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Les diagrammes suivants illustrent la mdthode. 1 2 3 1 2 3 4 5 6 MICROCOPY RESOtUIION TEST CH4RI ANSI u..d ISO TEST CHART N> ; 1.0 I.I mil i.8 1.25 '•4 111.6 ^ -APPLIED \f\MC^ f t On the Toxicity of Various Commercial Preparations of Emetin Hydrochlorid iv I. 1. 1' \ ^■, Ml). AMI I. I .. i\ < > w \ T k r I.. M.I). i'. M ri Ml iif hilcniol Mcluinc Aviiilc «v MimcAl. As-niUTinv lui llrM,,!,, ,,,n Thiiitv livp NcinTii IlrMiFniiv Smre 19lfi ox nil. TOXICnv OF \AR10US COMMERCIAL I'K'I-.I'ARATIOXS OF FMKTIX HVDROCHLORID* R. I,. IVXY. Mn. ANn I.. (;, nAi.riMORE ROWKTRFF. M.n In VK'w „i thr wido^.irca,! n^c of oiiictin hydrodilnrid in the treat- "iint ,,1 anid.i. .h^cntrry and of pyorrlica alvi'olaris, more precise knowledge .,1 tlie toxicity of the coiuniercial preparations emjiloved i. higlily desirable. The following case reports forcibly emphasize this tact: Case F-I. R (Me.l. Xo. ,1^209). wliito, n,alo, aso.l % a native of Balmnore wa^ a-lnnUc.l to ,l,e surgical service Oct. u'vm. co^p ^n ^ o an uFcat.-u r.ctutn." I-,ttcen y.-ars previously lie !,a,I !,a,i a cha.u-re follow^, by a seconon note over the maiuihriun.. The svstolic pressure vsas ISO nun Hg; d,a.stohc 7(1 The urine was negative. The hlood shoved red hood curpusces, ../.>,VRH1; white blood corpuscles, 7,350; hemoglobin (Sahli) 92 per -nt. I h. .htterentia! count was norn.al. The Wasser.nann react.un was o unc. .\ctnely motile amehas were found m the stooi. an,l October 2u the a;:r :^,:t"'' " """ '"^""' ^'"^^^ '-'' ^ '-''-'- °^ '-- -^ At this time the stools containe.l a few pus cells and a little nuicus but repeated examinations revealed no amebas, Sigmoidoseopic .xamination showed no ulceration or blecduig points; 10 cm. from the anus there were two smal ;cars. probably of healed .ros,ons. There was a coUM.Ierable number of small internal hemorrhoids. sni.ui During the first three weeks of his stay in the hospital the patient was iiaving only one or two stools -laily. r'n-ember S. however .liarrheaev loped '... the bueenlb he had eh. e„ bowel movements. Xo amel>as were foumi ' Inutmct and Ceur^c.-Noveniber 17, subcutaneous injections of emetin hsdrcJlor.d were begun. Tliree times a day. from the seventeemh t o , e weny-l,„h, mclus.ve. the patient received 'L. grain; on the twentv- xt?a d .weny-seve,,,b_ ■. gram ; and from Xovemhor 28 to December 5. .^Khts?^ ./.i? r 'V" '"'" '«-«""""« the emctiii treatment the number of stools lH'""U' h-~. Ihe Mnpr,.vement. however, was onlv tempo.arv am on November 26 there were nuie, and December 3, eigh-een stools in he twenty- ou hours. It ,s nou worthy tba, Decnnb.r 10. !»,. days allcr .1,,. em,„„ w fs ,1 " continued, the diarrlira iierm.-.nently ceased. *I-rom the .Medical Clinic ..| ibr \u\m. Hopkins ll,,s.,iid 'Fight of tlie icn original tracings accompanying this' article were lost by the engravers the records appearing in Figures 1. J. .1 4 5 .,„^ q .,_... been suppbe.l by ,he authors in this . mergency. Thev do no! niusiralc the various points brought out in the paper as satisfaclorilv as di,l the oriijinils inasmuch as they represent tracings which had prcviouslv been discarded ' I )(C(MilH'r 4. a irarc of aliiiiiiiin .iml a Irw uraniiUir ra-i^ n|iprari'il in tlio uriiu . I la^trir aii.i1.\-i^ sliouiil ^liylit siiliac'iilil> IJecomlier 8, tlie phthalcin cxcretinii was IX ]irr cent, in Iwo hours. Twn ilay.s later, the nnnpnitein nitrii).:en nf the I)1iiiiil \va~ \\2 niu. I'l r lIKI c e. ; thr urea nitrogen, ''_' mj ^ill.inlx' list' n\raKi| ilu- r\i^linre ni a liieh ijr.iile acidosis. The anioitnt of all'iniun hi ihe urnie gradually increased, and December 11. (lour days hctore dyspneic and ciiinplanu'd oi n.uisea and pain ni ilu- unihilical region, i )ii the foiirti'cnth, the pid-e was weak and rapid, tlic hreathing was of the Chcyno- .siokrs \,iriet\ and co.ir-; talcs u , re heard throughout the chest, Mu li nk"- cMis had ri-iii to 14,oO(l. Ihe s\,t,,li.