Quinine causing muscle disorders

Dr. FrankHinman,San Francisco: I wishto reopenthecontroversy of transurethral resectionandperineal prostatectomy. I think it is proper in viewof Dr. Lewis's remarks.Thereason that I wishto do this is that I thinkthepointofDr.Young's paper has been entirelyoverlooked.Hyperplasiaof theprostatedoes notalways occur as an isolated condition,andanymethod of treatment whichalwaystreats it as anisolated condition does not conformtothehigheststandard ofcure. We knowthat infections in the prostate,stones of theprostate, and carcinoma of the prostateare frequentlyassociatedwithhyperplasia.Carcinoma occurs intwoforms: primary carcinoma in theposteriorlobe andprimarycarcinomathat occurs in the hyperplasiaitself. In a recent paper, ahistologie study by Heyntschakin Vienna showed that 3 percent of the prostates removedby suprapubic prostatectomyhad carcinoma in them unsuspected. Thesepatientsbeforeoperationpresumably wereall curedbyremoval of thishyperplasia.It seems to me that the matter hasdegeneratedintomore or less of a questionof choice of the operator himself.Perineal prostatectomynotonlyconserves incertain cases thesexual function and not onlyrestores theabilityto urinatenormally but it gives an opportunityto treat these associatedconditions,andparticularlythe carcinoma. Theperineal routeis theonlymethodbywhich one can radically remove carcinoma of the prostate; the perineal route is theonlymethodbywhichstones can beradically removed,andtherefore,inaconsideration of the standard of cure, a methodthat does nottake into consideration this association does not conformtothe higheststandard of cure.QUININEIN MYOTONIA AND PRO-STIGMINE IN MYASTHENIAA CLINICAL EVALUATIONFOSTER KENNEDY, M.D.,F.R.S. (Edin.)andALEXANDER WOLF,M.D.NEW YORKWith Walker's1discoverythat prostigminealleviatesthe muscular weakness ofmyasthenia gravisandWolf's2findingthatquinineabolishes themyotonusofcongenitalandatrophicmyotonia,newimpetuswasgiventothestudyofthepathophysiologyof thesedis-orders.Theclinical observation3 thatprostigmineexaggerates myotoniaand thatquinine exaggeratesmyastheniaestablished arelationshipofoppositioninresponsetodrugsthat accentuatedtheobviouscontrastbetweenthesemuscular states. It isthiscontrast thatmakesappropriateacomparativeevaluation of theirsymptomaticresponsetopharmacologicantagonists.ItistwoyearssinceWalker's1contributionandoneyearsince Wolf2suggestedtheuseofquinine,sothatanappraisalofthe clinical usefulness ofprostigmineandquinineis due. Inthisperiodwe havestudied,seenorbeeninindirect contact withninepatientswithmyasthenia gravis,ninepatientswithmyotoniacon-genitaandeighteen patientswithmyotonia atrophica.Every patientwithmyasthenia gravisshowed animmediate excellentresponsetoprostigmine,withgeneralizedincreaseinmuscularpower.Patientspreviouslybedridden andgaspingfor breath becameambulatoryandtooklightexercise.However,withinone to fourmonths fourpatients beganto show aprogressively poorer response toprostigmine,so thatthe dose had to be increasedgraduallyto maintainswallowingand aidrespiration.Inspiteofincreasesin medication of fromtwo toten,fifteen and eventwenty-four ampules (0.5 mg. per ampule)intwenty-fourhours, thesepatientswereat timesalmost at thepointof death. Evenwiththesehighdosesnopainfulperistalsisoccurred.Sweating, however,was markedinall cases. It semedthat,ifprostigminewasgivenbeyonda certainpoint, patientsbecamerefractorytowardits beneficial effects. Yet if insufficientprostigminewasgiven, respirationbecame labored andswallowing impossible. Accordingly,theadministrationofprostigminewasdiscontinuedforfromthirty-sixtoforty-eight hours,during whichtimetheadministrationofpotassiumchlorideandephedrinesulfatewaspushedtoapoint justbelowintolerance. Orderswereleft toinstituteartificialrespirationand togiveprostigmineincaseofemergency. Swallowingbecameimpossible,sothatfeedingbytubewasrequired.Afterfromthirty-six toforty-eighthoursprostigminemedication wasresumedinonecasewithoneampule (0.5mg.)twiceaday.Thispatientshowed a much betterresponseto twoampulesafter a twodayabstinence than shepreviouslyhad totwenty-four ampules. Gradually,however,her medication has