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EXPERIENCES WITH ANTI - SYPHILITICTREATMENT FROM THE PRE-SAL-VARSAN ERA TO THE PRESENT ANDTHEIR POSSIBLE BEARING ON PRESENTTREATMENT PRACTICE *

By L. W. HARRISON

SINCE I undertook the preparation of this paper Ihave realised that considerations of time and spacewould allow me to deal with the subject only superficially.My first experience of the treatment of syphilis was

thirty odd years ago in a hospital in India where theroutine practice in early syphilis was to give the patienta mixture of liquor hydrarg. perchlor. and potassiumiodide for only the six weeks or so that he was in hospitalwith open lesions.Although my useful knowledge of syphilis at that time

could have been written out on a sheet of notepaper, itdid seem to me that a treatment of syphilis that lastedfor only a few weeks must be hopelessly inefficient, andwhen the late Colonel F. J. Lambkin visited us to preachthe advantages of a proposed new scheme of registration,under which syphilitic soldiers would be insured aminimum of two years' treatment by injections of mer-cury, I heartily supported him against the prevalentopposition. I suppose that at that time the treatmentof syphilis in the Army must have been suffering fromthe change-over from the old regimental system to thatunder which the medical staff of the Army becamewelded into a corps. The old regimental system, what-ever its drawbacks, and they were many, had the advan-tage that every man in a unit was known to the regimentaldoctor, who looked after him throughout his life in theArmy in the way the family doctor looks after his patients'families. A good old regimental doctor told me oncethat he used to make his syphilitic patients take mercurialpills for a number of years. He said it was interesting

* The basis of an address to the Medical Society for the Study of VenerealDiseases, November 27th, I936.

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BRITISH JOURNAL OF VENEREAL DISEASES

to see how they began to look healthy again after aboutthree years of this treatment.My interest in the treatment of syphilis did not become

really close, however, until I909, when the accident of amedical officer's sudden illness caused my transfer aspathologist to the Military Hospital, Rochester Row,at that time under the command of Colonel Lambkin.Not very long ago it was unnecessary to explain theMilitary Hospital, Rochester Row, because everyoneinterested in syphilology knew it as the British militaryhospital devoted entirely to treatment of venerealdiseases, investigation of new methods of treatment andinstruction of Army medical officers in the subject. Ithad been a Guards' regimental hospital, and owed toLambkin its assignment to V.D. about the year i908,when the Royal Army Medical College and Queen Alex-andra's Military Hospital, Millbank, were still in theirinfancy. Colonel Lambkin had pressed on the WarOffice the importance to the Army of medical officersbeing instructed in what were even then called modernmethods of diagnosis and treatment of V.D., and it hadbeen ordained that every medical officer of the R.A.M.C.should twice in his career, on joining and before theprofessional examination for promotion to major, receivesome instruction at the Military Hospital, RochesterRow. You will remember that the year I909 was afterthe discoveries of S. pallida and the Wassermann reac-tion, but before the publication of " 6o6." About thattime a great amount of interest was being taken in theuse of certain pentavalent compounds of arsenic, espe-cially atoxyl and arsacetin, and in atoxylate of mercury.Atoxyl had been reported by Thomas 1 in I905 to begood for trypanosomiasis, and when Schaudinn sug-gested a relationship between S. pallida and trypanosomesit was not long before workers were trying its effect onsyphilis, the first publication reporting good effectsbeing that by Salmon 2 in I907. By I909 nuimerousworkers had reported favourablv on the effect of atoxylin syphilis; Colonel Lambkin was particularly enthusiasticabout it, and later I had an opportunity of verifying itsgood anti-syphilitic properties in the favourable bloodreactions of over 200 cases of syphilis that had beentreated at the Rochester Row Hospital solely with thisdrug. By the latter end of I909, however, it had acquired

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ANTI-SYPHILITIC TREATMENT

a bad reputation owing to its tendency to cause blind-ness, and its use was rapidly being abandoned. At thetime I joined the Rochester Row Hospital, Ehrlich'spreparation arsacetin 3 was in use, as it had been foundby various workers to have just as great a trypanocidaland spirochaeticidal power as atoxyl, but its toxicity wasonly one-third or one-fourth.

o 0As/OH + 5H20 As OH + 4H20\\ONa /\ONa

NH2 NH. CO. CH3(a) (b)

FIG. I.-(a) Atoxyl. (b) Arsacetin.

At the same time atoxylate of mercury was also beinggiven there and in many clinics on the strength ofexperimental work by Uhlenhuth and Manteufel,4 whohad reported that it had acted better than atoxyl intrypanosomiasis, hen-spirillosis and experimental syphilisof rabbits. Lambkin was also trying to pluck up hiscourage to give the latest preparation from Ehrlich'slaboratory, viz., " 4I8," the disodium salt of Arseno-phenyl-p-glycine 5 (" Spirarsyl ") which seems to havebeen the first of the trivalent arsenical remedies usedin this field of medicine.

As = As

NaOOC . CH2 . HN NH. CH2 . COONaFIG. 2.-Sodium arsenophenylglycinate, "' 4I8," or " Spirarsyl," commonly

termed Arsenophenylglvcin.

We discussed the question of trying out a sample hehad received from Ehrlich, but decided to await thereceipt of more reports on its effects before doing so. Itwas just as well we did so, because the drug was in bulk,exposed to air and must by then have become decom-posed. It was found by Alt,6 Neisser 7 and others that,while its antisyphilitic action was good, it was veryeasily oxidised and then gave rise to severe toxic effects.

