[PAGE 1]
i. Durisg the course of rocent discussioss detveen representatives of this Agencyand Dr. ad the use of a reletively nev drug nred Cytorel vas elaired by vho,as you koy, is a vell-knowm psychiatrist and one of the bourd rerbers or the y Clinic ut the Uaiversity ofa Redical School end hospitals. Detzils folloy.

2. In disucssing the hanaling of ccute alcoholic cases, particularly those ho are in deleriu or even spprouching a serious physicl conditioa, Dr.s stuted that he nd his essociutes bave recontly bees testing cytorel. Dr. steted that this crug has had as ctsolutely cuzing effect on the breldng up of D's end counterccting alcoholie overinlulgence. Accoriing to Drma this aruss shen givea is heavy dosos, generally intrzvezously, vill breuk up LT's and alcoholic convlsions or wlcoholic erburrsszents often in a Eutter of a few rizutes. Ha cited exrples where the drug had boen üced sith startling effect, end Dr. aars Bu vhe vas present, stcted that ko too há begu use of the drug iu auute alcobolic cases. Both doctors stcted that this wus particularly valuuble in situtioas who ure violent ard are ballucinuting and control is necessary as soon as possible. Dr. a sussestod that this night te of core use to the Azency, sussesting thit this could be vsed cs heretofore stated. Asency reprezentutives present et this reeting imodiately asked Dr.asen if this drus vould have sn intenss sobering effect vhich night serve for operatiorl ro\_socs to vhich Dr. replied thut it sould be definitely useful in that connection cnd thct it should be eximined rost carefully.

2. Dr. s stated thit Cytozel nou coros in epparentiy capsule forn of 5 LCG but thst houvy doacges of 25 kCG vere being used. exerirentally. Eoth doctors sugsested that the arg coula bo used very effectively. ir pluced uder tho tongie or given rectlly, althouch as zentiozed previously in a clinicl uy it w..s being used intruvenously. lhen questioned es to ihether or not thore vere siãe effects, both doctors stated that there were no siãe effects thst bol boea estiblished.

3. koa çuestioned as to whether the drvg coula be useā gs s preventutive or a teelique for rintziaiag sobricty even vhea heavy drinking vas reculrod, both doctors .ere of the opinion that it vould probubly be hirhly sfficicnt long these lines.

4. Wea coked the nme of tho dnic house prolucing cytorol, Dr. belioved tht it ns Cib sd iniicted thzt be ould cuther literature en the dug .nd cond it iedicoly to lr.  of the Osice

390

Chiet, OD/S

allix i

8 Deceber 1961

Chief, Soarrity Research Statã, 03

Cytozel

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of Eecrity.

5. In viev of the ebove, it is the cpiniba of the Agency represeatatives to kcld the discussion that nedical cuthorities or tho Ageney shoula urzertike an exsinatioa of the properties of this árug vith a viev tourd its possible operutiozl uss ss outlised. It is susgested thst i2 this dris hes ouch sropertias sad ia cs eifective ea indieatad w Dr. l Deen, pornpa it coula te rde in the fomn o a "life-saver" or a throzt lozenge, shich could to carried by en Ageney represcutztive ia a rcutizo znzer cnì vhich vould not eroato undue interost if plzeei in the routh.

. 6. Ir. vil foruard anyinforation reccived on theircg eytonel to your office iroedistcly upon receipt.

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[PAGE 3]
Dear Mr. :

Enclosed is The New England Journal of Medicine, which contains the article on Intravenous Cytomol.. You nay make photostatic copies of this article and then return the magazine to me for my files, The I.V. Cytomel works beautifully on cases of acute alcoholisn. It is not available as yet for general use.

What you are more interested in is the use.of oral Cytomel. This too has brought exceedingly good results in the clearing of acute alcoholism. We generally give a .25 or 50 microgran tablet. Very shortly the person is sober.

Since Cytomel is a.thyroid drug, one should not continue on such nedication since it will depress the thyroid so much that after five days of continuous medication the thyroid gland is totally depressed. However, with one or two tablets of Cytomel the effect will be minimal.

As I pointed out to you, it may well be that an agent who has to drink to be sociable while on an important assignment could slip a tablet in his mouth after taking several drinks and should be sober within twenty to thirty ainutes. Cytonel is supposed to oxidize the alcohol. I believe that this could be an important adjunct to your work. Certainly it is worthwhile to study it further. lo doubt you will want to get some qualified specialist in internal medicino to pass his judgment upon it. Make sure, however, he is truly qualified and knows somathing about the study bofore passing a decision. I sinccrely hope this will be of help to your dopartment.

