Results of Prolonged Treatment with Pentolinium Tartrate with Special Reference to the Addition of Rauwolfia, Hydralazine or Both By EDWARD D. FREIS, M.D., AND ILSE M. WILSON, M.D. A series of 96 patients with severe hypertension has been treated with pentolinium tartrate for an average period of 12 months. Seventeen patients died. Therapy was more effective in arresting changes in the optic fundi and in the heart than in the kidneys. Various combinntions of h-po- tensive agents were tested and it was concluded that in general the combination of pentolinium tart,rate, Rauwolfia and hydralazine resulted in the great,est reduction of bloocl pressure with thcl least degree of side effects due to ganglionic `%lockade." S OOK after pentolinium tartrate was syn- thesized by Libman, Pain and Slack,' pharmacologic studies by Wein and Mason? indicated that it was a potent gangli- onic blocking agent with a prolonged duratiolr of action. Preliminary clinical results were re- ported by Campbell and Maxmell,3 Smirk4 and from this clinic5 These report)s indicated that pentolinium tartrate was an orally effective, potent, antihypertensive drug t#hat appeared to be useful in the treatment of patients with more severe, fixed types of hypertension. In the present report, the long-term experience with penbolinium tartrate both alone and in combination with certain other hypot,ensivc agents is presented. MATERIALS AND METHODS The treatment group con&ted of 96 p&tie&s selected because of severe. sustained hypertension (table 1). Their ages ranged from 27 to 65 years, From the Cardiovascular Research Laboratory, Georgetown University Hospital, the Department of Medicine, Georgetown University School of Medicine and the Veterans Administration Hospital, Washing- ton, D. C. Supported in part by research grants from Wyeth Laboratories, Inc., Philadelphia, Pa., the i'iational Heart Institute, U. S. Public Health Service, the Squibb Institute for Medical Research, New Bruns- wick, N. J. and Irwin, Ncisler and Company, Decatur, III. Pentolinium tartrate (Ansolysen) was generously supplied by Daniel I,. Shaw, Jr., M.D., Wyeth I,abo- ratories, Phil:tdelphia, P:i. wit11 an average age of 17 scars. .\I1 csccl)t 15 of these patients were hosyit.aiizetl prior to or during the initiation of treatment with pentoliniu~ii. Prior to therapy, 56 per cent cshibite(l grade III or more changes in the optic fundi and 39 per c*ent llatl some degree of nitrogen retention. Electrocardiograms were taken of 83 patients :11x1 6fj exhibited the patt,ern of left I-entricular l~ppcr- trophy. Frank congestive heart failure was diagnosed in 13 of the patients, although lesser degrees of wrdiac decompensation as manifpstet I 1)~ esertionnl dyspnea were common. Cardiac rnlsrgement' was present in 5% of 76 patients who hat1 loelit,Rrnofrnlns taken prior to treatment. The method of adjusting dosages of pentoliniutn tartrate has been described in previous communic;L- tions.6-* The duration of treatment ranged from 3 to 27 months, with a mean of 12 months. Seven werr treat'ed for 21 months or longer, 41 were treated from 12 to 24 months, 26 from G to 12 months, and 18 from 3 to 6 months. In the majority of the capes, various other hypotensive agents were added to pentolinium tartrate for periods of time as are described below. RESULTS Mortality There were 17 deaths ill the entire series. Of these, 10 exhibited grade IV fundi; 4, grade III; and 3, grade II fundi prior to therapy. The survival from beginning of treatment to death in this group averaged 11 mont,hs, and in the malignant group, 13 months. The causes of death were as follows: nephrosclerosis wit11 uremia in 11, cerebral hemorrhage in 4, rup- `;> of Total Male. 71 T4 Female., 25 26 Ol>t ir fundi : grade IV. 34 35 gr:rde III. 20 21 grade II. 30 / 12 gmdc 1. 