- Idi">d ]ir('ssnri'. whicli hcfon had r.uiL;i d from ISO to lyo mm. Hg, had fallen to 95. l)(ceinher 1,^. alter a periled of niaikeil dvspnea. the patient coll.ipsid and died. The lipase content ii!iLiil Ijhi'luosis. — S>phi1ilic aortitis; chronic aortic emlocirdiiis ; dila- tation of the heart; chrotuc p.is-ive coiigestioi: of the \iscera; arteriosclerosis; chronic indurative colitis; lnal' d tuberculosis of ilie lung .nid hilic glands; hroncliopiieumonia. .Ibslract of Xolcs.—Liiii() iiie;.i,- or 1.,^ nig. per ki; hi l>il,>. In re.cne.l 2" ur;iii,s i 1 74 i^m i. or 2.=^ iiiR, per kc;. .\ iireviotisK cNisliiij,' ili.irrlK;i \\.is at first ;ipp:treiillv sniiic\vli;it imic'liorated. tluii iii;irl.elir liad liad since cbildliood. presented all tlic essential features of mii;raiiie. I'lKiiknlatidn nf tlic arms after exposure to the sun. and occasional attacks of diarrlua fidlouinir in.iiscreti<.ins in diet, had sug- gested to her physician the possihiljiy of iirllaura. I.nt id evidence was found in support of this diagno.^is. Exiimiiialion.—ihi e.xaminalion. she wa- -nn to he a thin, pale woman with well-marked pyorrhea alveolaris and uinKivitis. The hlooi. showed a profound secondary anemia. Kepcateil examinations of tiie stools revealed no ova or parasites, even after the administration of VL-rmifue'es. The gastric analysis was normal. .\ faini trace of alhmnin ncjted in tlie urine on the I'irst examination soon disap])eare(l. Xo casts were o1>serveil. 'Ircalnicnt nil J Coins,-.- .\{ the suggestion of the dental department. U' grain of emetin hydrochloric! was administered subcutaneously each day for four ilays. beginning April 2. .Npril .i tlie patient had a slight chill, followed by an elevation of tem|)eratnrc to 101. April 4 a distressing diarrhea began; there were ten bowel movements during the night. She complained of aching all over, (if pain in the back and abdomen, and of tenesmus. The stools at this time coiuained large nmnbers of leukocytes and a few red blood cell;.. N'o amcbas were found. The leukocytes rose to 13,800. During the following six days there were from li\c ifi ten stools in the twenty-four hours, all containing pn- and blond, .\jiiil ''. alliumin rcajipeared in the urine. April 11, six days aftir discontinuing tlie iiiuiin. the diarrhea promptly stopped, and did not recur during her ~tay in iln hns|,ii,d. The alhuminuria also disappeared. Stoid luhnri-, pilvic and proioseopic examinations were negative. Following the on.it of the iharrlie.i. a toxic delirious state developed, witli great mental confusion and vi-ual .and auditorx hallucinalii.'ns. necessitating the transfer of the patient i.i ihi I'hipp- I'-Ncluatric I linic. In the course of a week the |i-ychosis cband up. and -he was discliargeil mentally and physically nuich improved. A htur frnni her lui-hand rccei\cil July l.s -t.ite- tli.at 'Mie is in better shape than she has been for iwihe ycar> ; -he weighs 11(1' . punnds — more than she has i\ir uiigheil in bei life.'' .\ siciind Utiir wa- rietixid. (iriohcr I. s.i\in,g that s,i\c fur an occasional attack of migraine, and a fieling of weakness on exertion, the patient was doing wall. Si'.MM.sm .\m anemic, mideniouri-heil woman, weighiiifj 95 |i(innd-- (4,1.2 1%^;. I. received >u!iculaneoit>ly '^ <,Main nf emetin liydro- clilorid ilaily for foitr d.iys. .\ii intense' diarrhea developed, associated with .■ilidniiiinal p.iin ainl tenesmti>. which ceased six days after di-C(intinui:)L; the eiiu'iin treatment. .\t the same time she was in ;i toxic deliriou.s st.itt, which lasieo tor one week. She recovered rapi(ll\ and left the ho-pil;il much improved. 'i'lie daily (lo>c of cmclin was '- grain ( .iO iiij^.) or 0.7 w^. \>cr kg. Two grains i 120 nig.) were given in toto, or 277 mg. per kg. The symptoms iiere following emetin administration wer^ quite out of proportion to tb.e moderate dosage employed, and the jiarticular preparation was sus])erted of l.eing unusually toxii'. At rordinglv, a dog weighing 10.5 kg. was given 10 mg. suln-ut;;neously daily for three day.s. On the third day a bloody diarrhea set in and the animal died on the same day. .\t necropsy, an e.Mensive hemorrhagic gastro- enteritis was found. This dog received daily 1.0 mg. per kg., or, in toto, 3 mg. per kg. -appnjxin.ately the same relative dosage as had been given to the i>atient. Il will be seen from the experimental observa- tions which follow that this |]articular preparation of emetin was decidedlv more toxic than usual i:x:>i;h!i.Mi,MS (i.