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Neisser, in fact, later reported some deaths from it. Oursample of arsenophenylglycin would probably have hadsuch toxic effects as would later have seriously deterredus from taking up its great successor " 6o6," but it isonly fair to mention that, in his article on it publishedsix years later, Neisser,7 on the strength of five years'work with it, expressed the view that it deserved to beused more. He was particularly impressed by its causingno discomfort when injected intramuscularly, and hethought that it might be used when intravenous injec-tions of salvarsan or neosalvarsan were impracticable.

Colonel Lambkin's departure from Rochester Row andthe bad name which arsenic had by that time acquiredamongst syphilologists resulted in our falling back in thewinter of I909-I0 and the subsequent spring on treat-ment by mercurial injections. It gave me an opportunityof learning for myself the therapeutic properties of theinsoluble preparations of mercury that were being givenby the intramuscular route at that time. I learnt enoughto make me regard the outlook for a syphilitic patienttreated only by mercury with gloomy foreboding. Itwas quite usual for patients to relapse with clinical signsof syphilis during courses of intramuscular injections,and only three months after completion of the twoyears of regular treatment which was then prescribedin the Army as a matter of course for early.syphilis noless than 42 per cent. gave positive reactions to theoriginal Wassermann reaction, while over 75 per cent.were positive to Stern's modification of this test. It isinteresting now to see the touching faith wvhich manypractitioners still have in treatment for two years withmercurial pills after what we know now to be quite aninadequate treatment by the modern arsenical remedies.To anticipate, during the period between I909 and I9I3we 8 investigated the incidence of clinical relapses incases of primary and secondary syphilis by studying thesyphilis case sheets of the Brigade of Guards returnedto the War Office between I906 and I9I2, and in the 378cases judged to have been well treated by mercurial injec-tions or inunctions for at least a year. I found that in thefirst year 3I5 had relapsed clinically at least once (morethan half of them two or more times). The results ofthe investigation are shown in Table I., in which arecontrasted the effects of purely mercurial treatment

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carried out steadily for a year with those of a short courseof salvarsan and mercury lasting no longer than threemonths.

TABLE I.-Total Relapses and Average Time lost by eachSoldier in Hospital and attending as an Out-Patientunder Treatment with Mercury and with Mercuryand Salvarsan respectively, during the first year.(From Paper by Gibbard and Harrison, Int. Med.Congress, I913.)

Clinical relapses X Average time lost byAverage each man in days

numberTreatment Total of days in 9.I CZt f ga

cases hospital 0 bose :t

admissiontramn oud sa o0 c,~~~~~~~~I

Mercury alone. 378 42'0 151 115 49 315 83-o 66-2 176 83-8Mercury an d

Salvarsan 152 23-2 6 o o 6 3.9 25,2 15,8 4l0

What I have said may help those of you who took upthe treatment of syphilis after i9i0 and take for grantedthe effects of modern treatment to understand the excite-ment of syphilologists in I9IO when they read the firstreport by Alt 9 of the effects of a drug known as " 6o6,"

As = As As As As As

H2N NH2 HC1.H2N I NH2HCI H2N NH2OH OH OH OH ONa ONa

(a) (b) (c)FIG. 3.-(a) 3 3' diamino-4 4'-dihydroxyarsenobenzene or " 592,"

the insoluble arsphenamine base. (b) The dihydrochloride of (a),or " 606," or arsphenamine. (c) Disodium arsphenamine, intowhich arsphenamine must be converted for intravenous injection.

or the Ehrlich-Hata remedy. Alt's paper was read firstat a meeting of the Medical Society of Magdeburg onMarch 3rd, I9IO, and it is interesting to read in theproceedings 10 that, after Schreiber had demonstratedthe effect of the remedy on a number of cases of syphilis,two members taking part in the discussion said in effectthat the results were quite nice, but no better than theycould obtain with mercury. We learnt that the remedy

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could not be put on the market until it had been welltried out in reliable clinics. After we had representedto Professor Ehrlich that we were in a very favourableposition to test it, he was good enough to send us asupply and continued to meet our requests for moreuntil " 6o6 " was put on the market under the tradename " Salvarsan " towards the end of I9IO, abouteight months after the publication of Alt's paper. Fromour receipt of the first doses of " 6o6 " until August, 19I4,we took full advantage of the fact that as long as a syphi-litic soldier remained in the Army he could be observed,and we carried out a systematic investigation of theremedy. As soon as we learnt that it was not a one-dosecure of syphilis, we set out to discover what was theminimum amount of it which would suffice to cure anaverage case of early syphilis. In the first series of caseseach received a single dose of " 6o6 " by the intra-muscular or deep subcutaneous route. Less than fiftyof these had been given when our attention was drawnto a paper by Schreiber and Hoppe 11 on intravenousinjection of the remedy, and intramuscular and deepsubcutaneous injections were gladly abandoned becauseof the agony they caused. Our next series received each asingle dose of o-6 gm. intravenously, and then withoutwaiting for results successive series were treated asfollows. (i) Two intravenous of o-6 gm. at two weeks'interval. (2) One of o-6 followed by three of o03 gm.at two-weekly intervals. (3) Three of o-6 gm. at two-weekly intervals and four of calomel cream, gr. 3 ineach, at weekly intervals, total length of course, onemonth. (4) One of o-6 gm. " 6o6," then nine of mercurialcream, Hg gr. I in each, at weekly intervals, and at theend one of o-6 gm. " 6o6." (5) A similar course, but withan initial dose of o03 gm. " 6o6," soon abandoned forreasons to be given later, and finally (6) a series in whicheach patient received one of o-6 gm. " 6o6," five of Hgat weekly intervals, one of o-6 gm. " 6o6," five more Hgand a final dose of o-6 gm. " 6o6." The results of thesecourses were watched either by ourselves, or in the caseof patients moved to other stations by medical officersthere, who reported the clinical condition to us and sentus specimens of blood whenever we called for them.

