: Lancet 1: 142, 1917. 28. Bergamini: Policlinico (sez. prat.) 26: 1225 (Oct. 12) 1919. 38. Griffith: J. Hygiene 18: 59 (April) 1919. 29. Hata: M\l=u"\nchen. med. Wchnschr. 59: 854, 1912. 39. Inada, Ido, et al.: J. Exper. Med. 23: 377, 1916. 30. Tileston, Wilder: The Etiology and Treatment of Rat-Bite Fever, 40. Noguchi: J. Exper. Med. 29: 547, 565, 585 (June) 1919; ibid. J. A. M. A. 66: 995 (April 1) 1916. 30:1, 9, 13 (July) 1919; ibid. 30: 87, 95 (Aug.) 1919. 31. Delal: Practitioner 92: 449, 1914. 41. Arago: Brazil-medico 33: 201 (June 28) 1919. 32. Surveyor: Lancet 2: 1764, 1913. 42. In a personal communication to the authors, April 8, 1920.

Downloaded From: http://jama.jamanetwork.com/ by a Northeastern University Libraries User on 05/26/2015 Dengue and Pappataci.—These are two diseases of the granulomas, and usually involves the naso- which closely resemble yellow fever except that their pharyngeal tissues. The end-result is frequently the manifestations are of a far milder type. Craig,43 in complete destruction of the tissues entering into the a discussion of the three diseases, concluded that when structure of the nose with resultant cicatrization and a the causal organisms were discovered they would be destruction of the pharyngeal vault. Similar ulcers found to be closely related species, belonging to the have been noted on the extremities. same genera. The reports of all observers are unanimous and We have found no literature bearing on the treat¬ show conclusively that there is no disease more amen¬ ment of these diseases with arsphenamin and neo- able to treatment with arsphenamin than is gangosa. arsphenamin. We should expect the results to be Early cases show an almost miraculous improvement about the same as with yellow fever. As a matter of within the course of twenty-four hours. There is no scientific interest, reports of such treatment would be apparent tendency toward relapse. When there has of value. been a considerable destruction of tissue, it is of course Yaws or Frambesia.—This disease is found in the impossible to do more than to delay the further prog¬ tropical regions of Africa, Asia, America and Australia. ress of the disease and to induce cicatrization of the It is the spirochetal disease most resembling syphilis affected area. both in its manifestations and in the characteristics of Verruca Peruana.—This is a little known disease the organism. It is very doubtful whether Treponema found in South America on the west slope of the the cause of yaws, can be differentiated from Andes. It had been supposed by some observers to be pertenue, 52 Treponema pallidum on a basis of morphology, except a severe type of yaws. Strong concludes that ver¬ perhaps after prolonged observations and measure¬ ruca is not a variety of yaws but a distinct disease, ments at the hands of an expert. The growth in the the lesions are dissimilar, he was unable to find any rabbit is very similar and can be differentiated from constant organisms in the lesions, the lesion in the rab¬ syphilis only after considerable experience. The cul¬ bit's testicle was not characteristic of yaws, and no tural characteristics are practically the same. The spirochetes could be found in the testicle. Finally, the disease gives a positive though weaker complement disease is not cured by arsphenamin. fixation to the Wassermann technic. ordinary SPIROCHETAL DISEASES AMONG THE LOWER We have both demonstrated to our satisfaction entire ANIMALS the curative effect of arsphenamin in experimental disease known as yaws in the rabbit. Equine Influenza.