1 I 3 ITncl:mifietl* 1 1 Elevi~tion of blood ureil nitrogen or nonprotein llitrogeu 38 40 All)uminuri:t: 2 to 4 + 37 39 trttcr to 1 + 27 28 total 64 67 15min. cs~~~ctio~~l~henols~~lfonphth;tlein (55 r:ms) UIldPl. 15 per cent 35 1 l':le~t.roc:tl.tliogr;L111 (83 cases) LVH p:1ttrrn 66 Incre~ed transverse diameter of heart (76 cnses) 58 * (Zorncal ol):tcities prrvrnted esaminat ion. iurr of an aortica anrurys~u in 1, and myocsar- dial infar&on in 1. Twent,y-four of the grade I\- patients still survive, !I hauc been under Irwtment, for periods varying from 19 t,o 27 mont>hs, 7 from 12 to 18 mont,hs, and 8 from 3 to IO mollths. RIyocwdial infawtioll ocrurred in only one vase listed al)ov(?. Two patie& developed per- sistcllt, allgill: \vit,h electrocardiographic evi- denw of mywardial ischemia. In t]hese t'\vo and in one other patient, wit,h electrocardio- graphic changes, it was necessary to discon- t,inue pcntolinium tartrate because of angina. In one ot,hcr patient, the routfine "check-up" elc~trocartliograln revealed t,he decelopment~ of a pat,t,crn consistent, kt,h an old myocnrdial infawtion although t,hr patient, had experi- enced 110 symptoms. 111 addition to the four who died wit,h cerc- brovascular hemorrages, two patients developed cercbrovascular accidents of slight degree while under trent,mc~llt . Only one patient required hospitalization. The results (table 2) indicate t,hat the symp- t,oms of headache, dizziness, palpitation and dyspnca usually improved, whereas in the case of angina a few improved but, an equal number mere made worse. Nocturia usually decreased but in some it increased, particu- larly in t,hose who exhibit,ed considerable pos- t,ural hypot,ension, the latt,cr t,ending t,o pro- duce oliguria during the day. Seven patients had cerebral vascular aw- dents with residuals prior t,o treatment. Xonv showed any skiking improvement, and t'herv so. of Patient: iI 1 5 6 5 70 Dizziness 15 CVA resitlu:ds 7 Corn- plcle Krlief 2 2 0 21 5 0 100 2 ~ 6; 3 1 40 11 ' 70 0 100 i 0 IV III II I 34 20 40 1 2 6 22 0 3 13 0 0 22 0 0 0 Cardi:ac tliamrter Ihl:wgetl Normd F:lc~troc:Lrtliogr:~l)tl~- LVH ~xttlcrn Normal 76 5x 18 75 65 11 After Treatment So. of Cow in Each Grour>ins was a temporary IV~WII of paresis or difliwlty in speech in four of these eases during periods of marked hypotcnsion. 1. Optic Fundi. As show1 i11 tahlr :3 in t,hr total series, 67 patients, or 71 per cent, ex- hibit,ed improvement iti the optjic fundi (fig. 1); 28 cases, or 29 per cent, rcmaincd unchanged. 2. ?`ra~wwsr Diavwtvr 0.j the Cardiac Sil- houette. Roent,genograms of the chest were baker1 hcfore and after trcatmcnt in 76 of the paticnb (table 4). Fifty-eight were believed to show cardiac enlargement. Thirt'y-three cxhib- it,ed a decrease in cardiac diam&er, averaging I .I! c7n. (range 0.3 to 1.5 cm.), I!) \verc trot- ehangcd at~tl (i showed an increase :t\waging 1 .O em. The cardiac diamet,er was wnsidtwd normal prior to trcatmcnt in 18 patietits. E'ourt,ccn of these exhihit,ed no sigttifiwnt change, while iti four there was an iiicwasc in size, averaging I.2 cm. 3. h'kctrocardiographic Changes. The dcrtro- cardiogram was recorded in 75 pat,icnts before and aft'er treatment (table 4). Sixty-five ex- hibitcd thr pattern of left, ventricular hyper- trophy. ;1ft.cr treatment, 4 revert,ed to tiorma3, 4 sho\ved improvement toward normal, 36 were unchanged aud I exhibited further pro- gressioii. Of I I patients whose elec~trowrdio- FREIS AND WILSON x59 nitrogen or urea nit,rogen. I~;levalcd. Normal .4ll)uminnri:~. 4 ]lllls. 3 plus ~ 2 plus. 1 plus trace. negative I~:s~retion of phenol- sulfo~rpht~h:tleir~. 1,rss tt1a11 15% 1.5 to 2,570 64 31 33 i6 10 13 7 8 21 17 45 19 26 8 28 2 3 1 4 1" 14 10 7 6 5 4 7 4 5 2 x 12 4 3 45 100 54 86 62 19 37 15 grams were normal before treatment, 10 remained normal while I developed changes caharac%eristic of left vctttriwlar hyperkophy. 