had to be increased totwelveampulesaday,andagainshe is much lessresponsive.Asecondpatient, formerly givenfromeighteento twenty-fourampules,has maintainedafairdegreeofstrengthwhilereceivingfourampulesadayafter a twodayabstinence. A thirdpatientwasformerlygivenfromeighteentotwenty-four ampules,despite whichswallowingremainedimpossible.Hehashad noprostigminenowfor four months and showsfewsignsofdeprivation.Hemaybe in a state ofspontaneousremission. Thedosageinthefourthcasehasnotyetbeenreduced.Whycertain of ourpatientsshould after a whilebecomerefractorytoprostigmineisnot clear;nor canwebecertain thatthepatientswhohaverespondedwellso far will not at some time becomerefractory.Intheoreticalexplanationit could bepostulatedthatcholineesterasekeepsincreasingintheblood,requiringconstantlyhigherconcentrationsofprostigmine.Thisnotion is difficult to maintain inthelightof contradictoryreportson thebloodcholineesteraseinpatientswith myasthenia gravis.Stedman4obtained lowvalues.McGeorger>reportedthree cases ofmyastheniagravisinwhich theactivityof the serumesterase was wellwithinnormal limits and showed littlevariationfromdaytoday.However, Brown,Dale andFeldberghavestressedtheimportanceof thelocal concentrationofacetylcholineat theend-plate.Onecanimaginetheconcentration of cholineesteraseat the myoneural junction asexcessive,a state unrevealedby studyof theblood. Anotherpossibilityis theperiodicexhaustionofacetylcholineat theend-plate.At suchtimes itwould not matter howstronglyesterase was inhibitedbyanyquantityofprostigmine.Akeytothis{jroblemmaylieinBoothby's7clinicalobservation, andwecanThiswork hasbeen doneunder theauspicesof the Child NeurologyResearch Foundation.ReadbeforetheSectionon Nervousand Mental Diseases at theEighty\x=req-\Eighth Annual Sessionof the American Medical Association, AtlanticCity, N. J., June 10,1937.1. Walker, Mary: Case ShowingEffect of Prostigmin on MyastheniaGravis,Proc. Roy.Soc. Med. 28:759-761 (April)1935.2. Wolf, Alexander: Quinine:An EffectiveFormof Treatment forMyotonia,Arch. Neurol. & Psychiat. 36:382-383 (Aug.) 1936.3. Kennedy, Foster,andWolf, Alexander: Experiments withQuinineandProstigmininTreatment ofMyotonia and Myasthenia, Arch. Neurol.&Psychiat.37:68-74 (Jan.) 1937.4.Stedman,Edgar: The Choline Esterase Content of Bloodin Myas-theniaGravis,J.Physiol. 84:56P(July) 1935.5. McGeorge, Murray: Choline EsteraseActivity in Disease withSpecialReference toMyasthenia Gravis, Lancet 1:69-72(Jan. 9) 1937.6.Brown,G. L.; Dale, H. H.,andFeldberg, W.: Reactions ofNormal Mammalian Muscle toAcetylcholineand to Eserine, J. Physiol.87:394-424 (Sept. 8)1936.7.Boothby,W. M.:Myasthenia Gravis, Ann. Int. Med. 9: 143-149(Aug.) 1935.confirmthis,that thereisadefinitecorrelationbetweenthepatient'sgeneralconditionandthe amount ofdry,stringyoral mucus. Theproductionof this mucus ismoremarkedwhenthepatientisworse. Itappearstous that thisdry,viscous mucus makes itsappearanceonlywhen there isinadequate flowingsalivation.Stavraky8 quotesanexperiment byHeidenhain,9inwhichheparalyzedthesecretoryeffects of thechordatympaniwithquinine althoughthesympatheticnervestill acted. It followsthat thevagushormoneorpara-sympatheticstimulationproduceswaterysalivationandthatinextrememyasthniestatesthereis adeficiencyofacetylcholineresultingininadequatesalivation anddryoral mucus. Yet thesuppositionofmyoneuralacetylcholineinsufficiencywearsthinunder theexperimentalobservation thatacetylcholineoracetyl-beta-methylcholineadministered at such times does notincreasemuscularpower.Therefractorycharacterof prostigmine afteranearlyextendedperiodof usefulnesshas beennotedbyotherinvestigators.Minski and Stokes10noted immediatetoxicsymptoms, alimentary,cardiovascular and nervous, causingcompleteprostration.Wehavenot seensuchsymptoms exceptafterprolongedand excessivemedication. But Minski and Stokes stated that it ishopelessto undertake continuous treatment withprostigmineoutside thehospital. Theyconfirmed theremarkablespecificeffect ofprostigminebut said itsusefulness is limited.We, however,have been abletoadministerprostigmine hypodermicallyororallytofourpatientsoutside thehospitalformanymonths.Hyland1Xpointedout thedramaticbut