—The equine influenza is due to an unknown filtrable virus. According to Stitt,45 it can certainly be stated that in The which follow are due to a arsphenamin we have an absolute specific for yaws, the pneumonias undoubtedly results which are obtained in a few almost secondary infection. Arsphenamin was first used days being for this disease in 1911 and Kirsten in Ger¬ miraculous when one considers the protracted normal by Rips course of the disease. The method of administration many and Linizky in Russia. Their reports, and those of are is the same as in syphilis, and results are best obtained Nevermann and Naess of Norway, convincing when the arsphenamin is given early in the course of as to the value of the treatment. They recommend the the disease. A dose of 0.4 gm. of arsphenamin usually use of arsphenamin given intravenously, 0.01 gm. per suffices and often effects a cure. Bergen noted relapses kilogram of body weight. In a later report, Rips and in about 4 per cent, of cases treated with arsphenamin Neven advise the use of neo-arsphenamin in equivalent and neo-arsphenamin. Manson 46 states that arsphen¬ dosage. There follows a slight rise in temperature for amin, or preferably neo-arsphenamin, has a rapid and a few hours, and then an amelioration of symptoms remarkable curative effect in every stage of the disease. which ordinarily disappear within twenty-four hours. It is the recognized specific treatment and may be Torgensen states that in the presence of pneumonia and given intravenously or intramuscularly. He further extreme weakness, untoward results may occur. It recommends the systematic used of arsphenamin in get¬ would follow that treatment should be given early in ting rid of the endemic. Castellani4T says : "The the course of the disease, and on account of expense it most efficacious and quickest treatment is by arsphen¬ would probably be limited in its use to the treatment of amin or neo-arsphenamin. These drugs seem to act valuable animals. in frambesia more and than in quickly powerfully any Spirochetosis of Fowls.—A very exhaustive report other or condition. In spirochetal treponemal fact, on the spirochetosis of fowls found in the Sudan, South 'therapia sterilisans magna' in Ehrlich's meaning, by a American and possibly the United States deals with can there be realized." single dose, the effect of arphenamin on Spironema gallinarum There are many available which confirm reports {Spiroschaudinnia marchouxi). The fowls were cured these and no adverse It may opinions, testimony. in a number of cases, some of them therefore be that we have in and though proved accepted arsphenamin somewhat resistant. doses were for yaws. Intravenous Repeated occasionally neo-arsphenamin, specifics found necessary, and young fowls did not stand the of from 0.4 to 0.6 gm. of should injections arsphenamin well. The was mixed in olive oil be and as the of the case shows arsphenamin drug given repeated progress and into the tissues. necessary. injected Gangosa.—Gangosa is a disease found in the West PROTOZOAL DISEASES Indies, Africa, Guam, Australia and other tropical A considerable amount of work has been done in the of an countries. Briefly speaking, it consists ulcer¬ treatment of diseases with and and destructive the characteristics protozoal arsphenamin ative process, having with some claims of favorable results, though not so 43. Craig: New York M. J. 93: 360, 1911. favorable nor so much in accord as with certain of the 45. Stitt: Diagnostics and Treatment of Tropical Diseases, Ed. 3, diseases. Philadelphia, P. Blakiston's Son & Co., 1919, p. 349. spirochetal 46. Manson: Tropical Diseases, Ed. 6, New York, William Wood & Co., 1919, p. 668. 52. Strong: Harvard School of Tropical Medicine, Report of First 47. Castellani: Manual of Tropical Diseases, 1913. Expedition to South America, Cambridge, 1915.