It may be convenient at this stage to comment on theresults of the different courses of treatment during the

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pre-war period and the lessons derived therefrom eitherthen or later.

Thle first concerns the deep subcutaneous or epifascial injections. Although this route proved quite animpracticable one for " 6o6," the experience of it led meto two discoveries which seemed useful. The first relatedto the therapeutic value of the route and the second tothe size of the individual dose.With regard to route, in a certain number of the cases

injected deep subcutaneously sloughs formed and onremoval, sometimes many months after the injections,they were found by Colonel Beveridge at the R.A.M.College to contain comparatively large amounts ofarsenic. Thus in one-third of a slough removed morethan a year after an injection of o-6 gm. " 6o6" wasfound o0o4 gm. arsenious oxide,8 which would corre-spond to about a fifth of the original dose, while inanother removed four months after an injection of o04 gm.Colonel Beveridge and Captain Dunbar Walker 12 foundan amount of arsenic equivalent to o0O75 gm. of theremedy. Yet in spite of the comparatively indifferentabsorption of the original dose which these analysessuggested, the immediate effects had been what we thencommonly called magical in healing of clinical lesions,and without any other treatment the Wassermannreaction had in due course become negative in a highproportion of the cases, as is shown in Table II. extractedfrom a paper published by Colonel Gibbard 13 and myselfin I9II. I doubt if anyone to-day would expect suchresults from a single injection.At the time we made this discovery we had not

found the results much better after a single dose ofo-6 gm. salvarsan given intravenously than after asingle one given deep subcutaneously. I was wonderingwhy a single dose failed to cure when it had such marvel-lous effects on open lesions, and a possible explanationseemed to be that at the time of its administration acertain proportion of the spirochaetes were inaccessible.If this was the case, then, seeing how well a deep sub-cutaneous injection acted in spite of its being absorbedvery indifferently, it seemed possible that a single dose ofo03 gm. " 6o6 " given intravenously would do as muchgood eventually as one of o-6 gm., because it might wellbe that a large portion of a dose of o-6 gm. given intra-

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TABLE II.-Serum Reactions after a Single DeepSubcutaneous Injection of Salvarsan

Wassermann reactionsInterval

between injec-tion and Positive After injection

blood test beforeinjection

PositivePositive Weaker Negative after being

Weeks negative

I to 2 17 I3 I 3 02,, 3 I5 8 3 4 03, 4 IO 4 4 2 04,, 5 15 4 I 8 25,, 6 7 I I 5 0

IO ,,14 24 0 2 2I II4 ,,I8 28 3 I i8 6I8 ,,26 7 0 0 4 3

venously was excreted before it could reach spirochaetesburied within cellular infiltrates; that before thesespirochetes could be destroyed they would have to belaid bare by absorption of infiltrates. I ought to explainhere that I had found that S. pallida seemed to dis-appear from the secretion of early syphilitic lesions asrapidly after o03 gm. " 6o6 " intravenously as aftero*6 gm. subcutaneously. Accordingly, I suggested ourtreating a series of cases with an initial dose of o03 gm." 6o6," then nine intramuscular injections of mercuryand lastly a dose of o03 gm. " 6o6." This course wasvery quickly found to be useless. Patients relapsedclinically before the series of intramuscular injectionsof mercury had been completed. The inferences seemedto be (a) that, other things being equal, the therapeuticeffect of a deep subcutaneous or intramuscular injectionof " 6o6" (or of probably any other arsenobenzenecompound) must be greater than that of the samecompound given intravenously, and (b) that the biggerthe individual dose the more lasting its effect. I believethat subsequent experiences have proved both of theseinferences to be correct.During the war at various weekly meetings of medical

officers in military hospitals which I commanded I saidthat, if a method of giving " 6o6 " or "9I4" deep

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subcutaneously or intramuscularly without undue paincould be discovered, it would oust the others, because theresults would be so much better. I judged the sub-cutaneous route would act better because by fixing theremedy in the tissues it would give a better opportunityfor the formation of that derivative which we know isnecessary to the therapeutic action. This was taken upin two military hospitals, in each of which a series ofpatients received a course of deep subcutaneous injec-tions of "9I4" (dissolved in an anaesthetic solution toAs As As = As

NH21 I INH.CH2.0.SONa NaOS.O.CH2HN NH.CH2.O.S.ONaOH OH OH OH

(a) (b)FIG. 4.-Alternative formule of "914 " or neoarsphenamine. (a) The

original formula sodium 3 3'-diamino-4: 4'-dihydroxyarseno-benzene-N-methylenesulphoxylate. (b) The formula ascribed byA. D. Macallum to the French form of neoarsphenamine.