\ .\xi.\i.\i.s Studies were made on sixty-two .-iiiinials. the serii's conipri-ing dogs, eats and rabbits. I'ive commercial preparations of emetin liydro- chlorid were investigated: llurroughs Wellcome & Co., ( ami)Oules') ; ICli Lilly & Co., lam|ioules); .Merck iV Co., (crystals); I'arke, Davis & Co., (ampoules), and Sharp ^: Dohme, (hypodermic tablets). Injections were made in part subcutancously, in jtart intravenously. 'I'he points particularly observed were: (1) toxicity; (2) elTects on tile circulation and respiration; (,^) pathological changes; (4) effect on the coagulation of the blood; (5) effect on renal function and the development of acidosis. 1. Toxicity. A Siihiiilaiu-iius Iiij,\ti,iiis.-~-{^ijc 'Yd\>\c I). Dogs receiving single small injections of 10 mg. ( 1 to 2 mg. per kg.) show- no appreciable reaction. Rejieatcd daily injections of 10 mg. cause death (usually witii gastro-enteritis ) in from three to lifteen days (average, seven to ten d:iys). I'.ither tliere is an actual cumulative action of the drug or an altered tissue response on the part of the animals. Larger ^ingle subcutaneous injections of ,iO to 45 mg. (3 to 5 mg. per kg.) cause death in from two to tive days. The same gastro- intestinal lesions :iri' found at nccropsv. Cats tolerate larger dose-. D,iily injections of from 2 to 5 mg. j)er kg. kill the animals in from seven to eleven d.iys .\s a rule, the anatomical lesions present are exceedingly slight. The results in kittens arc essentially simil.ir to those in adult cats. In rabbits, daily doses ot 5 mg. (3 to 4 mg. per kg.) are unifon Iv fatal in from (i\e to six il.iys. .\s in c;its, necropsy usu;illy reveals but slight an:ilomical changes. • >.^ •= C3 ^ 2 n = =3 i £ '■ — ~ -« a j ^ ;;= . .t: - ; 5 a ~ V r:jr.J3 -r^ a - = ?i :: 7: - < - = {; i * . as 3 !5 S « IS §3 e?; s: i=a i-i §3 ■51 ill III 11^ HI K^ a 23 S. 1^ > W ■ *rf a n 35^ 01 ■» '^ " ^ e^ " ei s 3 1 'illirnu't'- 111 llic imu- iKTc--,ir\ tn kill .ivr ili|iriiilriit in mirl mi \ai"iatiiiii- in iip\iiii\ n\ llic iiri'iMiatioii^ n-ci!, ami in part, |n."iiia]i-, (jii varying; ilrmTc^ ni ir--i-laiuc In iiilnNu alimi ni iii(li\ iihial animals. \\liair\ir tin' '.niM, tlu'-r \aiiaiiiiiiN ,iic iNtrinir. In dugs, lor ni>tanrc. ,a lul.il >iii-aL;r m ,i ni;^. pir ki,', uf llu nm^i tuxii" ]irr[iar;it'. ni iL^i\c!f ^ulu-uIaiu'iir,-!\- killid witliiii tlnw ■la\-, wliirra^, 1'' nii;. ]n-v kg'. 1)1 aiiuilur . I iinnirfiiai pri. |i,;i;iti(pn i\i|nit\il cK-Mii il:i\-. In rat-, 14 nijj;, ]n'i' i^^^ ilnt.al ild-ai^r i iif iPiic ]irr|i;irali(in ('au-rd ikatli in three 'la\-. w k.i'ri',1-. J'l iiil;, per k^;- ni .aiKptlu-r killfij unK .al'lri' M'\cn davs. l-'iir ininifdi.itv death l"i plk p\\ iiii;" inlra\a'ni pn> ailniini-,r,itiijn, t int;. jior ki;, in OIK' iii^lanoo, and IS hil;. per kt;. in annther, were iicces^arv. I he >Miiplipin-. ppI iiilci\iealiiin ,i- a rnk' ni,iml'e-t tlieinselves two or .liree d,i\^ Ipelnre de.ilh There i^ ixtreine imi-enlar weaknes- and I)roiloniKeil U lli.iii,;\ , I lie aniniaU lie mi their -ide-- in the e,nv^.^ ;|,](J ;irc roii--iMl w nh pJilVieulty Mdre than half pif the pI -^ .hipI eat- \(iniit ; iiiaii} have iniiiieiiiu- thin, tin I'm iiupI -tmil- Sumi' ipf the dtp-- -iitle.' ironi., hi 1\ ili.irrhe.i : ,i lew have l.iri,;e iieninrrhaye- frppni llu' Imwcl un the da\ oi' death. .Mu^eiilar treiiMr- ue. ur oeea-ioiially in dogs aiii' raliliils. Urooliiiy Iroin tlie iiKPiith i- unminn, e~]peeia11y in e.'its. 11. Iiilnimioiis Injections. — (See lahle 2i. llu Ktlial d() l.irgelv plepeiuleiit on atliotint, dilution and ra]iidily ni iiiieetupii In e.Nceiitional instances, dug- may temporarily survive -ingle injeelioii> of from .?.5 ;o 1^ nig. per kg. lull death gcner,ill\ ipienr< within two da\>. X'edder' has fotiiiil tli.it "2r nig pir kg iiitravenou?l\ i- the ininimtim fat.al (lose iipi- r.ihhii-, while mih- r.ilihil plied as the re-iilt of J() mg. pel kg aplmiiii-tered -iiheni.niep m-h . I he rahhit- tn wliieh tiie drug wa-- given intravencm-lv iIupI m i irw -eepnipl-. .ipp.ireutlv ,is the result of centric ]iaralysi-. 