transient relieffromsymptomsin fourpatientsand warnedagainstrepeatedadministration on thegroundsthat itmaybe followedby alarminglyincreased weakness. Headmitted, however, that there are several casesonrecordinwhichratherlargedosesweregiveneverydaywithout illeffect.Boothby12hasemphasizedthat treatmentwithprostigminemaybefollowedbymentaldepressionandgreaterweaknessafterearlyimprovement.C. K.Rssel13 described hisexperiencewith a case ofmyastheniagravis:"It wasdisappointingthat,whiletheeffect lastedfor four or fivehours,there resultedwhat seemedtobe adecidedlet-down,andhewasnotnearlyso well after theinjection;so Ifelt hesitantaboutrepeatingit moreoftenthan wasnecessary.IhadtoputhimintheDrinkerrespirator,and the useof therespirator andthe drugwascontinued forseveraldays,but hefinallydied. Thelet-downabout fiveorsixhours after the administration of theprostigmineseemed to me a seriousdisadvantage." HarveyandWhitehill,14 whilegrantingthatprostigmine producesstrikingimmediateimprovementand seems atpresentto be the most valuabletherapeutic agent,describedthreepatientsinwhombeneficial effectsdecreasedwiththecontinueduseof thedrug untiltheydied. Anotherpatientnever became able to walkabout inspiteof15mg.nine or ten times aday.In a fifthpatient,althoughprostigmine,30mg.threetimesaday, helpedchewing, swallowinganddiplopia,its effects woreoffinfrom twotothreehours,andthepatientthoughthismuscular weakness was worse than before thedrugwas taken.It is our belief thatprostigmine givenin doses offromISto30mg.twoorthreetimesadaymaybe lifesaving, but ifgivenover aconsiderableperiodinexcessof thisdosage orover too longatime in thislowdosage,itmaybecomeintoxicatingandresult indeath. Prostigminefacilitates the action ofacetylcholineand sostimulates thevoluntarymuscles via themyoneuraljunction, but inlargedoses itappearstoexert acurarelikeeffect, whichverylikelyresultsinweakness,thenparalysis and finally death,when therespiratorymusclesbecome affected. Theoptimumdose must lie in themarginal safetyzone betweenprostigminestimulationandprostigmine"curarization" of themotorend-plate.Thisdosevaries foreachpatient.Ourexperiencewithquininein the treatment ofmyotonusextendsoversixcasesofmyotoniacongenitaandfifteencasesofmyotoniaatrophicafor aperiodofone year.Inadditionweknowthroughpersonalcommunication from aphysician in anotherhospital ofthreecases ofmyotonia atrophica.Smithl hasrecently-reportedthree cases ofmyotoniacongenitathesymptomsof whichwereentirelyabolishedby quinine.Ineach patient of ourseries from2J^to5, 10 or 15 grains(0.16to0.32,0.64or 0.96Gm.)ofquininehydrochlo-rideby mouth twoorthreetimesaday eliminatedeveryvestigeofmyotonus. Anyformofquinine maybeused ;forexample, hydrochloride, sulfate,bisulfateorhydrobromide.Of thegroup, however, thehydro-chlorideappearsto be the most soluble andquicklyabsorbed withoutdisturbing gastro-intestinaleffects.Thehydrobromide maybe used with "nervous"patients.Anexplanationof the continuous neutralization ofmyotonusliesinthemaintenanceof analmost constantlevel ofquinineafter it is administeredbymouth.1"The drug canbedetected in the bloodforabout twenty-fivehours,agooddeallongerthan ifgivenintravenously.The bloodquininecontent does not riseabove3percentofthe dosegiven.Hartmann andZila"demonstratedthat after intravenousinjectionof0.5 Gm. ofquininetheconcentrationinthebloodfellquicklyat first, thensteadilymoreslowly,until aftereighthoursnonewas left. When quininewastakenbymouth the bloodquininecontent was lower but wasnearlyconstant for abouttwenty-fourhours.Quinineis absorbedslowly.Part of it circulatesinthe bloodbefore excretionunchangedintheurine. About onethird is excreted withintwenty-fourhours.18 Theremainder isdestroyed bythebodymetabolism.19 Inonlyonepatient (J. P.)wasthereasign ofcinchonism,evidencedbyringingintheears. Thisoccurredwhenshetook10 grains (0.64Gm.)ofquinine hydrochloridethreetimes adaybymouth. Doses of 5grains (0.328.Stavraky, G. W.: Effect ofQuinine on theParasympatheticandSympatheticInnervation of theSalivary Glands, J. Pharmacol. &Exper.Therap. 