make it tolerable), and the results were compared withthose of a course of " 6o6" given intravenously to aseries of patients in the same stages of the disease. Thepublished report 14 on the results related to I5I casestreated by the subcutaneous route and 25I by the intra-venous. In the intravenous series each received a totalof 2-8 gm. " 6o6 " in seven doses of 0-3 to 05 gm., givenover a period of fifty days, and in the subcutaneousseries the total amounts of " 9I4 " administered in forty-three days were 4-3 gm. to 27 patients, 4 05 gm. to 40and 3.9 gm. to 99, so that the total amount of " 9I4"averaged in terms of arsenic less than the total " 6o6."The results in the two hospitals agreed very closely,and were combined as shown in Table III.The table shows that in spite of the well-known fact

that " 9I4 " given intravenously is less active thera-peutically than is its equivalent in " 6o6" given intra-venously, yet when given subcutaneously it resulted inapproximately I2 per cent. more negative reactions inprimary and in secondary cases than did a little morethan its arsenical equivalent in the form of " 6o6 " givenintravenously.The second point, as to the effects of the larger indivi-

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TABLE III.--Comparison of Effect of a Courtse of Neo-salvarsan administered by the Deep SubcutaneousRoute wvith that of an approximately equivalent amountof Salvarsan administered Intravenously. (Frompaper by Harrison, White and Mills.14)

Wassermann reactions at end of course

Stage Route Cases + ± ± -

No. Per No Per No. Per No Percent. cent. cent. cent.

P S.C. 67 0 0 0 0 3 4.4 64 95.5Primary

.6o6685-lI.V. 79 3 3.7 6 7*5 4 5'° 66 83@5

Secondary . I S.C. 76 I I I4-4 4 5.2 7 9-2 54 7I 0(I.V. 14I 35 24-8 i6 II3 8 5 6 82 58&I

Tertiary . (I S.C. I8 IO 55.5 3 i6-6 I 5.5 4 22-2I.V. 3I i8 58-o I 3'2 3 9|6 9 29|O

Explanation.-S.C. = Subcutaneous (" 914"); I.V. Intravenous.(" 6o6 "); +- = positive; 4- = doubtful; + = almost negative;-= negative.

dual dose, is supported by our later experience. In ourpre-war series the usual individual dose of " 6o6 " was.o-6 gm., and in the series of primary and secondary cases.treated by two doses of " 6o6 " separated by nine injec-tions of mercury, as well as in that treated with threedoses of " 6o6 " with ten of mercury, the serum reactions.at the end of the course were practically always negative.Such immediate results have not been achieved since,although the total amount per course was increased atthe beginning of the war, and is now in terms of arsenic-more than twice the total of any of our pre-war courses,and I am convinced it is partially because since I9I4 wehave used smaller individual doses. At the beginning ofthe war I had to devise a course which could be given safelyin a much smaller time than ten weeks and would befollowed by fewer relapses (within a year after suspensionof treatment) than any pre-war course, our best results.then having been represented by 28 per cent. clinical and

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serological relapses a year or more after the last injections.I aimed at first to increase the total from i-8 gm. to 2-4gm. " 6o6" and to give it in a month, and judged that,unless the individual doses were reduced, there would beseveral deaths from haemorrhagic encephalitis. Accord-ingly, the individual dose was reduced to o03 gm. " 606 "at first, and though it was increased later, it neverreached its pre-war size. It might be argued that thedifference between the immediate results of our pre-warcourses and those being given to-day in this countryis due to the lower therapeutic value of " 9I4," whichin this country has now supplanted " 6o6." This maybe so to some extent, but Table III. shows worse imme-diate results with 28 gm. original " 6o6" given intra-venously than we had got from i-8 or even only I2 gim.in our pre-war courses.

There is further support for my contention that asmall total dosage given in a few large individual doseswll. have a better therapeutic effect than a rathler largertotal dosage given in smaller individual doses in thereport on the analysis of records collected in five countriesunder the auspices of the League of Nations HealthOrganisation.15 In this the Danish results were shownto be on the whole the best of those under " intermit-tent " treatment, and in oral discussion it was attributedpartly to the fact that syphilologists in Denmark, underthe influence of Professor Rasch's teaching, have tendedto give quite high individual doses of " 9I4." It wasthis which led the Experts' Committee to make a recom-mendation " To employ a comparatively heavy individualdosage of the arsenobenzene and of the bismuth ormercurial compounds."

In this matter I admit myself to be rather a convert.At one time I thought that, so long as one gave an indivi-dual dose which would cause the spirochaetes to disappearfrom the secretion of early lesions, what mattered wasthe total dosage per course. My discovery that oursmall total but large individual dosage course employedbefore I9I4 gave better immediate results than the largertotal, but smaller individual dosage courses given duringthe war and later prepared me to agree with Rasch'sviews when these were backed by the Danish results inthe League's inquiry. It is interesting to see howfrightened syphilologists to-day seem to be of giving