Downloaded From: http://jama.jamanetwork.com/ by a Northeastern University Libraries User on 05/26/2015 Malaria—-The various types of malaria have been account of the close relationship of these organisms, on from many sources, but the results are not the material will be under this one heading. reported grouped e3 on the whole so favorable as with quinin. Stephens, Sleeping Sickness : Broden and Rodhain report Yorke and Blacklock53 found that in simple tertian good results from the Congo, following the use of malaria, single intravenous injections of neo-arsphen¬ arsphenamin, but only when examination of the spinal amin in doses of from 0.45 to 0.9 gm. stop the parox¬ fluid indicates no involvement of the nervous system. ysms and eliminate the parasites from the cutaneous Atoxyl is probably a more efficacious form of medica¬ blood, as a rule within one day. Parasitic relapses tion, and it is possible that any good effects may be due occur, on an average, in twenty-one days. The cura¬ only to the contained arsenic. Lurz 4 makes a further tive effect of a single injection is of no perma¬ report on the use of arsphenamin in sleeping sickness. nent value. Stott54 found that arsphenamin had All patients having over 10 cells per cubic millimeter apparently some specific action on the asepcual were rejected. Patients weighing less than 50 kg. were forms of malarial parasites, but no influence in the given 0.3 gm., and those weighing over 50 kg. were prevention of the evolution of the sexual cycle. given 0.4 gm, every other day for two weeks. The It does not produce the immediate and progres¬ results were unsatisfactory. Branden 5 reported a sive beneficial effect in malarial diseases which favorable effect in human trypanosomiasis, but believes commonly follows the administration of quinin. He that not all trypanosomes are affected alike. Some concludes that it may be of some value as an has been made to use a modified form of 5G adjuvant. attempt Neff reports on the use of arsphenamin in five cases Swift-Ellis treatment in those showing nervous involve¬ of tertian malaria which had resisted the administration ment, but no conclusive results have been reported. of quinin. Results seemed to indicate a cure in all Surra : This trypanosome infection, due to Trypano¬ cases for periods of from four to eight weeks during soma evansi, is a fatal disease of horses, camels and which they were under observation. Reed56 and cattle, and is found in southern Asia, Malaya and the Goldthwait57 each report a case of malaria resistant to Philippines. Arsphenamin seems to have little favora¬ quinin, which yielded to a single intravenous injection ble effect, though Strong 66 reports some good results of arsphenamin. Manson 58 states that recent experi¬ from the use of arsenophenylglycin given intraven¬ ments show that although and neo- ' arsphenamin ously. arsphenamin have some effect on the quartan and ter¬ Dourine : Dourine, or mal du coit, is caused by tian parasites, they have but little, if any, on the estivo- Trypanosoma equiperdum. It affects stallions, brood autumnal. Kopanaris,59 having seen some benefits in mares and donkeys, and is found in South Europe, tertian malaria in man from the use of arsphenamin, North Africa, Chile, and has been imported into the made a very thorough study of the effect on proteosoma United States. Some good reports have been made of which is the similar organism causing bird malaria. the use of arsphenamin in this disease, though they are He found that infected birds treated with arsphenamin not yet conclusive. The experimental study of Scham- in both large and small doses, showed far greater berg, Kolmer and Raiziss6T is, however, very con¬ intensity and continuance of infection than the control vincing