It was such a very grcat pleasure to meet with you, Mr.a and Yr.  aes and to discuss our mutual problem. Regt assured should the situation arise again, I will handlc it to the best of ny ability.

With all good wishes,

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é á d á

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[PAGE 4]
HE efeet ef the eid Lomoce, L-idiodathy ronite, in mapidy slericg up acutely intoxiared. alcohole jatients hs been rentioréd by Rawson, Koch ard Flach and ey cie of ts (NG. Sirce the pre.icus regots neire! to topies othc: thaa the mvvagéreat of éeke scsholiaa, boaever, the details concerning this taede of ueattrnt were not incluced. Our cunent experience wiih the intravezous use of a preparation of thé lerrone ia the terapy of acute alcoholisi one thai empioys an ob. jective paranmeter of changing leveis of aicokolic intoxicaton," serial bicod akohoi •deterainatens has teen most impressive. The félloting teport is intended to present, in brief, qur fndings in 12 pateau with ácute akohclsm, tieated intravenonsly with L-tri-iodothyroniné as comjzred with 8 vntreated acuitely intoxicated controis MATÉRLLS AND METÍóDS The 20 patients, 14 males and 6 funales, were selected at random fer tlis study froą the paiients admited to the Alecholc Ward of St. Vincent's Hospátal Te ages rarged from Swgät-sesen te fittyéight years. Oaing to the linited sumder of patunts with aauite aleoboism admitted to the hosital per week and availabie lor study, no attempt was made to match the centrols and treated paticats by srx, age or approximate size, The tandom proces tmpleyed to assign acutely intoxicated paticats to the coatrol or tréated grouzs consiited only of witlibrollirg er adminisrátion of the laormone on altemate weeks dus. ing, the interval of investigation. - Fortultousy, the average value of iritial blood alcobol levels for the two gröups (ell in tie sme approximate vicinity:- 338 nyg. per 100 ml. for the treated patients ard 321 mg. per J00 nil. for the controis (Fig. 1), Thrge paticat avigned to the contrel groap and l’arignéd "o the treated group wert excluded frou the pres. ent, data Lecause the initial bioed alcohol leveis obtained q chem were less than 150 iag. per 100 mal. — án arbitray level generally azcepted to indicate delinite intosication. .

The majority were krown'to have cronic alo. holsm, wih several previons admniviors to the hes. pital for excessive driaking. The solutiea for intrayerps use was prepared frem sdiom tri-lodoty

GÉRNAL OF MEDNE Try. 29, 1540
N ACUTE ALCOHOLIC INTOXICATION
y Repoπ
RR: HEnR AND MARc HURGwITz\$ sonsne powder.f Once dissolved in a solution of pH 10. and refrigeratd, it will remmain stable for approximately five to seveó days; it is stable at room. tempemvuae for ene or two days. A cae of 200 mécroga yes schrcnd for ali treued fatieets in thés study, Spécisvns fer bhad alrohol level were drawy before zad at interak of tao, four zad cight bours afier adirinitration; tpecimens were drawa from the controls át the sune interyals. The metlvad deseribéd
by Leifhci' was utilized in u:e chemical determinatien ef bjood alcohel concentration, and all speciinens
were run ia daplicáte.

In addition to the'decline in Llood"alcoho!, Ja folioving clinical eriteria were employed to ases chargé toward sobriety: ability to give a rational kistory in patients initially in a stuporous state; ahiity to walk a straight line; ability to hold arns and fiagers outretched without a noticeable uremor; and disappearunce of tle odor of aleohol from the breath (as esti:nated by several observers).

RESUITS

As shosn in Tables 1 znd 2, the muean rate of tabolim of akohol — as exprersed in tcrms of the decline in bleed alcohol in mitligramns per t00 aL per iour (Widmark's beta) — was 521 mg. ia the treate3 pitieàs, as compared with 15.0' ing. in the contre's. The decine was twice as rapid in dhe forarer. Te fál in bäed alcohol had particular theropeutie vale in patiens auch as Al. and R.H, whose iritial