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large individual doses of neoarsphenamine, consideringthat when neosalvarsan was first published we regularlygave doses of o9 gim. even twice a week, and I oftengave single doses of I-2 gm., as I believe do some Frenchsyphilologists to-day. Schreiber,16 who was, I. think, thefirst to publish a paper on the administration of neo-salvarsan, at first recommended huge doses, such as og9,I*2, I*35 and I-5 gm., to men on alternate days, andmentioned that he had given as much as 6o gm. withinseven days. In this article he reported on 97 cases inwhich no serious toxic effect appears to have occurred,but later, in I9I2, he reported some serious exanthemataand recommended some caution in the initial dosage,e.g., o04 to o*6 gm. for men, with an interval of two weeksbefore the next dose, mercury being given meantime.As Schreiber mentioned in his second article, Iversenwas also in the habit of giving from 4 to 6 gm. neo-salvarsan in a week. Although one would hesitate togive such heroic doses as these, I would again suggestthat we might get better results with a smaller totaldosage and therefore with less dermatitis, etc., by givinglarger single doses.The subject of individual dosage leads naturally to

individual type of preparation and to an experience justafter the war which showed that certain arsphenaminepreparations of apparently the same chemical composi-tion can differ very strongly in therapeutic effect. Shortlyafter the war some of us, members of the Medical ResearchCouncil's Salvarsan Committee, noticed that clinicalrelapses were occurring rather frequently after the firstcourse of treatment, and investigation by Dale, Whiteand colleagues 17 showed that certain brands of " 9I4 "which had been used in the treatment of these caseswere inferior in trypanocidal and spirochaeticidal effect toanother with which they were compared at the same time.A conference with the manufacturers concerned revealedthat all manufacturers were not using the same method,and that some were preparing a product which resembleda mixture of what we now call sulpharsphenamine withneoarsphenamine, rather than the latter compoundalone. I learnt from this experience that it is a goodthing to test one's arsphenamine preparations periodicallyto see that they retain their power of causing rapiddisappearance of S. pallida from the secretion of early

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lesions, and also that the group of remedies now officiallytermed sulpharsphenamine is far inferior to neoarsphena-mine when given intravenously. Animal experiments

As --As

0I. O~~~~~~~~~~~~~~~~~~~~~~~~~I

H2N INH. CH2. O.SONa

OH OH(a)

As - As

Na OS .O. CH2. HN NH. CH2 .O.SO Na

OH OH(b)

As As O

0 0OH2 . .OSO NaNaOu.S.S . CH2 .HN IN

\/ \/ \CH2 . O. S O NaOH OH CH..SN

(c)FIG. 5.-Alternative formula of sulpharsphenamine. (a) Sulfarsenol

brand, of Lehnhoff-Wyld. (b) American formula, of Voegtlin,Johnson and Dyer. (c) Formula of one British brand (privatecommunication).

seem to show that, when given deep subcutaneously, theeffect of sulpharsphenamine is enhanced sufficientlv tomake it equal to neoarsphenamine given intravenously.Unfortunately the sulpharsphenamine preparations losetheir advantage of being tolerable wlhen given sub-cutaneously in their proneness to cause purpura.

Before leaving this subject it may be of interest toreflect a little on the chemical structure of these com-pounds, illustrated in Figs. 3, 4 and 5, in relation to thepain they cause when injected subcutaneously or intra-muscularly and also to their therapeutic effects. Thefollowing remarks are made with great diffidence, as Iam no chemist With regard to pain, it is of course well

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known that " 6o6" is the worst, that " 9I4," or neo-arsphenamine, to give it its official name, hurts too muchto make the subcutaneous route practicable for it inroutine work, and that sulpharsphenamine is commonlygiven by this route. The difference between them,especially between neo- and sulpharsphenamine, is in thecombination with the NH2 group. With regard to thequestion of therapeutic effect, the amino combinationagain seems to be the important factor. In the case of" 6o6," in the form it enters the circulation, the NH;, groupis combined only with the benzene ring. In the case of" 9I4," one (or both) is, so to speak, tied up. In Fig. 4two alternative graphic formulae for " 9I4" are shown,and respecting these Schlossberger 18 states that thesecond, with both NH2 groups substituted, is less toxic,but also less active therapeutically. He adds that theneoarsphenamine of commerce is a mixture of the mono-and the disubstitution products. In the case of sulphars-phenamine the extra atom of oxygen has made the pro-duct more stable, less toxic and less active therapeuticallywhen given intravenously. Fig. 5 shows three alternativeformulx, the original one by Lehnhoff-Wyld, the Americanof Voegtlin, Johnson and Dyer, and that ascribed tohis preparation by one of the British makers (privatecommunication). One is tempted to speculate if theproducts sold in this country are closer to the Frenchthan to the American and if the difference accounts forthe fact that, although our sulpharsphenamine certainlydoes seem to be more prone to cause purpura than doesour " 9I4," yet, judging by the literature, it is certainlynot so bad in this respect as the American products ofthis type.To revert to pre-war experience. I should like here

to mention another systematic investigation of salvarsanwhich was carried out at the same time as ours by Marine-Oberstabsarzt Gennerich,19 because I believe that nofiner results than his have ever been published. Gen-nerich took advantage of the control over his cases whichhis position as a naval surgeon gave him to carry outthe most scrupulous observation of them for long aftersuspension of treatment. His paper giving his latestresults, which was published in I9I4 in celebration ofEhrlich's sixtieth birthday, ought to be read by everyonewho is interested in discovering the perfect scheme of