10 mg, per kg, -iiheiitanei)iisl\ on two suc- cessive days is a nnil"orml\ fat.il dose for white rats." 2. Effects Oh III,- (iicuhitioH ,ittd Rrsl^imtion. — Kvmograpliic leeorcls were made w illi the animals uinier etiier ;mcsthcsia ,ind electro- cardiograms were taken on chloretoned dogs. The >iilicutaiieoiis injection ni .a relatively Large dose (4(J mg.) in .1 dipg weighing 10.2 kg. e.iiiseil mi ,ippreciahle fall in lilood jiressurc within fifteen minutes; ai the eml of h.ill an liinn the pressure had droppcil iiPiii! l.-'i nun In l(ier,d KPiidiinpii Single sm.dler Mihcutaneous doses of 10 mg I 1 111 2 mg per kg i have no i)erce|)iilp|e elfects. 3. Vedtler. K. B.- Jour. .\iii Mc.l .\smi , lOM, Ixii, .Sni. ^z: r - £ I a ^ c — S3 a St* >-')^ "^ Si 9; ?s C- .J -3 ii Ss 3< Hut ill ^ y a -< 5! til # if. t^ % c •y. z > c t- u (T. .£ £ o «j O ij J 0^ Ul « 3 tr O u -li 3 C C tA. l- Ji o c u „ ; ^ ^ — ■" <"! *" o tc "ZZ •^ c n o j: c? c Of *■ U ■u. E ft A A L. O' T — ■ » bf Ul ^ ul u y. • III ^louly |.uiMMU,l .n,iiii,,I., ^uhurN (,| uiaMud -mall dailv -u!,- au;nuuu. injtvl.nn- , 1 tn _' „,. ,,,,- k^,, ,, (Iktc i> a nurke.l 'lail in Iiiv.-,-urL' renin, Imt uilli ilu- a|i|aaraiu-c of tuxi.- ,-vniptcmiv lii uuv ainnial ,.i 5,5 !<-. wliidi nvruo! -rvrn JaiK injoiions of 10 iiit,'. cadi tlictv ua- a .lilhrnuv ,,i K^i „ini. luiuccii th. oricnnal nifasureincnt ■""' '''•" '•''^'" "" tli> '!■'> "I ■Ic'atli Tin. ,,„].,■ in tlir sick animal, i, rapid and Miiall llir I'lfcci ni nilrax.nnn- mjcrtums depends ,,n several factors- 111 the ,|ua^tlI^ mjolcd. iJi it> dilution; (3) ihr rate ,,r injection. and n. a lessor extent , 4 i liie preparation cmploved ; and i 5 I the indi- \idiial -u-ceptih:liiv of ihc animal. Tiic lii-M .1 ihe-e 1- ,.l,\i,,ilv Relatively Miiali ani.-nnl- , S n, 4 ni- per k.c. I i;uen in Miiall \ulume (5 to 10 c.c. ) an.! rapidh injected cause an ahnipt tail in hi 1 pre-^ure and death in a few minute, heart and re-pnatH.n. -n.ppni- -viKh,nn.,udy ( Fi^s J and ,^ ) Ihe lethal effect is due niamlx lu the loxir action of the druu on the heart »ui-. le prnper. cauM,,.,. an a,uie cardiac dilata!,,,,, \\ hdhcr there is at the same time a va-omotor paralois is not dear. The venous conscst.on of the ahdmninal orijan^ snK5^est> thai ,hi. element nnv i'ia\ a rule. On the other lund, uhen ihc eilietin iv udl ddulcd .an. I dnnlx a.lnnniMcn d. -nnicnd,.,,- do.e, mav he udl i,on,e, ( )ne dot; n-eidm.;' in ku' r.,.ucd 1-L' in^ ,n 200 c.c. of salt sohitim, dnrimr a thirlv'^ "•"Uite penod. !)c,„I, fullovved n fmal rapid cncemr.,...! injection (40 m- m 10 cc c Ihi. .anim.d received in all 1X.S2 m^, per k-,-an mm-u.illy Iar;,'e .iiihaini I ke \ariou- ■ a.mmercial preparations, as udl a- diliVrent Ids from th. -.me iMin. \ar\ sMineuhat in toxicitv ( Tahles 1 and 2. and Ca-e 'l Haermai.n and iienuniaiin' have made a -imiiar ol.ser'vafion ]t"is e = 1 E £ \A # • Ipl ■P V i » I 1=1 11 2 = 5 ■? - u S I • H H I - 2 ^ P ^1 a o t E ^ n o — u — ^ 1=1 ^ I ■ -^ .2 -■^ I a! " M :- ■/: 3 — -^ ? I- V M -a m In M,mr ,.1 the anunaU ;. r, n.arkaMc ranliac arrl,Ml,;,„a ,^ ,,l,.crvol Iherc 1- a ~n,l,!.,n irauMii..,! in,„, t|„. nnrnial kMnuyiapliio tr ui,,. „, one show,,,;, u„k, ,n,.„i,, ,,,,,,,. , |,,^^ , ^,„;| ,,, ^_^ ,i,,„,„^-al! .n Woo.l i,rc..u,v and .l.ath fr,.,„ aau,- ,ar,lia>- ,l,lalat,n„ n,av t„ll„u tins .m•gula^t^, or the- ,u.,n,al iraonn. at a I„^^1kt K^d.mav 1,. ^•>..„,c,l ,].,^. 5 an,l r,,. l;k..„-,„ard,o«ra|.hK- .!udu.> i.avc .liown ll.at ,ln. ,nv,ulari,> w diu- t., a coar>. (>,,. .„ vau.icular lil.nllati,,,, ^ tiilic one Imia- prior t. k.iJ. K.cinul .'.,-5 will- .Idoicioiie l.y slomacli tran.,t,o„ t„ cnars.- ,>,,<. „f vu.tricular r,l.r,llation. ' '^""^"•■"' ?ho\V5 In ordrr tliat thr nuvhaniMii ni cardiac dcall, niidn la ul^crvcl n.cd,an tl.oracoton.y ua. done „, an ani.nal ,ovi.i„. intratracheal ^emndc-^ The annclc. ,l,cn cca-cd t„ cn.ract. hcconiin.c ensorgcd o n I ;■'■' "^"'"' "■'^^■"^^■■■^ spontaiuously „<,r can it be cftorc t" .< no nnal luncon l,y any nictbo,! i„ general use for the treat.nent of -, li ' climcal .Kajh . Ko,,inson, <;. CM ^ l'^;;^. '^:;,^i ',^[ ~'-'v ^"- in C'eSSes""' ^'-^Crac^ Aro.Iern Me.licine. ic. 106) siates : ••Fibrillation tru Mitncle^ . . . ,s sinnlar m tlie condition of fibrillation in tbe aur,.