4. Renal Puncfion. The blood ttonprotein nitrogen or urea nitrogen \vas estimated in 61 cases before and after treatment. The results (table 5) indicate no cottsiskvtt trend, some showing improvement) and an equal number inrreasing azotrmia. The presence of albutninuria \vas est)itnated semiquantitatively using the heat, and a,cctic: acid method on freshly voided spec4mcns of urine in `iti patients. The results (table 5) indi- cAat)e that, X3 per cent of t*he 38 patients w&h 1 plus or more albuminuria showed improvc- 111e11t. The percentage of phettolsulfonpht~halcin ex- rrcted 15 minut,es after injection was deter- tnined in 45 cases before and after treat,tnent (table 5). In 26 of t,he vases prior to t,herapy, t,he 15 minute excretion ranged between 15 and 25 per wnt of t,he injwted dye. Aftjet txeattnent there was an increased excretion averaging 7 per cent above control values in 4 of the patiettt,s, no essettt,ial vhattgo in 3 (aaRcs, while in l!l patiettts th(w was a de- creased excretiott averaging JO per vent belo\\ the pretreatment level. In t,he remainittg I!) cases t,he control escwtion was less t,hatt I5 per vent, of dye in 1.5 minutes; of t,his numbet 7 showed an ittvrease following therapy aver- aging 8 pvr wttt of t,he injcc+ed phenolsulfott- phthalritt, -l ww: utwhanged, and 8 exhibited a further dccwaw averaging 5 per cent,. l'rcatmcnf ,uith Pcnlolinium Alone Fifty-four paticnt,s \vere t'reatcd initially with pctttolinium for an average period of 2 tnonths (range 2 days to 19 months, fig. 2). The average pwtreatmcttt blood pressure was 222,/1:27 mm. Hg (range l!JO/llO to 270 `1.X). Following treatment, the average pressure itt the supine position \\xs I74/1O6 mm. Fig (rattge M/95 to 208,, l:Z5), and 16l/lOl 111111. Hg cwvt (rattge 130~;88 to 200:`125). This represcwted a rc&ic+oti of "tncati" artwial AVLIAOC DAILY DOW. OF CL*1OLIIIUY TARTnATE s 0 Pc*ToLInIuM ALOIL ?* ? o ??o????o?? ??? ?????????? ?? ???o???o??? ??? WYORALALIYL ??? m PC*YoLIII~nYoIALAz*(L **D IIAUWOLFIA PER ???? ?????????? ?? ????? o "EsI""L-*"PIL ?? ? ?? ??? 0 10 20 30 40 so 60 70 PER CENT VI<:. 3. Chart showing incidence of side effects of ganglionic "blockade" experienced with pentolinium tartjr:tte alone md with the various comhirrvtions of hypotcnsive drugs. The incidence of such side effects appeared t,o be somewhat reduced with all of the comk)inations used, pressure, averaging 22 per cent supine (range 11 to 39 per cent) and 26 per cent erect (range 14 to 41 per cent). The values mere obtained frotn the average of many hospital, home and office readings; in each patient ittdividual read- ings may have ranged considerably above or below the average reading. Dosages were administered 3 titnes daily at approximately 8 hour ittt,ervals. The average tot,al daily dosage was 867 mg. (range 60-1400 mg.). In many instances in order to prevent marked fluctuations of blood pressure the morning doses were smaller than t'he afternoon or night doses. The incidence of side effects is shown in figure 3. Impotence was complained of in 33 per cent, although probably present in the majority of patients over the age of 45. Diffi- culty in emptying the urinary bladder was not, complained of. Because of the development of tolerance to the hypotensive effect of pento- linium or of marked side effects from ganglionic blockade or because of marked fluctuations in blood pressure, all, except one patient, were given combinations of pent~olittium wit,h rcwr- pine or hydralazine or both. Pentolinium l'artrate ad RauwolJia There were 71 cases in t,his group, the avr~- age durat,iotl of treat,ment with Rauwlfia serpcntinn being 6 tnont,hs (range !) days to 19 months, fig. 2). Dosages of pentolittium avcr- aged 492 mg. (range 60 to 1800) as wtttrasted to 867 mg. on pentolittium alone. Rauwolfia was administered t,o 61 patients as rcscrpittct in doses of 0.25 to 1 mg. per day, and