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treatment of early syphilis; when I first read it I wasfilled with envy because at the time our best resultslooked very poor in comparison with his. Ours showedapproximately 28 per cent. of clinical and serologicalrelapses in the primary and secondary cases treated withI-2 to i-8 gm. " 6o6" in two to three doses and nine toten mercurial injections and observed for twelve monthsor longer. His showed in the last series of cases, observedfor a year or longer clinically, by blood tests and byexamination of the spinal fluid after suspension of treat-ment, 92 primary cases with 3 relapses (I serologicaland 2 with slight changes in the fluid), and 70 earlysecondary cases with 4 relapses (3 clinical and i sero-logical). For 3 of these relapses he blamed the use ofneosalvarsan which, after trial, he considered to be veryinferior to salvarsan. His courses of treatment hadbeen increased after I9I0 until in the year ending March,I9I4, they had become as follows. For sero-negativeprimary cases, six to eight salvarsan injections of 0o4 to0o5 gm. " 6o6 " with fifteen calomel (he consideredcalomel much superior to mercurial cream). For sero-positive primary cases two to three more salvarsaninjections, especially when the individual dose in anycase was lower than 0-4 gm. For early secondary casestwo courses of six salvarsan injections each, with aninterval of thirty days between the courses; in thesecond course there was usually an interval of three tofour weeks after the fourth injection; two to four injec-tions would be given after this break. The total numberof calomel injections appears to have been fifteen totwenty. His paper shows that, while we were increasingour dosage comparatively slowly, his jumped in threeyears to double or treble ours. Even so, Gennerich'stotal dosage in terms of arsenic was much less than isbeing given to-day with results which are by no means sogood. I believe that the superiority of his results wasattributable to his use of the more efficient salvarsan, infairly large individual doses and simultaneously with aheavy metal in a form that was likely to be absorbedevenly and at reasonable speed.

In the I,052 cases which we treated with salvarsan atRochester Row before the war there was no death orjaundice, and the only instance of a dermatosis was i caseof transient erythema.

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With regard to neuro-recurrences, only 2 of cranialnerve disturbance occurred. In i it was clear that thefacial paralysis was an ordinary Bell's palsy, the bloodand cerebrospinal fluid being quite negative. In theother the patient had received previously two injectionsof neosalvarsan followed by o*3 gm. " 6o6 " without anymercury and had developed facial paralysis two mnonthslater. We saw 2 other cases of neuro-recurrence thathad been treated in other hospitals, each witlh a singledose of salvarsan, and in one of our papers 8 we reportedthat Captain Frost had had 6 in the first ioo cases hehad treated with salvarsan. Five of these had had onedose and i had had two doses without any other treat-ment. In I9II the incidence of neuro-relapse wasexciting a great amount of discussion, and Benario 20was prominent in defending " 6o6" against the chargethat the increase in cranial nerve disturbances was dueto a neurotropic effect of the remedy. In a paper pub-lished in I9II he gave particulars of ii8 cases of post-salvarsan cranial nerve disturbance. Besides showingthat they were syphilitic, he attributed them to aninsufficient treatment, and it is significant that he urgedvery strongly the use of mercury and iodides in conjunc-tion with salvarsan, as first recommended by Neisserand then by Gennerich, Kromayer and others.My own experience of neuro-relapse in the form of

cranial nerve disturbance and my study of the literatureat that time left on my mind the strong impression:(i) That this form of syphilis had increased since thepublication of " 6o6 " and (2) that it had occurred chieflyif not exclusively in cases treated only witlh the arseno-benzene compounds. In Gennerich's I,200 or more casestreated before the war there appear to have been only2 neuro-relapses with clinical signs. During the war nocase treated in either of the two military hospitals Icommanded developed a neuro-recurrence, and I cannotremember any such case being shown to me in any ofthe military hospitals whose treatment of V.D. I had tosupervise. I believe that our freedom from this kind oftrouble arose from the fact that we gave mercury in*conjunction with salvarsan from a very early date in thesalvarsan era and that, moreover, we made a practiceof starting to give it early in the course of treatment.Since the war, in various papers, I 21 have contrasted my

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experience in this respect before, during and after thewar with that of others who have been less fortunate,and have attributed the difference to the fact that, inearly cases, these others have delayed the giving of heavymetal for a number of weeks. I should like to take thisopportunity of saying that in early cases treated undermy supervision after the war at the St. Thomas's Hos-pital, the evidence of their practical immunity fromclinically manifest neuro-recurrence has now been sup-ported by examinations of a fairly large number of speci-mens of cerebrospinal fluid taken by medical officers ofthat Treatment Centre during the time I was its Director.The number of specimens from primary and secondarycases that had received varying amounts of treatmentwas 270, of which I45 were taken less than twelve monthsafter cessation of treatment and I25 from one to five ormore years later. Of the 270 fluids, only one gave a posi-tive Wassermann (with a volume of neat fluid, globulin +,and cells 9 per cm.). One gave a doubtful with two neatvolumes (globulin, a trace, and cells 3 per cm.); theremainder gave completely negative reactions, evenwith two volumes of neat fluid. Of the 268 fluids withcompletely negative Wassermann reactions the numberwith six to eight cells per cm. was thirteen; nonehad more than eight cells. Of the thirteen fluids withsix to eight cells, eleven were taken less than twelvemonths after the last injection, as was also the fluidwith a positive Wassermann. This was from a latesecondary case which, after an initial course of neo-arsphenamine and bismuth, had received a furthercourse of practically only sulpharsphenamine (only0-4 gm. Bi), and had relapsed five months later withpositive serum. He had then again received only sulph-arsphenamine for four months before the lumbarpuncture. Of the other cases in which the fluid hadover five cells per cm., 3 had received less than thirteenarsphenamine and thirteen Bi injections; 3 had receivedless than twelve arsenical but from ten to forty-sixinjections of Bi. The remainder had received twelve totwenty-seven arsenical and nineteen to forty-three injec-tions of Bi.