-c.: wben ,t conu.. coordinate svMole in the ventricle is '"•• '"''-y- "'■ -'•'* ''^^ °''^"^''' "' •■' ^^■°'"^'"- recovery from fihrdlatinn of the ventricles which lasted for two second, at tl- e-ulV/nn aUa.K of parowsnial tachycardia. 16 ^'";' ''''^"-l-. Ill- ^■-••■.^1.^...nn,„uM t„nl,r,l!aic i,.ra Inn.. : imallv ""':."'^ ';:•" \;"""'^ "-■ "k-.Ih.x of th. luan >-onti,uK-,l in th^ asl„„n, HLnllan .,.mrar.i,,„s ,,,,-siMc.l tor hvc „r ivn ,>,inuic. after he h.ari iKul >aa.ol Lcatint,. h, several inMan.v.. ..p.ciallv in cat- 1.C heart 01 the animal. st,„l,e,l i,„„u .Iku.Iv after .kalh, onuinite.l to .ibr.llato tor as lo„.. as uiu.-u uuuuw^. In a „„ . ,|,e left ventriele was .onnd nrn,l^ w.ntraele.i n, .yM.le. the r„ht llaMn an,! dilated i HTe ,s „o s,j.,„,-K,.,„i ,.l,.,„^r,. i„ resimatiun i j--,^,. 2 and fn unf' Jt^t he.orc death. The,, ,he,-e a,-e a^phyxial ,a.,,. a, l„n, intervals: Art.t.cal ,-e.,,„-al,nn ,. nnavailino i„ ,,.„,,„„. „„ ,,,,,,j „,,,,,, ,,„^.^. j^ I'as ceased ,„ I,,,,, CnalK lua,-- and n-.pnat,,,,, M,.p ,„-ae,iealK .-y„ehi-oi,(,iisl_v I I'l-,. 2 and S,, \ i <>. ( nt.in.i. the va,i,d hefo.v or after the in,eei,on prudneed „n elVeet in the response { l-\g S). _ .V J'athohgio.l iluuuys.- In ,/.„,.. ,he eharaeter.stic legion i. an .nflan„„a„on ,., the .aM.a.inteMinal trac. The .arhe^l change is ohM-rved ,n an animal aeuteh poisoned hy intvaven„n. utjeetio," and ^l>.n|; at tl,e e,al ,„ ahunt an hour. There is „dl delnied n.ieetion and Mvelhn;, o, the ,nn,„n~ men,h,-ane of the nnall ,ntes,ine, e;poeiallv of l.e,le„,n. \\l.e".lea,l,,,e,n,-..uhi,,a,V. nnnn,...,hehea,-tisf,;,,,d "^"•;-"''""- y '•''•■'•"l. 1" 'I'.-.MohV Mand-till. \\ he,-e entailer ,|„antitie> are .njected ,„t,■a^en„n.lv. „r da.lv M,h, ntaue, „■.. niiectton. are ..iven over a bn.^er penod. and the annnal M.r^ue. „.r tuentv-fonr hours or >'''"e. there ,. a m ve,e ,a^tr„ entern ,. ,„ten hemorrhagic in character Ihe „,i,cous memhrane nf the nncMnu- i, .pollen, its ve^-eN a,a o..j;or^ed and a n,nc„p,„ „Ie,n exudate n,,,v >,.,,• ,,„nion, of its H,r- ''",/"'"'""""- '"■''^""--"■—-cnnnnn The dettm appears '-"'•-•»'-'■ .^>>ho.,,h the en,,,v ,ast,-,M,,,est,nal trac. •.fn,n,!'rdn 'oa.np. '-o„,e,„ne. .died u„h a hloo.lv. „„,coidn,aterial. In two tite (lU(jclenu,ii an.l nj-per leinnnni Microscopicalh,- there ,.. n,a,ked e„n,e.„„n and edcna of the n.uo.a: -uhn,ucosa and ,nuMularis p.-esetn .ntdar hn, le-- ,narke,l lun ev 1 he adjacent n.e.enleric fat ,nay he cono,,ted „„; ,„,„„,.„ All the ahdo,nn,al o,-n,an. a,e en,.„-,,.ed ^^\xh hlood. The liver and k.'lne>-. hot, srossly an.l n„cn,-,.„pi. alK, dn.v con,e-,ion and clon,lv suelhn^. ,e.v -.nall he,norrha,e. a,e -nneti.nes observed in the -al tnednll,, In one ,ns,ance ,he en,i,e head of the pancreas n-a< >urroun,led and ,n„hra.ed 1. . x„-av,as,ued Mood, .huh under the ...K-roscope was seen ,o Ik.c forced Us .ay hc.een the lohules. I„ us ~„u„al .here .a. a snhcap.,lar he.nor.ha.e into the cortex of tic k>d,ex._ I.ronchopne.unnn.a and pnlmonarv edema each were observed tw ee ,„ association with the usual intestinal lesions. 8. We arc i.wiCncI ,o n. T. V. S„ru,u for note. o„ d,e .nicro.copic pad,oIosv. I ■-e a t; — >' U5 — w =n < r 'i 1, ^ — " 'I ^- - H J .St l" Mrs i: — 1» 111 lilts lutii rui'hils. |>athiiluui,-.il cli.iii-i^ ;ii\ ^li-ht ami iiu-(iii-taiit. I Ik'Tc is ,s,'(ni.rally -diiic iiiirctidii ni tin- m—vU irf Uu' u]i|ai- ])(irti(in ni" llio Miiall iiducl, rill' li\tr an.l kuliu\> avc iuiiov-t> .1, and in i-ldwiy pdiMiiiid anini,il> ^\h,:v > Icnuly -wrllini; in cnc cat. Iiriiiijfiiiar;c (Kanirrid in iIr- hcA nijiiin ; in anuiiirr iIrtl' was a iiiiM L;ra(lc i.f I'lilmfiiiary ccKnia. I lit- ti iiilrney \n\- rajjliit-- jKii^iMnii hy cnutin (Kia^ionalK In (Icvclup iiciiiorriia.Liic |nilnionarv Ic^Kin- la- \\ a nnnilHT nf |ii<\i(,us cili>tT\ors. i iiis lias lncii lapiiliinnd jiy limlrii; in one (it nur animals a jiatcliy, iu'iiidrrhat;!!- iirdniiidpncnniunia with a.iua! Mcf.lini,' intn the liin,<,' tis-iif. .MirniM-,,],i,-allv. tluTc tnnld hr -irii -cxiTal tmint- df niii- tiiia- in the -nialldr artt-ru'- of ihe Iuiil;. ivdiii whirh hi I wa- pdinain,' mtd tlu' alvddii. 4, liffi-ct o)i the ('.HUjulalio)! ,<{ llw lUrod.