47:321-338 (March) 1933.9.Heidenhain,R.: Stud. d.Physiol. Inst. zu Breslau 4:85, 1868.10.Minski, Louis, and Stokes, A. B.: Treatment ofMyastheniaGravis, Brit. M.J. 1:1095-1098(May 30)1936.11.Hyland,H. H.: Treatment ofMyastheniaGravis, Canad. M.A. J.35:372-381(Oct.) 1936.12.Boothby, W. M.: MyastheniaGravis: EighthReport, Tr. A.Am.Physicians 51:188-198, 1936.13.Russel, C. K., in discussion ofWinkelman, N. W., andMoore,M. T.:Prostigmininthe Treatment ofMyastheniaGravis andMuscularDystrophy, Arch. Neurol. & Psychiat. 37:237-252 (Feb.) 1937.14.Harvey,A.M., andWhitehill, M. R.:Prostigmin as an Aid inthe Diagnosis of Myasthenia Gravis, J.A. M. A.108:1329-1333(April 17) 1937.15.Smith,W. A.:Quinine Treatment ofMyotonia Congenita, J. A.M. A.108:43(Jan. 2) 1937.16.Meyer,H.H.,andGottlieb, R.:Experimental Pharmacology as aBasisforTherapeutics, translatedbyV. E.Henderson, Philadelphia, J. B.LippincottCompany, 1926, p. 561.17.Hartmann,H., and Zila, L.: Ueber diesogenannte Chiningew\l=o"\h-nung, M\l=u"\nchen.med.Wchnschr. 64: 1597, 1917.18. Giemsa, G.: Ueber die therapeutische Verwertbarkeit der freienChininbase, Arch. f. Schiffs- u. Tropen- Hyg. 11:300-302, 1907.Nishi,M.: Ueber eine neueBestimmungsmethode des Chinins und\l=u"\berseineAusscheidungimHarne, Arch. f. exper. Path. u. Pharmakol. 60:312\x=req-\323, 1909.19.Grosser, P.: Ueber das Verhalten des Chinins imOrganismus,Biochem. Ztschr. 8:98-117, 1908.Gm.)threetimes adaywerewell tolerated andadequatetoeliminatesymptoms.Ineverycase ofmyotoniacongenitaquinineprovedto be ofuniquevalue. When administration of thedrugwasstopped,evidenceofmyotonia returned withintwenty-four hours butwas notcomplete beforeseventy-two hours. Patientsconsistentlyasked forquininewhenit was notgiven, insistingon its beneficial subjectiveeffect. The solution ofmyotonuswasequallyevident onobjectiveexamination,eventothedissolvingofpercussion myotonusin thevoluntarymuscles,includingthetongue.Inrareinstanceswhenmyotoniawas not evident onvolition,a remnant of it couldbeelicitedonpercussion.In cases ofmyotonia atrophica, although quininereadilyneutralizedmyotonicreactions,it had lessclinical usefulness. The reason for this issimple.Thepatientwiththeatrophie varietyofmyotoniaisincapacitatedmuchmorebyatrophythanbymyotonus.Inat least twoor threepatientsthestageofmyotoniahad beenoutlivedor had neverdeveloped.Yet therewas noquestionthatthey belongedinthisdiagnosticclass.Onlythree ofeighteen patientswithatrophiemyotoniademandedtocontinuetaking quinine,indicatinganeedandappreciationof thedrugnot evidentintheothers.One man withmyotoniacongenitaand one womanwithmyotonia atrophica appearedto have aslightdecrease inmyotonusfor several weeks aftertheystopped takingthedrug.The manhad usedquininefor ten months;the woman had used it for threemonths. Whether thispartialrelease frommyotoniawill betransient orpermanentremainstobe seen.Inaprevious paperwe3reportedtheexaggerationofmyotoniabyprostigmine.WehavesincebeenabletoconfirmRusselland Stedman's-similarexperiencewithpotassium,whichpiles upmore evidence for thebrief ofpharmacologie antagonismbetweenmyotoniaandmyasthenia.We have also confirmed Stedman'sScottish observation that alcoholgiven bymouthreducesmyotonus considerably.Its soledisadvantageisofcoursechronicinebriationandtheexcitingtoenvyof lessfortunatepatients,not tospeakof somedamagetothe discipline ofthewards.Possibly,however,theseby-productsof thistherapy would naturallyattract littleornoattentionnorthof theTweed.We have been confronted with cases ofsupposedmyotonia congenitain which theattending physicianprotestedthatquininewas ineffective. Careful examinationshowedthepatientstobesufferingfromotherdisorders,suchashmiplgiespasticityortetany.Thisledtoaninvestigationof theeffect ofquinineandprostigmineon other neuromuscular disorders. Beforerecordingourownexperienceweshall mentionthat ofothers. Everts21employed prostigminein cases ofmyotoniacongenita,alcoholicpolyneuritis, postencepha-liticparkinsonism, facioscapulohumeral myopathyandamyotrophiclateral sclerosis. Someimprovementfollowed,butthepatientswerenot treatedregularlyorfor asufficientlylongperiod.ItiscurioustofindthatEverts notedimprovementinpatientswithmyotoniafollowingtheadministrationofprostigmine.Wehavegiventhisdrugmanytimes incases