as to the favorable effect of arsphenamin on birds which had not received arsphenamin. He also the organism in rats. They conclude that the trypano¬ found that treatment with arsphenamin lowered the somes react in a large measure to the influence of drugs resistance of normal birds to subsequent infection. as do the spirochetes. On the other hand, the usual effect was obtained from Mal de Caderas : Mal de caderas is caused by Try¬ the administration of quinin in this disease. J. W. W. panosoma equinum, and is found in horses in Panama Stephens 60 obtained no curative results whatever from and Colombia. Teague and H. C. Clark showed that the use of neo-arsphenamin in malignant tertian mala¬ arsphenamin had a favorable effect in this disease. ria. The addition of arsenic to quinin is no more Nagana: Trypanosoma brucei is the cause of effective than quinin alone. Böhme 61 recommends the nagana, which is a fatal disease of horses and cattle combined use of quinin and neo-arsphenamin. Wor- and is found in Africa. It is shown 6S that arsphen¬ ner62 considers neo-arsphenamin useful for general amin causes a temporary decrease in the number of treatment and for improving the state of the blood but organisms in infected gerbils, and will delay death for of no value for gametocyte carriers. several days. Schilling recommends arsphenamin for The mass of literature on the treatment of malaria is horses affected with Tr. brucei, and advises the use of so great, and the recommendations of arsphenamin and 0.05 gm. per kilogram of body weight. when are so that neo-arsphenamin made half-hearted, From the foregoing it would seem that arsphenamin we for that these must conclude, the present, drugs may have a favorable effect on some of the trypano¬ have a limited influence on the course of the disease. somes, but that it may vary in different species. condition in man due to Tripanosomiasis.—The Further investigation is necessary before definite con¬ infection with Trypanosoma rhodesiense, or the less clusions can be reached. severe infection due to T. as well as other gambieuse, Leishmanias.is.—This term includes kala azar, or animal have been studied in trypanosome infections, oriental sore, and of natural host as well as On tropical splenomegaly, espundia their experimentally. South America. Stitt50 states that arsphenamin has 53. Stephens, Yorke and Blacklock: Ann. Trop. Med. 12: 197, 201, been tried in leishmania infection but without much 211, 217 (Oct. 13) 1918. success. In a of kala azar ß8 it is stated that on 54. Stott: Indian Med. Gaz. 50 (July 15) 1915. study 55. Neff, F. C.: Report of Five Cases of Tertian Malaria Treated with Diarsenol Intravenously J. A. M. A. 67: 1058 (Oct. 7) 1916. 63. Broden and Rodhain, in Manson: Tropical Diseases, Ed. 6, 56. Reed: U. S. Nav. M. Bull. 7: 1913. New York, William Wood & Co., p. 179 57. Goldthwait: Mil. Surg. 31:1912. 64 Lurz: Archiv. f. Schiffs. u. Tropen-Hyg. 23: 308 (July) 1919. 58. Manson: Tropical Diseases, Ed. 6, New York, William Wood & 65. Branden: Arch. f. Schiffs- u. Tropen-Hyg. 17: 845. Co., 1919, p. 129. 66. Strong: Philippine J. Sc. 5: (Feb.) 1910. 59. Kopanaris: Archiv f. Schiffs- u. Tropen-Hyg. 15: 566, 1911. 67. Schamberg, J. F.; Kolmer, J. A., and Raiziss, G. W.: Summary 60. Stephens, J. W. W.: Ann. Trop. Med. 13: 63, 69, 73, 75 (May of Chemotherapeutic Studies in Experimental Trypanosomiasis, J. A. 12) 1919. M. A. 65: 2142 (Dec. 18) 1915. 61. Bohme: Med. Klin. 15: 458 (May 11) 1919. 68. Fourth Report of the Wellcome Research Laboratory, London, 62. Worner: Med. Klin. 15: No. 25, 1919. Bailli\l=e`\re,Tindall and Cox, 1911.