—\\ wa- iidt.'d that the hlddd of poisoned aniiiiaK cldtted nnn-nallv .ld\\l\ and that tlie .ddt \\a> ndiin1ra>-til,- m .liara.ler. S<'vt-ral -pivnnen- di hi,,,,,! wcit examined hv l'rdt\...,,r 11,, well, wh,, h.a- \er\ hni,ll\ made the l'. ill, , win- n.ites: D(«; 1.— Utmlit. 10 kv.. Givci- 45 ihr. emctiii lydroclilori.l Mi!,cut;uiedii-1\. On tlic folIewitiK (l.iy. profuse. lil,)Ofly diarrlKa ami vonutini;. Dcaili <.ii iliin! ■lay. I'.lood for e\nmiiialion taken on v,coiicl day: eoll,c!e.l in ,.\,dalc -oliuiou; |'i..ide. Under the iiltramicroscope," the dot .bowed no visible striicliirc whatever, whereas, the lu.i mal clot show< a nia-.s of inlerlaciim necllc- or -piculee. I).ii;2-1. Wiiulit. 14 5 kL' K.eu\,,| Ml inK'. emeiin Iiy,lrochlonrl intravenously. Die. I in thiriy hours wiili a bemorrli.iHic i;a>tro-enieriti<. .\, specimen of bloo.l was taken immediately after death. oN.ilati.I and eeiitri- fiiKalized. Plasma very scanty in amount (about half ii,.nii.ili ,iiid vellowish in color. \\ li, n iliriinibin solutions were added, ch.tiini: u.,- sl,,u- anil imperfecu as thonuh t)l.riii,.«, ii were delicieiit in .Mii.nini. Tin liiial result was a tlo.itim.' clot. Lnder the ultramicroscope snnie librin necilles formed Init were scanty .'■cattered needles or small clnmps of needles in place of the thickly meshed needles of n,'rnial pl.isma. .^. Studies oj Rriiil iiiiictii'ii and . I riih'sis- - ht increase ''. In this cnnection see article by I'r.,!, IP.utll: Aimr. Juur I'hvsiol 1914 XXXV. 14.1 ■ " ■■ ■ 19 111 the li\ iliii^cn inn tum cntratiini of llic IiIuimI -cniiii. hii' no chaniic' in tli:it of ihe wIkiIc IiIoik!,'" I lir C'( )_, trn-:un ul ihc a!\ciilar air was al-ii ^onirwliai IdwiTnl. in ijni' animal lallini:; In ,^,> mm. llj^ several linur> Ijvinrc (iiatli. Tlii^ ])iiun(imt'niin has hcxMi nottd Ijv Mcver and W iniam>" in (.•\]icriinrnlai cmriin pui-Diiinu. sr.M MAln 'I I'KIAInIS I.NIl.KIMI.N lAI. WORK oX I.MllIX In ISl/, M,iL;rii(ii<- and I'lllrtici'- annninici d ill, it llit-y liail iMjlalril an i-nirtic -ubslauLa- ('iihiluir 7'umilhr") irom the \>h\ut fsychotria cmclica. 1 his sul). stancc iliey called cmctiii. lliey loiiiul tliat it had an emetic and [inrKative action and tluu it po-scsscd marked narcotic |)rn|)crties when sivm to aninial>. In order to determine the toxicity of the drne,. 10 j;rain> were given to a doR. X'oniitinK and Mnpor I'l.lk.ueil, and lli.- animal died in (ii'tcen lionrs. "Anatomical examination -liowrd tliat the animal had -ncciimhed to a vioK in iiillammation of tile tissue of t!.e Umus and of tlie mih.ais niembrane of the intestinal tract. ii"m cardi.i to aims." After olitainiim -imilar effects with a number of animals, lbe> conclndi d tliat "llieve ol)ser\.iii.'iis ,ire important, inasmuch as tin y show iliat em tin, ,i.;i\rn in lar,i{e du.ses, may produce gravi' results." Diiiiim the ruuaiuder of the nineteenth century, a number of investigators imdertcHik the siudy (pf iiiecacuaiilia and its uculy discovercleteness and accuracy of observation ,ire the articles of D\ce Diickwortli" and I'odwyssot/ki." The latter iieited uiili wonder the cardiac arrhythmia uhicli we liave shown to be uuc to ventricular librillation. Of ftmdamental importance w,is the work of I'anl and Cowtdey'' in l,so,;, demoiistratim; tlial the so-called emetin ni previous workers w.is in rralit\ a mixture of two alkaloids— the one. eiiulin, an amorphous sulist.ince. to which they assiiriied llie forniuli (' II. .\i) ; ilu- .iihcr. which the\ named cephailiii. a cijsialliii subsi.uui lia\inH ihe formula C ll.\li. I.niriiu bvclmclilorith Ci.-,H.,Xi 1 lii'l. i1k\ were alilc to make in cryslallin form. 'I'lie presence of a third alk.ilnid. psyclminn. was determined by them two \,ais laid. il was isnlited in small amounts as lemon-yellow, rliombic [irisnis The ainouiit ..f alkaloids in ipecacuanha they loanil to be aljont 2 per cent. Willi ' in l,s;');, wiirkiiii.' for tlie iirst tim. wiili iluse pure alkaloids, wliicii he olitained fr..m r.inl. inveslij.;ated and iMinpared their pharmacolo.aical action. He fcnind ih.ii 'h.iIi emetin .and ce|ihaelin are emetics, the emetic dose of the latter being h.ilf thai of emetin. Both lower the Idood pressure. The deiin-si.iii prcdncid In the eiiuli.