I am glad to see that, in my views on the importanceof using heavy metal in conjunction with an arseno-benzene compound in at any rate the early weeks of

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treatment of early syphilis, I am now supported by J. E.Moore,22 whose experience in respect of neuro-recurrencescontrasted with my own, and had more or less crystallisedmy views on this matter. Although Moore, for whosework in this field I have great admiration, remains aconvinced adherent to the so-called " continuous "method of treatment, in which courses of arsphenaminealternate with courses of heavy metal, he makes thefollowing concession: " However, it does seem definitethat the administration of a small amount of heavy metalearly in the course of treatment serves as some protectionagainst the appearance of this particular form of relapse.For this reason I believe that combined treatment witharsphenamine and a heavy metal should be employedduring the first few weeks of the management of a patientwith early syphilis, and that a short period of combineduse does not materially enhance the risk of toxic effects."I am not troubled by his ending up the paragraph bysaying: "Following the first course of treatment, how-ever, the two types of drugs should be used in alterna-tion and not together," because, apart from this questionof neuro-relapse, with all respect to the work of theAmerican Co-operative Clinical Group, which I admireimmensely, their comparisons of the results of continuoustreatment practised in U.S.A. with the results of theso-called intermittent treatment which their patients hadreceived do not settle the question of the respective meritsof the best form of continuous and the best forms of inter-mittent treatment. If the so-called " intermittent "treatment employs injections of heavy metal in an in-soluble form and, as recommended by the League ofNations Experts Committee, allows intervals betweencourses of only three to five weeks, it is in effect con-tinuous treatment, because of the continued absorptionof heavy metal from the sites of injection during theintervals.

During the war, as opportunity occurred, I increasedthe course of treatment given to military patients, andthen we began to see jaundice and dermatitis. So muchhas been written on the subject of toxic effects that Ido not think any useful object would be served by mydiscussing them here at any length. It seems now to beclear that, other things being equal, the more intensivethe treatment the greater the incidence of jaundice and

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dermatitis, but intensity of treatment and size of dosageare not the only factors, as is shown by the comparativeimmunity from these troubles of the Danish cases dealtwith in the League of Nations Enquiry, in spite of thefact that their individual dosage was higher than ours.

I will not occupy any time discussing treatment withthe heavy metals except to say that what I learnt ofthe effects of injections of mercurial cream and salicylateof mercury would incline me now, if I wanted to includemercurial injections in a patient's treatment, to usecalomel, as recommended by Gennerich. With regard tobismuth compounds, all one's experience tends to showthat the violent but evanescent effect of the arseno-benzene preparations ought to be supplemented by amore persistent, if milder, effect of heavy metals, andthis suggests the use of insoluble rather than solublecompounds.To sum up these experiences in the treatment of early

syphilis, when I contrast the effects of our best pre-warcourse of salvarsan and mercury and especially Gennerich'sresults with those of the present-day courses of " 9I4 "with bismuth, it does occur to me that we might considerif it would not be better to use fewer but comparativelylarge doses of an arsphenamine preparation, perhapsseparating each pair by two weeks or so of treatment bya heavy metal. Also the contrast between therapeuticeffects of " 6o6 " and of " 9I4 " given intravenouslymakes one wish it was practicable to give " 6o6" in ourclinics. As we cannot, because of side effects, and as,after all, " 9I4 " given subcutaneously seems to giveresults that are as good, research to find a tolerablemethod of giving it by this route seems likely to be wellworth while. I say neoarsphenamine for the subcutaneousroute and not sulpharsphenamine advisedly, because Ido not believe the therapeutic effect of the sulphars-phenamine preparation to be nearly so good. On thequestion of alternating arseno-benzene courses withcourses of heavy metal versus the concurrent use of bothtypes in early cases, I remain a convinced adherent to theconcurrent plan, and emphatically so in the first courseof treatment.

So far I have spoken of experiences in the treatment ofearly cases and have occupied so much time in it thatthere is too little left to deal adequately with late cases,

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but here I would mention a thing which experience hastaught me to be most important. It is to examine thecerebrospinal fluid of every case of syphilis with aninfection of more than four years' duration. Whateverone may think of the importance of examining the fluidof early cases that have been well and regularly treated,there is no question of its necessity in the later cases ifone does not want the mortification of occasionally seeinga late case of syphilis that one has treated regularlyfor many months with the ordinary trivalent arsenicalpreparations develop G.P.I.

It is interesting that in the beginning of the salvarsanera the pentavalent arsenicals were taboo because of aneurotropic effect, and that now (Fig. 6) in the form of

/ONa /OH /OHAs=O As=O As O/\\OH /\\OH /\\OH . NH(C2H5)2

-NH. COCH3 NH. CO. CH3

NH. CH2 . CONH2 OH OH(a) (b) (c)

FIG. 6.-(a) Sodium N-phenylglycineamide-p-arsonate, or Tryparsa-mide. (b) 3-Acetylamino-4-hydroxyphenylarsonic acid (No. 594of Ehrlich's series, No. I90 of Fourneau's) or Acetarsone. Soldas Stovarsol Orarsan, Spirocid, or Kharophen. (c) Diethylaminesalt of acetarsone, or acetylarsan.

tryparsamide, acetylarsan, stovarsol (spirocid, kharophenor orarsan) they are the arsenicals we prefer in lateneuro-syphilis.When the examination of the spinal fluid becomes

routine in these late cases and the treatment is guidedthereby, there will be some reduction in the incidence oflate neuro-syphilis.