Downloaded From: http://jama.jamanetwork.com/ by a Northeastern University Libraries User on 05/26/2015 the whole the effect of arsphenamin has been favorable, Amebic Dysentery.—As is to be expected, there are but that nothing in the nature of a curative effect was a number of reports on the use of arsphenamin in this obtained. These diseases also require further study disease, and some of them appear favorable. Winn ,0 before final conclusions can be reached;· though some treated twelve cases of intestinal amebiasis, and states marked favorable action may eventually be demon¬ that the amebia disappeared from the stools in from strated. to seventy-two hours, and that the stools COMPLICATIONS OF SYPHILIS twenty-four were changed materially in character and reduced in Pneumonia, Secondary Infections, Anemias, etc., in number. Willets86 describes the treatment of 132 *9 Syphilitics.—Head and Seabloom call attention to the cases of dysenteric and nondysenteric ameba carriers. fact, noted by a number of other observers, that certain In the nondysenteric cases he found that neo-arsphen- acute diseases or disturbances of metabolism will so amin freed the bowel of endameba in 100 per cent, of derange the protective mechanism of the body that an cases, ipecac in 70.6 per cent, and emetin in 36.8 per old infection apparently dormant will become reacti¬ cent, of cases. The treatment of seventeen cases of vated. They have noticed that syphilitics having amebic dysentery is reported on by Gunn.87 He con¬ pneumonia are liable to show delayed resolution for cludes that a radical cure is difficult to obtain either weeks or months at a time. They cite instances show¬ with emetin or arsphenamin used separately but that, ing very prompt resolution following the administration if combined, radical cures may be expected in a large of arsphenamin. This should be borne in mind in the number of cases, especially if the arsphenamin be given diagnosis and treatment of the various conditions, both while the patient is under the influence of the emetin. medical and surgical, including postoperative, not This form of treatment is also recommended by readily amenable to treatment, which take place in Ravaut and Krolinitzky.88 Milian 89 reports the rapid syphilitics. cure of amebic Others who OTHER DISEASES dysentery by arsphenamin. have reported favorably are Valencia,90 Chalmers and Arsphenamin and neo-arsphenamin have been admin¬ Archibald,91 Ravaut and Charpin 92 and Mink.93 istered by many investigators in many other diseases, Anthrax.—Of all bacterial diseases treated with including anthrax, glanders, sporotrichosis, leprosy, arsphenamin, the most favorable results have been Malta fever, influenza, meningitis, typhus fever, pel¬ reported in anthrax. Case reports have been published lagra, plague, rabies, various pyogenic affections and by Bettman and Laubenheimer,94 Becker,95 and Mokr- pulmonary tuberculosis, but with the following excep¬ zecki.96 Reports of cultural and experimental studies tions, the reports have not been sufficiently encouraging have been made by Bettman and Laubenheimer,94 to warrant citation and analysis.70 Schuster 97 and Roos.98 The number of cases treated Chronic Pemphigus.—There has been considerable is too small for our the are in purposes, though reports written of the use of arsphenamin chronic pemphi¬ most encouraging. It seems to have been demonstrated gus, and it would appear that in a number of cases its beyond question that with rabbits, the immediate injec¬ administration has been followed by a beneficial effect. tion of 0.04 gm. of arsphenamin per kilogram of body differentiation of this disease from The question of the weight will save the life of the animal from a lethal bullous dermatitis herpetiformis should, however, be injection of anthrax. With guinea-pigs, practically the considered as well as the occasional tendency toward same results can be obtained. In