- d.is,- .,f ripharhn i- U'ss ilian ih.it pr .diurd I>\ ihe l.n-Li'-r fiiutic dnsr ,,f Mueliii. The \asciilar dT'ils fr.ini rnirtin .ire gr(ater. llntli produce wiakriiiiig. T.iwini; and ■liasiiilic .irri st of the heart. 10. Ill making ;hcse deteriuination-. the imihoil recently described by I-cvy, Rowiiirec and Marriott was employed ( llii .\k. iiims js\. Mkd., 1915, xvi, 389), 11. -\Ii\cr and Williams: Arch. f. < \p. r. I'.nh, ii I'harmakol.. IH8i. xiii. 70, \2. M.tgendie ami i'ellitiir: lour, ih- pli.inn,. I,s:l7. iii. !4,s. 1,1 Duckworth, Dyce: St. ITiriholomew's ll,,isp, Kip. iSo9. v. 218; also 1871, vii. 'II. 14. I'oilwyssnt/ki : .\rch. f. exper. P.iih. u. 1 'h.ii iiiak. il.. 1.S79. xi. 2.51. 15. Paul. 11. II.. and Cownley. .\. J.; riiarin. .buir. and Trans.. 1893, liii. Ol ; also 1894. liv. iii. 16. I'aul. H. n,. and Cownlcy, A. J.: riiarm. Jour, au'l Trans., 1895. liv. 6'X). 17. Wild, R. B.: Lancet, London, 1895, Ixxiii. 1274. t; o J = :l!| liilll t ^ 5 ** 5 P ~ - 7 " S M^' ~ ~ " = P= " ^ =•= " = S _ ~ ^ »: s -3 — a a '^ ss 3 ? a <: '^ m:-- , — a.::: t* ^ *- ■^iillsl ..^i' §?^' ^Ss •SiS nu "Z .^ ~ : a t; c o U < 1I s< il 5 < s si:* *- i u - s = «• « Ills ^n t = k = It ^i lr$ f ^ C = I M ir I-. ■ =*« =p5 ■A Jl I \\ \ 8 -2 '" ~ r- 3 - - ?■ ^ r ^ 'i "" ^ " ^ z.ii ~ o t i = = r i - .E f r 5. t - = jjif i^SJll > t^'J: - > ■ — a ^ '-^ = •= E- 04 - « _ _ ■?^ r- ix " ^ y - ^ i -r ^ '5 ^ B ^ r If __ — u ^ >> (», u^ c: « n n s • Si: . ill?! ij - 1 "7 ^ ^ i C — t« o ® -£-! I :-f E i — "o - S E • -C 'C - ."• X — H .-3 — ^ t- r/i i rr - .- -^ ™ c - ; = •- - •S J« - ,_ := X s « -— . •-' X . S 1 ~ - 2 t' c^ i_ Z^.X^'l 't-^l "C — ■"» • > -i .r u iri ^ — ' 191 atioi hort ^ a- ,^ .£ E o > = -1^ ,m. Med. . se med., 1 the ward several f emetin e than tli lard : Prt ull. of T. **• c our. Med. nal comm be report Jour. .■> d: Pres' 2). In ion. In emata o ire dilut and Co man : B ;c : Am. J : Perso are to Allen : haufTar (Case irritat tive en ons mi Spehl F.shle Weis : Lyons Hume Thev I. C trous duced purga soluti 7,. 4. in ^O !>. g 8 I 22 Lowiii" ill I'HC ill a rixiew of privioii-. wuik uii llu- -ul'in-t. uivis a .nniiili tc l.ibliciKr.iipby Ui (lati\ In addition to tlic facts ciniilia>i/< il I>y \\ iM, Ik iinilinns the cliaractorisUC ua>tro-intcstinal Ksion^ fonml li\ otlui> in puisoiud animals, and states that on tln' liiiiK^ (im-lin lia^ in. ariu.ii. ulurcas. in ccpliaclni poison- in^'. extravasation of blood into tbe hums was noted several times. Deleterious action on the kidneys is found to be more cliaraeteristie uf eephaelin. Poisoned animals die of cardiac paralysi ICmetin, liowevir. injures tbe lieart in tinich Miialler doses tban i; i 'I 1 . M I 11 .N That llie iheiapeulu .ulinitii-lra.ln m ui eilletiii shuulil iml lie rc'sardfil .1- .m alto,i,"-'llHi iiiniHiuitis procedure lias heeii ]ire\iously iiuled. II111-. e\eii .i- earl\ ,1- 1S<),^. Wild'" ;-a_\ s : ■•Hie lael ihat a .hhiti.ai ui 1 in Jll.iKXi .aiiMil diaslolk arrest ul the l'roK'> I'e.irt in lorty->ix niiiiutes. ri'iiders eaitlinii neee--;ir\ in uivini; l.ir.oi r dose> ol the alkaloid." liaiimami and lleiiiemaim' have iioled distre-sin;; ,iiul e\en al.irmiiiK svnip- toms following doses much larger than are usually employed. 'I'liey say: ".Sub- cutaneous injections produce in some instances . . shglit general malaise; otherwise, with small and moderate sized iloses of (i(l to 150 mg.. there arc no symptoms If 120 to 150 mg. are given in daily repeated injections, there appear, after th.cc or four injections, malaise, lassitude, slight vertigo and loss of appetite. These symptotns disappear in from 24 to 7Z hours after the emetin has been discontinued. "Intravenous injections of fX) to JlKI ing. cause no serioii- ilisliub.iiu ■■ ; there i, slight vertigo, transient tlnshing of the face and retching. If this dosage is exceeded and M».) to 4(X) lug. pre injected, serious symptoms are observed. These appear in from two to live mimiles after the injection and con-ist of general vascular paralysis, severe expiratory dyspnea with cessation of respira- tion, loss of consciousness with vomiting, the passage of thin stools, and great -lowing of the pulse. Although these phenomena are trans. cnt and arc ipnckty 18, Lowin, C. : .