ofmyotoniaandfound themyotonusto beconsistently exaggerated.WinkelmanandMoore22reportedtwooffourpatientswithpseudohypertrophicmusculardystrophywhoimprovedaftertakingprostigmine,onewith"musculardystrophy"whoresponded favorably,and one withscapulohumeralmusculardystrophy (Erb)and onewith amyotrophic lateral sclerosis who failed toimprove.Themajorityof thepatientswithmyasthenia gravishadreceivedephedrineor aminoaceticacidor bothforan extendedperiodwithoutany appreciable improvement. Ourexperiencewithaminoaceticacid(glycine)inthetreatment ofmyasthenia gravishaslikewisebeendiscouraging.Hamill andWalker23reportedincreasedmotorpowerin cases ofamyotrophiclateralsclerosisfollowingthe use of moderate doses ofprostigmine.Hurwitz and Gerstle2i found noimprovementinpatientswithamyotoniacongenitaaftertreatment withphysostigmineandprostigmine.Wehave usedprostigmineandquininein one caseof chronicchorea,twoofordinarychorea,oneof hemi-athetosis,a dozen ofspasticityassociated with hemi-plegia,one of ticinvolvingthe facial and cervicalmuscles,a dozen of chronicencephalitis,two ofspasmodictorticollis,one ofamyotoniacongenita,twoofprogressivemusculardystrophy,one ofWestphal'spseudosclerosisand one ofophthalmoplegiacausedbybotulism. Onepatientwith thefacioscapulohumeralmyopathyofLaudouzyandDejerineshowed someslightsubjectiveand objective improvement after taking0.5mg.ofprostigmine subcutaneouslythree times aclay.When this dose wasgivenfive times aclayextreme weaknessappeared, apparentlya "curare"effect fromexcessprostigmine.We3havereportedelsewhere anexperimentwhichindicates that themyotonic phenomenonis due to apathophysiologicstateresidentinmuscleorat themyo-neuraljunction independentof thespinalneuronalreflexarc. Sincemyotoniaandmyastheniaappeartobecounterparts respondingtopharmacologie antagonists,and sincemyastheniaisconceived as a state inwhich there is excess choline esterase orinadequateacetylcholineat the motorend-plate, myotonic phenomena are in all likelihood due to an accumulationofacetylcholineor to an insufficient concentration ofcholineesteraseat themotorend-plate.Yet it is difficult toimaginehowmyotonuscould be due to excessacetylcholine,whenatropine,anantagonistofacetylcholine,haslittleor no effect on the disease.Maybetheparasympathetic"stuff" at the motorend-plateorinmusclein this disease is somehow unaffectedbyatropine.Totest andconfirmour notionof thelocalizationofthepathophysiologicsiteinmyotoniaandmyasthenia,500 cc. of wholebloodwastransfusedfromapatientwithmyotonia congenita (J. D.)toapatientwithmyasthenia gravis(J. F.).Our feeling was that ifthesediseases werepathophysiologic oppositeswemighttransferparasympathetic"stuff" fromthe one to theother toproducea transient neutralization ofmyasthnieweaknessandincreasestrength.Theconverse,inasense,of thisexperiment,thetransfusionof 500cc.of wholebloodfromanormal individual(F. Q.)to apatientwithmyotonia congenita (J. D.),was also20. Russell,W.R.,andStedman, Edgar:Observations on Myotonia,Lancet 2:742-743 (Sept. 26) 1936.21. Everts,W. H.: The Treatment ofMyastheniaGravis by the OralAdministration ofProstigmine, Bull. Neurol. Inst. NewYork 4:523-530(Dec.)1935.22. Winkelman, N. W., and Moore, M. T.: Prostigminin the Treat-ment ofMyasthenia Gravis,Arch. Neurol. & Psychiat. 37:237-252(Feb.)1937.23. Hamill, P., andWalker,M. B.: The Actionof"Prostigmin"(Roche)in Neuromuscular Disorders, J. Physiol.84:36-37P(May 13)1935.24. Hurwitz, Samuel,andGerstle, Mark, Jr.: Amyotonia CongenitawithFamilial Incidence,Arch. Neurol.&Psychiat. 33: 1317-1323 (June)1935.performedbut wasnot followedbydiminishedpercussionor volitionalmyotonus.Inthefirstprocedureitwasanticipatedthat thehypotheticexcess ofacetylcholineinthemyotonicpatientcouldbetransferredtothemyasthnie subjectwho sufferedfromasupposedlackof thevagushormone. Inthesecondexperimentit was believed that the normal concentration ofcholineesterase in the blood of the unaffected individualmightneutralize the "excessacetylcholine"inmyotonia. Nochangeinmuscularsymptomswas noted.Thisexperimentconfirmed our belief that thepathologicchangeof thesedisordersliesinmuscleorat themyoneural junction.In aprevious experimentwe3established