the latter animal, if spontaneous involution. It would appear doubtful the injection is delayed for six hours or until some whether results are obtained in the acute septic type. edema is at the site of injection, death will be has been discussed R. L. present This form of treatment by prevented in some instances and delayed in others. If Sutton,71 Eschweiler,72 J. de Azua,73 Merz,74 Linde- delayed for from sixteen to twenty-two hours, death mann,75 A. P. Bergsonoff,76 Stumpke,77 Frieboes,78 and of the animals could only be delayed. Becker 95 believes Wolfe.79 that arsphenamin acts as an internal disinfectant for Sprue.—We were unable to find any information both anthrax and glanders. Roos 98 demonstrated that on which to base a favorable opinion of the use of arsphenamin has a very decided effect on anthrax in arsphenamin in sprue. vitro, compared with certain bacteria, as paratyphoid Tuberculids.—It seems established that good effects and the cocci, also that the serum of treated animals is have been obtained by a number of authorities in the strongly bactericidal to anthrax in culture. He also treatment of tuberculids with arsphenamin. Articles believes that the action is due to a deposition in the sub¬ have been presented by John H. Stokes,80 Benoit,81 A. stances of the organisms, as with Treponema pallidum. Zanck and E. Pelbois,82 Morin and Julia,83 and While recognizing that anthrax acts somewhat dif¬ Ravaut.84 The possibility of a generalized involve¬ ferently on man than on the animals mentioned in the ment after such treatment has been suggested. foregoing, it would seem established that arsphenamin does have a prophylactic and curative effect on anthrax, 69. Head, G. D., and Seabloom, J. L.: Arsphenamin in Pneumonia and that it should be in medium-sized doses intra¬ with Delayed Resolution in Syphilitic Soldiers, J. A. M. A. 73: 1344 given (Nov. 1) 1919. venously, as early as possible in the course of the 70. In order that this paper may be more complete, the paragraphs been disease. on pemphigus, sprue, tuberculids and amebic dysentery have added since the paper was read. 71. Sutton: Boston M. & S. J. 164: 336, 1911. 85. Winn: Proc. Canal Zone M. Assn. 5: pt. 1, 7, 1912. 72. Eschweiler: Dermat. Centralbl. 17: 262, 1913. 86. Willets: Philippine J. Sc. Section B, 9: 93, 1914. 73. de Azua: Rev. clin. de Madrid 8: 218, 1912. 87. Gunn: Calif. State J. M. 16: 240, 1918. 74. Merz: Deutsche med. Wchnschr. 37: 2231, 1911. 88. Ravaut and Krolinitzky: Bull. Soc. path. exot. 9: 510, 1916. 75. Lindemann: Inaugural Dissertation, Jena, 1912. 89. Milian: Bull. et m\l=e'\m.Soc. m\l=e'\d.d. h\l=o^\p.de Par. 39: 950, 1915. 76. Bergsonoff: Dermatologiya 2: 818, 1913. 90. Valencia: Repert. de med. y cirurg. 7: 260, 1916. 77. Stumpke: Berlin. klin. Wchschr. 44: 1267, 1912. 91. Chalmers and Archibald: J. Trop. Med. 18: 181, 1915. 78. Frieboes: Deutsche med. Wchnschr. 39: 1916, 1913. 92. Ravaut and Charpin: Paris m\l=e'\d. 22: 125, 1919. 79. Wolfe: Deutsche med. Wchnschr. 37: 527, 1911. 93. Mink: U. S. Nav. M. Bull. 8: 653, 1914. 80. Stokes: Am. J. M. Sc. 157: 522, 1919; Arch. Dermat. & Syph. 94. Bettman and Laubenheimer: Deutsche med. Wchnschr. 38: (Feb. 38: 573 (May) 1920. 22) 1912. 81. Benoit: Union m\l=e'\d. du Canada 45: 111, 1916. 95. Becker: Ehrlich Festschrift, Jena, G. Fischer, 1914. 82. Zanck and Pelbois: Ann. de dermat. et syph. 5: 65, 1914. 96. Mokrzecki: M\l=u"\nchen. med. Wchnschr. 60: 1089, 1913. 83. Morin and Julia: Ann. de dermat. et syph. 5: 89, 1914. 97. Schuster, in Ehrlich: Abhandlungen \l=u"\ber Salvarsan 3: 378. 84. Ravaut: Ann. de dermat. et syph. 4: [ill]70, 1913; Bull. Soc. fran\l=c;\. 98. Roos: Ztschr. f. Immunit\l=a"\tsforsch. u. exper. Therap., Orig. 15: de dermat. et syph. 24: 308, 1913. 487, 1912.