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alcohol a ct alehcl and iscrceent ued 12
the trcated patiénts A stati,dical anahsis of tese dara, enploying the
Fishet."t test" for unpaied éata showed the nseks
for the effect of the hormone on drdline of bioxi
alcolof , be highiy sizeifcant (t 6.6; p<0.001). As jo cimcar srat icaporit, of patcats
weré consi lered to be. relativeiy sober, whthin two
hours of the intravepoes jajecãoa of tri-iodothyrenine
by the critcria previously mentioned. The disappear
ance of the akobolie, odor fmm the breath within
this two-hour peried was particularly striking and uni
fommly observed In cemprison, anong the cortros,
an alccholie edor persisted on the breath for six to
ten hourx: The ability to obtain a. rational meticai lústory
within one or, two hours in patients who have con
sumed large quantities of alzobolic teverages and tre
admitt-d to the hespical in à stuporous or semicona
tose state is probably the greatest practical advantage
of this method of therapy. The following case histery ii illuétative: Ejrcttof Tii-iodsthyoine on Rate of Blood Al TABLE cohol Drclins i. 12 Trested Pesienis. R1 0 B1 LOOHOL Deais arna 1x HENT TZAT TAI VLN mesic) 3.4 165 10 31.0 33 29 0 31.2 no it 57.3 251.5 310 140.5 237 435 504 2i1 1t9 313 295 233 15 25.6 0.c 100 25 14 24.4 310 101 5:5 AW. 3 3 125 11.6 20 153 74 3.0 A.W. 323 2.OL 1X3 :0 12 3.2 526 15! 82.5 31:05 A S.D.

éainl to the bssra cn éet tr>:cht in i5 CAALLC d::or

je r1.
pot sv wlether pr mt the pateat rad been hit àr a car or
had tained auy tead injurirs. The siel sigrs were al
aoud vits de rsror of a tud prsere ei nrto. Oa aràaf en te Aicehair Ward. boad war drawn fer
Saine akehs ai ather Nerl cea fadaa, and 200
Wités I kour de putiert wa abe to st up in bed and wes
fully orrnted. He was tizn ahe to give a lucid kisery,
wat cacned d iupreson ef alccbote intosdcation and Tuite Data in U’atrcated Cortal Patienti Mcvsot ARO
R R 220
F.T. 32
R.X x 245
1C 25 227 1i 13.9
c.t. 4.9 H; 203
AML 0 205 1B3
J1 130 13.4
T.1I. 33: 24 11.2 AveazO 321 27 ZH 150 21

wa negstre for, trauisa. He zlo meatioced thai he was byperenive and usuaily ran a s,stolic bicnd preure of 2ã0. Withis dv ninses oi tat iatravcnozs mnecron de vas abie to wal a sraight Liae and to hald eut his hands without obvious tretsor. Fout orervess could no tonzer detert the oder uf zkolol on the breatl. He subsquently stept ia short napa uatil apprétimatly E bears afer adaisin w the ward,when he craini of being saky and treraou. The bloct aioel had ttes fales fruma an initia! vaiue of 378 to 125 mz. per ld 2l. He wa ten àrn 1ü0 to. of promaice ianrs ulady, wkich akviatd te smptoaa. The rraieer o de ber hoia sas poeed ae eventdiy.,

An adiairable review by Harger and Hulpieu" of numerous studies coacerniog ths natuaal rate of decine of blcod alcohel levels in both acutely intoxicated huuan being and laberatery aaimais has shown flunt the zverare value for Widmarà's beta is 15 mg. per 100 wl. pet hoor, vàth a rangeof 12 to 23 mg. These authors furtes stus that, to their knowlelge, no drug that is without han to the body and can sigaifcarth increase the diappearasce rate of akeohoi frors the blod lar 2s yet leen foutd - inehading such prct day tsapautit meanes as glucose-insutin infusions ard vorsus vitamnins for pareutzral adainiaation. Áèlevgi the pn sat data are deried fcom a läritd ramier of cases, they deaoustrate a fairiy coasistert in reasz in the rate of alechol mctabsarto écabie de ceaaol eahes in peteuts teccie in tr odyrráce inraverorsdy, as nel as à proup: tengp eet, wtich can te observed