theinnocenceof thespinalreflexarc,andnowthebloodisseennot tocarrytheoffending "stuff"inconcentrationsgreat enoughtoaffect thedisorderedmusclesorend-plates.Dr.H. G. Wolff,25inordertoascertainwhethertheconstrictionof the pupilisdue to action ofacetylcholine,theradial muscleof theirisorparasympatheticnerveendings,allowed thepostganglionic parasympatheticnervefiberstodegenerateafter removal of theciliaryganglioninthreecats.Acetylcholine, injectedintotheanterior chamber of theeye, producedmiosis. Thisexperimentindicated"that, at least for theirisof thecat,theactionofacetylcholineisperipheral tothepostganglionicfibers andpresumablydirect on the radialmuscles."Elsewhere Wolff has demonstrated the increasedvascularityof nervous tissue atsynapses, presumablybecause here there is animportantmetabolicprocessgoingon: theconductionof animpulsefromanaxonto a dendriteby acetylcholine,aprocess requiringoxygenand furnishedbythe increased bloodsupply.Binz26saidthattheactionofquinineas acell toxinisduetointerferencewithoxidationandshowedthat thechanges producedin lowerorganisms by quininearesimilartothoseproducedbylackofoxygen. Quinineprobablyinterferes with oxidativeprocessesat thesynapseand themyoneural junction, depressingtheaction ofacetylcholine.MeyerandGottlieb21citedHoffmanandLaqueur2Sinthestatement that "theacidformationinbloodfromaveinisinhibited,andtheformationofhippuricacidfrombenzoic acid andglycocoll [aminoacetic acid],whenaddedtothebloodperfusedthroughthekidney,isdecreasedby quinine."Theidea of inhibition ofacidformationbyquinineassociatesitselfwiththefactthatacetylcholineisdestroyedinanalkalinemedium,beingstableandpreserved onlyin an acidmedium.28Fhner30 too has demonstrated thatacetylcholineisprotectedfromesterasebyincreasedhydrogenconcentration;i. e., increased carbon dioxide tension.Perhapstheacidity (lactic?)ofmuscleinmyastheniaisdecreased as aresult of somemetabolicdisturbance,thusneutralizingtheexpressionof neuralimpulses,whichfinallydependonacetylcholine,ineffectualintoolowanacid, neutral or alkalinemedium.Conversely,theacidityofmyotonicmusclemaybe such as tostabilizeandimplementtheactionofacetylcholine.Ofcoursethis idea ispurelytheoretical andonlyaguideto research.Speakingofcongenital myotoniaasfar backas1891, Jolly3lspeculated that thecausemightbefoundratherinadisturbanceinmuscularchemistrythan in the well known anatomicchangesin muscle.Histheoryof half acenturyagoismorenearlyfacttoday.SUMMARY ANDCONCLUSIONSEighteenpatientswithmyotoniaatrophicaand ninepatients with myotonia congenitahavebeen treated withquinineinthepast year.Quinine abolishes myotonus foraslong as itisadministered.In twopatientsthere wassome diminution ofmyotonus after the administration ofquininewasdiscontinued.From2%to 5, 10 or 15grainsofquininehydrochloridetwoor threetimes adaygivenbymouthhasconsistentlyeliminated myotonusasadisturbingsymptom.Ninepatientswithmyasthenia gravishave beentreatedwithprostigmineinthepast yearandahalf.Fivepatientshave been restored to normalactivityby0.5mg.ofprostigminegiven subcutaneouslythreeor fourtimesadayor oneor twotablets(15mg. pertablet)threetimes aday.Afterearlyimprovementfourpatientshave becomeprogressivelyworse asprostigminemedication wasincreased.Increasingthedoseofprostigmineappearstoaggravatemyasthnie weakness,probably by"curare-like"action.Reduction of thedosage ofprostigmineinthesecaseswas followedbyimprovement.Quinineandprostigminehave beenassayedin thetreatment of agood manyother muscular disordersand foundtobewithout benefitexceptinone caseoffacioscapulohumeral myopathyofLandouzyandDejerine.Thereis additionalexperimentalevidencethatmyotoniaandmyastheniaareprimarydisorders of muscleorthemyoneural junction.410 EastFifty-Seventh Street.ABSTRACT OF DISCUSSIONDr. PeterBassoe, Chicago: The choice of meto openthis discussion on musculardystrophyisunfortunate, becausenotonlyhave I littleexperience with the treatment of suchcases but Iconfess to a certain lukewarm interest. I amtremendouslyinterestedinthepreventionof musculardystrophy.Physicians have beennegligentbecausetheyknowthat musculardystrophyreallyis ahereditary disease, andiftheygetthepublictounderstandthat it is a