Downloaded From: http://jama.jamanetwork.com/ by a Northeastern University Libraries User on 05/26/2015 Arsphenamin has been recommended as an alterative into play new responsibilities, and we must so order in various conditions, but under ordinary circumstances our professional lives as to meet these opportunities has little advantage over liquor potassii arsenitis. and responsibilities with a determination to make them serve the best interests of the individual and the SUMMARY community. For practical therapeutic purposes, the beneficial Medical practice of the past has been largely that effects of arsphenamin and neo-arsphenamin are most of individualistic endeavor without consideration of apparent in a limited number of spirochetal diseases. community needs. True, all physicians have given They act as a specific in Vincent's angina, relapsing without stint of their time and knowledge to social fever, yaws, gangosa and pulmonary spirochetosis (if work by serving the needy without thought of mone¬ given early) in man, and in equine influenza. tary return. But the solution of the problem of how A therapeutic effect is noted in rat-bite disease, in best to serve the public while still serving their own certain dental conditions and in fowl spirochetosis. interests only recently has been seriously considered. The complete measure of the effect in the latter con¬ Until recent times the individual, although realizing dition has not yet been established. his community relations, has followed his desires, his No apparent benefit has been found in such other thoughts and his actions without considering their spirochetal diseases as Weil's disease and yellow fever. effect on the public. Now we are coming to think in Good results have been obtained in syphilitics, in a the aggregate, and so to conduct our individual lives number of nonsyphilitic conditions, which are influ¬ that our actions may be reflected in community enced adversely by that disease. betterment. Their use has been recommended in conditions in THE MOVEMENT FOR REFORM which arsenic is indicated. In such case the effect is What are the indications on which the foregoing alterative rather than specific, and ordinarily there is assertions are based ? Strange to say, these indications no over arsenitis. special advantage liquor potassii are more largely in evidence in the thoughts and There is a limited effect on certain protozoal actions of the laity than they are in the medical pro¬ diseases, as malaria (tertian and quotidian), some of fession. In times of need the profession has been the trypanosomiases and leishmaniasis. It is possible, aroused to forestall hasty action by legislatures and however, that this effect may be nonspecific. other bodies in placing mandatory legislation on the With the exception of anthrax, and possibly glanders, statute books that was inimical to the interests of phy¬ few favorable results are reported in bacterial diseases. sicians. I refer particularly to health insurance and Except in Vincent's angina, arsphenamin and neo- similar schemes which their proponents have attempted arsphenamin should be administered intravenously in to force on the community without due consideration medium-sized dosage. Two or three injections usually of all the factors involved. There are individuals, accomplish the desired purpose, except in pulmonary societies and cults who feel it their duty to impose spirochetosis, which may require a series of injections. restrictions on the actions and conduct of the medical In diseases showing liver involvement, it has been rec¬ profession, and who feel that by - so doing they are ommended that neo-arsphenamin be given on account rendering some great additional service to the com¬ of its supposed lesser degree of toxicity. munity. In recent years almost every legislative session in some states has been besieged by these organizations in order to obtain the passage of their so-called "reform" measures. They work on the OPPORTUNITIES AND RESPONSIBILITIES sympathy of the public by insisting that such opposition OF THE PHYSICIAN OF TODAY as is voiced by the medical profession is due entirely to selfish and sordid motives. Unless we are con¬ FRANK L. RECTOR, B.S., M.D. stantly alert to such attempts to restrict our freedom NEW YORK of action and saddle on us new and untried schemes of social endeavor, we shall sooner or later find some The last decade has seen great changes in our con- disagreeable legislation on the statute books. ceptions of life and its social reactions. Intercourse We hear much these days about health centers, between nations, business and professional relations, prenatal care, infant welfare, child hygiene, physical individual and community obligations have all under- education in our schools, diagonistic clinics, and so on gone radical changes and are still in a condition through a long list of activities having for their of flux. None knows what the morrow will bring object the betterment of the health of the individual forth. Each is living a day at a time. The problems and the community. Have we ever stopped to analyze of the present demand our time and attention. The the forces behind these movements which to a large needs of the present hour apparently outweigh all extent must depend on the cooperation of the medi¬ other considerations, and we are bending our efforts cal profession to be carried to a successful conclusion? to maintain a seeming orderliness and not permit the If we make such an analysis we find them in many established customs of thought and action to be carried cases initiated, stimulated and directed by others than beyond our grasp and control by the rushing tide of medical men and women. The physician is asked to feverish impatience to set up a new social and economic execute the work, not to direct it. I would not belittle order. the motives or the personnel behind these most worthy In no occupation or profession is this change movements, but I fear for the successful realization becoming more apparent than among physicians and of their hopes without the counsel and advice that their related professional and social activities. Strug- only our profession can give. Sooner or later the be the gle as we will to maintain the noble conception of pro- physician will called into work ; but if he has fessional ethics and community relations, indications had no part in formulating the policy of the endeavor, can he are not lacking that new opportunities are bringing be held responsible for its unsatisfactory end-

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