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[PAGE 6]
ceah va tiy ia progaess. xé-dadohyronine Hazaally le -2sarselves showy ta te rife t err can nsiy te
given to tbe cooprase aetoic patient The ex
patirce ef Catz and ete ihorai adninisraion
has beca diappcintieg, asd in view of ibe unpre
dictable rare of ahsupton. tis route is pot recomit i t be enrhasred that our puesent fn lings in.
dicae dha: intaveses or sublicgeal adrinistration
of tiiodathyrocine is merely a useful adjunet to the
prerenly a ailible methods of treatment of ácute al
cokoliza, such as parentera! infusion of fuids,, vita
mins and tranquilizers, and not a means unto itseif.
We believe, bowever, that it has a unitque eftectiveness
in the rot usconnien siluation in which a contatose:
or semècomatese patieat with a strong odor of alcohol
dn the breath is taken to the hospital by ambulaner
or polce ricort and is usable to give a ciear medical
history. Since several hours usuaiy elupßse before the
attending physician cari detennine whetler or not the
condition is due to alcobolium alyne, coaplicaned
by serious' medical, surgical er néurotáge catasuophe.
an cffrctive meass by which one car rapidly sober up
such a patient suheietty to obtain a fitst-perso his
tory of cvents is highiy desirablee In contrast, the ad
ministration of sedativs or trarqnilizers does nething
to eccekeçate the sobering-ap puotesses, and may actu
àlly hinder them.: : Auong the 12 patients gien 200 mieregm. of ui
kdothyionine intravercusly and followed closely for any chiange in vitat signs or untoward responses. no side reactiors or evidence of toxitity has been ubserved. Freedem from any uatoward reactions has Bikewise been scen in an additional 10 patienus givca the hornone intravenóisly, in 18 patieps given 100 te 200 merogm. sublinguaily and in sęveral dog esperincents Considering that 200 ticagga of the hontune is the equivalent of approxisately e.1 to 0.5 gi. (6 to 8 gz) of desiccated tyroid and that an exoss ef circulating dyieid hornunes is known to hive a detrimiental Lafueace on cardiae function, bath by a direct texic efitet on the myceardium and by ¿oterctiating the astoa of the catechoi emines, we exetcised great caution in attempting to exclude any patien: wità. knowa corcrary-artery deeaee fom the Les: d grap. Adenal inuflicieney is Bewise a ueond corutaindication to thyroid-hoaaone therapy. A poniMe exeeptien, «bich nay be censideied a skie teaction to Leapy, bas lun the olservance of modérste uorriposnis and armes in 1 patient ss :-

ate od rapi akoizł witdrava rater tha tote adntinitered taroid hormse. hì the ftue an atirmpt to veriy this héjotèess uil be male by inzravenrss iajeetion of aleokad at' tbe tice such ymptn a rmuloase and nerisness eccar.

Oue látent withactie delriuan treaas marilested by auditory andvisual baßlucinatiors was Hewise teated with tci-iodothytaine iataeaously. Sinee the blced aicehol on atinission was reported to be 25 ug. per 100 ml. the eiéttof uhe duç on the rate at which alohoł was metabolized couid pot be deterniied. The laliacisatiens disapieared, however, véthin one hoor of the iajection, and did not ....
Finalls, one can only spécuiate aboat the precise site of action of the hormorie in actelerathug the napual pathways of alohol metabolisn. Considericg that ruuíerous stadies by Hetzel, Charnock and Geod?. and others have been unabie to detect a signifciu efect ef intravenousiy administered tri-ialothyronine on tisvie metaholisn earler than cight hours aiter injeution, it scems probable duat the acceleration uf al-¿ohol mnetabolism is not depratlent in ful on a general eahancernen, of body metatolim but more puebabiy is a direet etect on the bepatie eneyme systrtia that convert alcohol to aetadehyde. This, of curse, temains to le pgved. In faeí, studies ly Wola and Woal have demonstrated an inbibiting aaino of thyroid hormones on yeast akohol deiydrogunase in vivo, so that (if the theory outiined aboave is correct) other pathways of alcolol ¿ctoxification, such as the catalase reaction, meay be invehved.

SUMARY AND CONUMIOÑS

An investigatien of the ue of thyroid kocnare L-tri-iodothyronine in tia utaagtanent of acute alca-. holism has shown this agent to have a prenpt sohering-up action when given intravenoaly ào a tutf dosage of 200 mitrožm. Anong 12 putients who recvived this treatment and were counpared with 8 un; urated, acutely intxicated coatrois. the following tesults were citained: the rate of blood alcohei tirclire averaged 15.0 mg. per 100 ml. per hoar in the controls and 32.1 mg. per 10ò mal. per Loer in, the reated patients: patients given the honnane were jidged to he clinically sober and able to give a rational mmedi-at histery within two hours after ;he iajeetou; the odor ef alcohol was undetertable on ths breath two houts after treatnent, ahhough it pssisted lor sit to ten hocr ia dhe untreated contioh. Intrenous terapy appears to be a valuable aijunt in te ucatasnk of acute aleohelsan, particulary when cì a katent is admited to the hopita! in a sugetrs or saicontese sae seordry t sesse ivie tiee ad i aastke to cive a codernt maié