\rch. iiilernat. di- pharmacod. et de therap.. I'>l2. xi, 'J. 19. More recently, Lyons (New Orleans Med. anil Surg. Jour.. 1")12. \\\\ . KM4l. using sterilized fecal liltrates matle from the stools of individuals reciiving ipecac by mouth, cnutil demonstrate no amebicidal properties, in vitro, of the contents of the bowel. 23 nlicvcd li\ Miit;ili1i- nu'aMir<5. yil cm the Ikims of \hc-,- ol.s, rvali.m- \v. woiiM rcsard a'^ tlu' maximal imravtiious clo-c 250 mi;. Tir ku. nf IhhIv wcmlit. W r have never observed any injury to the kidneys, nor has tliere been any per- manent damage to the patient, even witli the higli intravenous doses." \eddcr's' connnents in this connection ar. wortli quoting in full. He says: "Since emetin. bv manv oliscrvcrs. has been regarded as a more or less harmless drug, and since I am of the opinion tliat the doses used by some, and particularly by c'aermann and Hcineinann, are too large, 1 wi^li to point out the possilde danger in not using due camion in tlie use of thi- \ir\ pcunt r'. "\fter seeittg rabbits die' innni.haldy after intravenous injections of com- parativelv small amounts (fr..ni .i to -^ my. i of emetin hydrochlorid. / .r/icU»M /i,-5i/.i/,- lu-fon- .tdminislcruui crcn I .I.m rvalion- warns against tlie use of large doses, as follows: "Too large dose^ cr t... pr.donged u>e of tnoderate closes may cause a diarrhea or be responsible for its persistence. Ilu-r,- ,.< vuraisina cvul.nc- lIuU Uir.ii- ih'.u-s of i-iii.-ln\ ar.- not u'itlh'id ill c/Jcc'/." '" llu- rcpcrleci t.i-e.- m uliuli til elJVet^ lia\c icdlcwrd the >litm-;il use cif etltetiii .ire .t,'i\etl in tile :ii■ Tito exiaTielue ol l.v.ni- witli tlie :i.lmiiii~lv:itinii of emetin l.y tnoutl' ineeluiles it> iim' liv the oral icitite He I'oiin-l il I'XcealiiiKly irritant even in sin,, 11 .Icm- X.niM-a, \oiiiiiiiil;. t;rii.itii,', iniriiation .an d.'se there was uncmtrollablr vomiting and a rapid pulse: the extremities became cdd and -tamp u.th perspiration. Death occurred in an liour aii.l a ball. -\t necr.ip^s ih. le u... Imui.l subacute couKesti.,,! ..i th.^ stomach and lirM two feet of the intestine. The heart was in diasiol.- I lu other organs were normal. Harrison comments that "the congeslion d the stomach was .-ertainly an insutlicient cause of .leath." SL'GCKSTIONS WITH Klr.AUH in A HATKlNAI. IMITIX TMF.rM'V llciw iiMv llic \<l lie axdi.kdr As the result liuth of ■ iioal aiui lalioralor)- olisorvatioiis tlic following suggestion- are iire-enled; 1. The ailiiiini:-tralion of eiiklin li\(lroclilori(l is not to be regarded as a hannles^ inui-edure, I'.veii ni llieraiH'Utir iloses ill effects may follow its use. .' lii,livi('iuali/alio!i l.y elo-i rlnii.al oli-ervalion i- e-i-- and safety ol llie tnaliiieiit. ratient- may differ iliaiKedK ui tlieir -u-.-e])tiliilit> lo llu diui;, and the \ariou- .oinmereial preparations \ary widelv m tosi. ity llie-e poiut> are strikingly demonstrated h\ llie t itv e\i'erinieiit- herein rejiorted. ,v idle ireatnient dionld he given in cour-e-. at intervals of several da_\> or a week. llu- -ulicutaiieous route i~ the one of elioiee. Indi- viilual dosage and the .luration of eaeli rour-e inn-t he determineafe dosage in amehie infeetious. It is rarely necessary to give more than l'^ grains daily. In the treatment of pyorrhea, Bass and Johns'-^ advocate 'j grain d.iilv for from three to six davs. and maintain that no ease need have more than -ix da\ -' treatment. I 'iider ordinary eireunistanees thi'- -ein " witliin the man^in of safetx'. it mn-t he home in mind, howevi thi .idinin- i-tralion of even ri'lati\el\ -m.ill do-e- oxer a lont; p( ,uid > : Iniie niav prove liarmful. 4 I he l.irgc dosage advoi"'.t>.ii h> l'..iernianii :ind 1 leineinaiin is imiieee-sary and dangeroU';. 5. Intravenous injeetions should hr em|iloyi<\ admini-lralion -eem- im|ier.itui', -mall doses, well diluted ( ' :■ Srain in 101 e e. -alt solution 1 -hould he -lowlv given, and the hlood pressure should he e.irefully observed rjuriiig the injection. 24. Bass. C. C, nnd Joliii-. IM .h"u \.n Me.l. .^^sii.. 101.-. Ixiv. .=;.i.V • •