Lastly, I would heartily endorse the remarks madehere some months ago by Dr. Osmond 23 on the meritsof the Sigma test as a gauge of the effects of treatment inlate cases. By the Sigma method the strength of thereaction is automatically expressed by a numeral.Consequently, instead of the serum at the end of courseafter course being reported as strongly positive, witlh noindication of any weakening, as occurs with such tests asthe Wassermann and the Kahn, the Sigma shows usuallya steady lowering of the number which indicates the

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strength of the reaction in a way that encourages boththe patient and his physician.

REFERENCES

(i) THOMAS, H. W.: "Some Experiments in the Treatment ofTrypanosomiasis," Brit. Med. Jour., 1905, ii., II40.

(2) SALMON, P.: " L'arsenic dans la syphilis," C. R. Soc. Biol.,I907, 62, 483; Annial. de l'Inst. Past., I908, 22, 66.

(3) EHRLICH, P.: "Chemotherapeutische Trypanosomenstudien."Berlin klin. Wschr., I907, 44, 280.

(4) UHLENHUTH and MANTEUFEL: Ueber die Wirkung vonatoxylsauren Quicksilber bei Spirochatenkrankheiten inbesondere beider experimentellen Syphilis," Med. Klin., I908, 4, i65I.

(5) EHRLICH, P.: " Ceber moderne Chemotherapie," Archiv. f.Schiffs. u. Tropenhyg., I909, 13, I30.

(6) ALT, K.: " Behandlungsversuclhe mit Arsenophenylglyzin beiParalytikern," Munch. med. Wschr., I909, 56, 1457.

(7) NEISSER, A.: " Ueber das Arsenophenylglyzin und seineVerwendung bei der Syphilisbehandlung," Archiv. f. Derm. u. Syph.,I9I5, 121, 579.

(8) GIBBARD, T. MS., and HARRISON, L. XV.: The Treatment ofSyphilis with Salvarsan," Proc. Int. Med. Contg., London, I9I3;II. Dermat. and Naval and Military Section I45, Jouir. Roy. ArmyMed. Corps, I9I4, 22, 247.

(9) ALT, K.: " Das neueste Ehrlich-Hatapraparat gegen Syphilis,"Munch. med. Wschr., I9IO, 57, 56I.

(io) " Medizin Gesellsch. zu Magdeburg," Sitzung von, 3/3/10,Miinch. med. Wschr., I9IO, 57, IO67.

(II) SCHREIBER, E., and HOPPE, J.: "Die intravenose Einspritzungdes neuen Ehrlich-Hata-Praparates gegen Syphilis," Berlini klin.Wschr., I9IO, 47, I448.

(I2) BEVERIDGE, W. WV. O., and WALKER, N. D.: "On the fate ofArsenic in the Body after Injection in the form of Salvarsan or' 6o6'"Jour. Roy. Army Med. Corps, I9I, 16, 376.

(13) GIBBARD, T. Wr., and HARRISON, L. XV.: "Observations on theUse of Salvarsan in Syphilis," Lancet, I9II, i., 726.

(I4) HARRISON, L. W., WHITE, C. F., and MILLS, C. H.: "TheIntramuscular or Subcutaneous Injection of Neosalvarsan," Brit.Med. Jour., I9I7, i., 569.

(I5) LEAGUE OF NATIONS: "Syphilis Treatment. Enquiry in FiveCountries carried out under the auspices of the Health Organisationof the League of Nations," League of Nations Quarterly Bulletin ofthe Health Organisation, I935, 4, I29.

(I6) SCHREIBER, E.: "Ueber Neosalvarsan," MInch. med. TW'schlr.,I9I2, 59, 905 and i850.

(I7) DALE, H. H., and WHITE, C. F., in collaboration with BURN,J. H., DURHAM, F. M., MARCHAL, J. E., and MILLS, C. H.: "Experi-mental and Clinical Comparisons of the Therapeutic Properties ofDifferent Preparations of ' 9I4' (Neosalvarsan)," Lancet, I922, i., 779.

(I8) SCHLOSSBERGER, H., " Die experimentellen Grundlagen der21


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Salvarsantherapie," in Kolle and Zieler's Handbuch der Salvarsan-therapie, I924, Bd. 1, p. 93.

(I9) GENNERICH: "Die bisherigen Erfolge der Salvarsanbehand-lung im Marinelazarett zu Wik," Miunch. med. Wschr., I9I4, 61, 5II.

(20) BENARIO, J.: " Ueber die Schwankungen im Verlaufe derNervensyphilis, Berlin klin. Wschr., I9II, 48, ii65. Zur Statistik undTheorie der Neurorezidive nach Salvarsan," Miunch. med. Wschr., 19II,58, 732.

(2I) HARRISON, L. WV.: "The Treatment of Syphilis. A Surveyof Records from St. Thomas's Hospital, I929," Medical ResearchCouncil Special Report Series, No. 132, P. 40. "The Modern Treat-ment of Syphilis," Practitioner, 193I, 126, I93.

(22) MOORE, J. E.: " The Modern Treatment of Syphilis," Balti-more: Charles C. Thomas, I933, P. I84.

(23) OSMOND, T. E.: " Quantitative Serum Tests in Syphilis,"Brit. jour. Ven. Dis., I935, 11, 248.

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