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about de vate of incravescis iajectioa o maragencat of acute hase shoén a lai in bed skeolel turves and hoaxd that áia cur REÉRENC25 F, 2d h, F. y. Tüd Mra MYCOTIC ENDOCARDITIS FOLLOW Report of PoNć Hs Hvs, MD., D.Se-(M PHLV särgery, has seldon been obeived.a Bacterial endocardiás çomplicating ecovery frein sudl eperations, however, is not uncammon, is. usually disclesd by blaod eulture and is often resensive to appiopriate antinictobial therapy. No disutinction between mycotic, and bactrrial endecardidides can be siads on cliaical grounds. Therefore, investigatioa ef postoperative fever calls fer procedures that wiil identily fungì as well as bixeteria It weulkd seem that mycouie endocarditis is inereas. ing.na If te, dás voild not be surpriting, considering te ubiquíty of funži and the rapidiy espandizg fell ef cardiac surgery. Withia a nice-montt pxriod, ‡ cues ef endecarditis due to Candida albicai were obered in twe of the hogitals associated with the Uriversity of Peanglvania Schoel ef Medicine, and théy.' ate summarized in this comnunication. The first case las beęn reported in detail elsewhere,' but, beczuse of the ratity of reports of this condition, it is izciuded in brief aleng with the other 3 reported for the frst time

Cae 1. A 10ad a (P.H.P. 101) was ad mited to te Prveran Hapaal in Pridendin, viere Cr  soss of rural iocieaty was estallshd. Co um feana sature of te cival nng was perforned 7 day Lairr, vea iariceat No auiories bad bea ghen pe ed.d..

D.

Lesit, C Cn drtraea  et zeol1 ed U. 5. de {a M. 1. 73A, 16
Ko, S, and Hue ià. è Teresad kcd abael rieerrara .  , ::
wC. Se a  tte el d Be,  S, ai lee R. R. Hacnr e a'nde. I H .P2z:
C.ta a
Ce b5. . l'eprd ea.
Hed, s S. Chanve, 1 s. ad Gd, 5. P. Capirien d a p 1. (Fa, Ev N d, E

On the 12tà pestoperatise day fever and dhsiß, devrlezsed, and the bioed rultanr wau pestive kr Srth.ccccut aateur, Pesirilia thorapy was inskated. When the aral toute was sáuittd fr dhe parentera route of prririln aduinisrasion at the end of 8 wreis fever prvaptly reurred, and Mod calnrs were aeain peitive fer Stazh. aaroa. Derpite trsenpten of pascrterat aúminstration the prticrt's cealida detrriorued; it irprard smmewlet on ACTH. souisoue and desoxytortiosterone acetaze., Aeaia, suhstitutioa of she er f the prstrl rte oí ponirillis zscinsatcs teood in prots reaprrarace o Sseth. aure in the èical strean, and the paticnt ded l0 dayt alter operztion.

Aútopry, revealed thrucbotc material contaiaing doth C. albizans and Stàph. surezt adhecnt to the circunirreuial sutire, the posterier half of whicht was lying free in the teft atticvatricular ravity. 1

Casz 2.A 37-year-old n (11.U.P. C81220) was al. réted t the Hsptal of dhe Üaisersty of Penpahania síterias loan acrtc steresis. After direa catietericatics of dhe lett side el the heart hesrqericarciurı dev-šped. Six. tren days later the ticut clerwznt aortic vakzidoy hv finger fractare. Preogerativrhy;, he hul beeu given peuicillia and sirepotytin for 2 weeks.

The iamediste poseperative course was marked by fevte, ihe :emperatnre ranging foea 90 to Juz°f. Replacenent of besiclle and streptoaydio bz tetrarerlte was accompanind by trore sąvere pyrexi, and the orisinal regimen was tee tded, with the additios nf hlarsepherdeol. Meiéple bieed vaturei weie trgatie vetil the 3e postererativa day, when hood and iEge-arzow eultues wete positive for C. 'bizese. Mavive antliote tarope. ntlizing suphorericin B, peniolin, buitracin atd asstatn, was thes itnitnted. live days afer the tu pospke Lkas eulture. Oders redes and cocjttival ptechise deelopvd. Nesiatin aud actidione wre giszn intravezonsiy to ihe patient, who diad 33 da aor de ts pritive blod cakare aad 2 math afier ie erration.

T scrificant aatopsy fadinz i.ctuded eacae hozer. mr. pariity e ited tvàef de aorte valse, vich wcrd by lasuhdn vegzarioas, aud afuudy te vzen t rpit se ad Valoia ase the rsat atrinn (ie. 1. Meeetie esbaì brrt ptesta in the rgh iiae artery, thr til aed ths spneazal pulzopay artery to the lelt ucerièr.

21.33  P. 01 Sud t the fgiti a Pe Ceharity of Pearsbania

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