crimeforpeople belonging;to families withthat disease to havechildren, thisdisease, ascivilizationprogresses,willdisappear fromthe earth. I knowit ispainfultodoit. I remember howunhappyayoungwomanwas who came tomyoffice. Her father and her brother haddystrophy, and she herself had a stationaryform,but I felt itwasmydutytotell hershewantedtoget married"It is allright foryoutoget married, butyoushouldbesterilizedfirst."Withregard tomyasthenia gravis, what littleexperience Ihavehadwithprostigminehas beenextremely happy. Resultshave been mostspectacular.Patients I have had under treat-25.Wolff,H. G.:Siteof ActionofAcetylcholineand ItsSignificance,readbeforethePhiladelphia Neurological Society, March27, 1936.26. Binz, C., quotedin an abstract of Wolfe, Eugene:Causation ofQuinine Blindness,Lancet 1: 1496-1497(June29) 1935, inArch. Neurol.& Psychiat. 855 (Oct.) 1936.27.Meyerand Gottlieb:Experimental Pharmacologyas a Basis forTherapeutics, p. 501.28.Hoffman,A.: Ueber dieHippursaurebildungin derNiere, Arch.exper. Path. u. Pharmakol. 7:233-246,1877.Laqueur, E.: Ueber dieWirkungdes Chinins auf FermentemitR\l=u"\cksichtauf seineBeeinflussungdes Stoffwechsels, Arch. f.exper. Path. u. Pharmakol. 55:240-262, 1906.29.Buth,H. R.: Chemical Mediation of NerveImpulses,Arch.Neurol. &Psychiat. 37:142-153 (Jan.) 1937.30.F\l=u"\hner,H., cited by Minz,B.:Pharmakologische UntersuchungenamBlutegelpr\l=a"\parat,Arch. f. exper. Path. u. Pharmakol. 168:292-304,1932; cited by Lambert, Alexander: The Action ofthe AutonomicNervousSystemas anExplanationfortheTherapeutic Value of theCarbonicAcidBaths inDegenerative CardiacDisease, NewYork StateJ.Med. 35:146-156 (Feb. 15) 1935.31.Jolly, F.: Ueber das elektrischeVerhaltender Nervenund Muskelbei Thomsenscher Krankheit, Arch. f. Psychiat. 22:S.521,1891.ment forsomethinglike ayear and a half have not had anyill effects. Thedosagehas been decreased andthe effect moreprolonged.When Ibeganwith thesepatients they were inbad condition. It wasnecessarytogivethemprostigmine byinjectionbecausetheycouldn't eat. I soon found that theresult wouldcarryover. For instance, a dose given at 5: 30intheeveningenabledthepatienttoeatsupperandalsobreakfast and then I changed, in thosepatients,to the prostigminetablets,to be given bymouth. The results weresatisfactoryand I have an idea that perhapsthe effect of thepreparationtakenbymouth is more prolonged.I have foundprostigmineuseful in cases difficult of diagnosisbetweenmyasthenia gravisand various other disorders.I found that the failure of anyresponsetoprostigminesettledthe diagnosisinfavor of somethingelse rather than myasthenia gravis.Dr. B. LandisElliott,KansasCity,Mo. : This is a fieldinwhich there aremany difficulties,both indiagnosisandintherapy. However, therapyhas undergone rapid developmentrecently.It mightbe said that in the case ofmyotoniaandthemuscular dystrophiestherehasn't beenanytreatmentworthyof thenameuntil theserecent communications. Until Dr. Wolfpointedout thevalueofquinineinmyotoniatherewas nothingeffective. Achangehas occurredin theemphasison the lineof attack in these diseases. There aremanyfacts in the caseofmyasthenia gravisand myotonia particularly pointing to apossibleendocrine origin.There is certain experimental evidence that endocrine disturbances affect thecontractilityof themuscle andinmyxedema,forexample,it has beenpointedoutthat there is sometimes ahyperexcitabilityof muscle. Thereareagreat manyfacts which cannot be harmonized by anytheoryorhypothesisyet put forward. At present the emphasishas shiftedtothemyoneural junction.It mustn't beforgotten,however,that thechangesin muscle still demand explanation.Thediscoveryof theactionofquinineonmyotoniaisanimportant advance. It can be administered without much difficultyexceptfor occasionalidiosyncrasy,and there is some evidencethat theeffect maypersist.Dr. H. E.Himwich, Albany,N. Y. : It has beensuggestedthat the primarysite of the lesion maybe in themyoneuraljunctionor inthe muscle. It is possible that there maybe aprimarysiteinthe myoneural junctionand that the lesions inthe muscle aresecondary.Insome preliminarywork done inthelaboratoryinAlbanytheeffect ofquinineontheproductionofacetylcholine bybrain slices hasrecentlybeen studied. Itwas found that in the presenceof minute amounts ofquininethe productionof acetylcholine was diminished. This seemsto besuggestive,eventhough obtained on another tissueandnot on the myoneural junction,that the therapeuticeffect ofquinine maybeproduced by diminishingthe productionofacetylcholine.Dr.KarlRothschild,NewBrunswick,N..J.: I had thesame experiencewithprostigminethat Dr. Bassoe reports, thedrug seemingto act better when takenbymouth. Patientstakeone, twoor threetabletsdaily.Ihavefoundina womanof 68 withmyasthenia gravis,in itself an unusual case, thatshe has beendoingwell for about a year and a half with adecreasingamount ofprostigminebymouth. Shereports thatshe does considerablybetter thanwith subcutaneousinjectionswhichI hadoriginallygivenher. I shouldliketomentionacaseofamyotoniacongenitainachildaged6months,whohasdone exceptionallywell with arelatively large amount, almostthe adult dose,ofprostigmine.Dr. Alexander Wolf,New York: Dr. Kennedyand Iareawarethat therearemanyendocrinechangesinmyastheniagravisand in myotonia congenita.We know of cases ofmyotoniacongenitawithmyxedemaandhaveseenseveral casesof myastheniagraviswithexophthalmic goiter.Wefeel,however,that a greatdeal ofresponsibilityfor the symptomsliesat the motor endplate.It isinterestingto hear thatacetylcholine is diminishedin the brain on the administration ofquinine.We gave quinineafter a spinalanesthesia andmyotonus disappeared.Inthe lightof thisexperimentit is ourbelief that quinineinhibitsacetylcholineat themotor end plateor inmuscle.THEEFFECT OF DIURESIS BYMERCURIALSON THE CLINICAL COURSE OF CONGESTIVEHEART FAILURELAURENCE E.HINES,M.D.CHICAGOThecourseofcongestiveheart failureis sovariablethat statistical studies fail tocompleteapatternwhichcanguidethephysicianindeterminingthelifeexpec-tancyof an individualpatient. Dyspnea, usuallythefirstsignofcongestive failure, mayexist foryearsbeforeothersignsdevelop.Somepatientshave rapidlyincreasing dyspnea, orthopneaand visceral stasis anddie within a fewweeks or months. Thevariabilityobservedintheseextremesandtheintermediatevaria-tions canbeexplainedbyseveral factors, suchasageof thepatient,extensiveness of theetiologic agent,complicatingpathologicconditions and faithfulness ofTable 1.Comparison ofFlaxman's Series with PatientsTreatedbyMercurial DiuresisDeadSeriesFlaxman'sReceivingSeries MercurialsLivingSeriesFlaxman'sReceivingSeries MercurialsDuration ofSymptoms1 day to6 months..7 months toi year..1 to5 years.Over5 years.Per Per Per PerTotal Cent Total Cent Total Cent TotalCent136 7524 1318 102 271215814262329474837810*11 121 01000All thelivingpatients inthis series were observedlongerthan oneTable 2.Incidenceof UremiaFlaxman's series.Series treated with mercurial diureticsTotal18960DeathsfromDeaths fromuremia,Cremia Percentage312118thepatient to the advice ofhisphysician.Sincestatisticsof mineor thoseofother observerscanofferlittle aid inestimatingthe lifespanofpatientswithcongestivefailure, itis exceedingly difficult to determinetheefficacyof atherapeutic agentfor this condition.Opinionsontheproblemmust for themostpartrestonexperiencewiththoroughlystudiedpatients.The treatment of theedema ofcongestiveheartfailurebymercurial diureticshasbeenpracticedwidelyand with enthusiasminrecentyears despitethe factthat the removal of edematous fluidusuallydoes notalter theprogressivecourseof theunderlyingdisease.Bingerand Keith1 commented on thecomplicatednatureof theproblemof edema andpointedout thatthereisnoevidencetoshowthatremoval of edemahasanycurativeeffect ontheprimarydisease. Nevertheless it is well known that edematouspatientsaresymptomaticallyrelievedbydiuresis. It is also wellknownthat rest inbed, digitalisandxanthinediureticsinsomepatientsandat some timeinthe progress oftheFromtheDepartmentofMedicine, NorthwesternUniversityMedicalSchool.Read before the Section on Pharmacology and Therapeutics at theEighty-EighthAnnualSession of the American MedicalAssociation,Atlantic City, N.J., June 10,1937.1. Binger, M.W.,and Keith, N. M.:TheEffect of Diuretics inDifferent TypesofEdema, J.A. M. A. 101:2009 (Dec. 23) 1933.