as an extract of the crude root, (Rauwiloid) itt closc~s of 2 to -1 tng. daily in 10 cases. The control blood pressuws averaged 228j 135 (range 200/115 to 3OO/liO) mm. Hg. After t~reatment the tnean supiw pressure was 197/109 (range 142/92 to 250/150) mm. Hg and in the erect, position 163'101 (range KM/80 t,o X0/115) mtn. Hg. The rcductiott of "mean" arterial pressure averaged I(i per cent, in the supine position and 26 per cent in thr: wecat position. The side effects of gangliottic bloc~kadc on this combination are shown in figure 3. Side effects due t,o t,he addiCon of Rauwolfia were nasal st,uffitiess in 18 per cettt, severe mental depression in 6 per cent,, weight gain in 21 per cent,, increase in appetite in 27 per cent, night,- mares in 2 patients and diarrhea in 2 cases. In 43 patients it was possible to determine the dosage requirement of pentoliniuttt after, as cotnpared to before, the addit,iott of Rau- wolfia (table 6). The average daily dosage of pentolinium when used alone was 550 mg., which produced an average blood pressure fall of 18 per cent in the supine position and 3,2 per cent in the erect, position. Aft,cr addition of Rauwolfia, the average daily requiretnettt of pentolinium was 422 mg. and t,he tnean reduc- tion of blood pressure was 25 per cent in the supine and 29 per cent in the erect position. The above data represent over-all aver- ages. In not all of the paGent's was it possible to reduce the dosage. In 23 or 54 per cent, of the 43 patients, the dosage of pentolinium could be decreased, in 16 it remained the same and in 4 it was increased. Twenty-four patients exhibited an additional reduct,ion of 5 per cent FREIS AND WILSON 861 TABLE 6.- The EJecf oj Added Rauwoljia or Hydralazine or Both on Nlood Z'resmre ctnd Dosage Kequirement of Pentoliniutrc Tartrak tn the Patients with Three or More Recordings oj Hloorl Z'ressure ZAil?l Jar Smeral ll'eeks Drug (`ombination I'cntolinium t:lrtrtlte and 12,2uwolfia.. l'cntolinium tartr:lt,e :tnd hydrnlnzinc l'entolinium t:xtrate, Rsu\~olfia :trrd hydtxla- zinr 43 13 27 612 550 WI 18 18 19 22 24 23 or more of "mean" arterial pressure after addi- t,ion of reserpine. Pentolinium Tarhtc ad Hydrula~ine Twent,y patients were given this combina- t,ion (fig. 2). The average duration of treat- ment w&h hydralazine and pentolinium t,ar- trate was 4 mont,hs (range 3 days to 8 months). The average daily dose of pentolinium t)artrat,e was 671 mg. before hydralazine was added and 540 mg. afterwards. The average dose of hy- dralazine was 120 mg. (range 50 to 300 mg.) per day. The dosages of hydralaxine xvcre de- liberately maint,ained at, a low level because of t#he reported serious reactions t,hat, may occur on long term use. The pretreatment, control blood pressure averaged 227/ 1% r11xxl. Ilg. (range 210/l 20 to 250/160) in t,his group of cases. After treat- ment, t,he average blood pressure was 173/104 mm. Hg (range 153,196 to 200/120) in t,he supine position. In t,hc erect' position the average blood pressure after treatment was 162/100 mm. Hg (range 140,/80 to 190/110). The reduction of `(mean" art'erial pressure averaged 23 per cent in the supine position and 26 per cent erect. The side effects due to pentolinium bartrate are shown in figure 3. Side effects thought to be due to the addition of hydralazine were: headache in 4, palpitation in 2 and edema in 2. There was no arkitis or dermatitis. In 13 patients it was possible to compare Pentolinium Combined Blood Pressure Average Daily - DOX Av. ": Additwnal `:; Reduction Reductwn 422 23 25 20 610 0 24 28 I 418 / 35 27 31 dosage requirements and blood pressure rc- sponse before and after addition of hydralazine. The resuks are shown in table 6. In seven patient)s it was possible to reduce the dosage of pcntolinium. There were 50 patients in this group (fig. 2). The avcragc length of treatment was 4 months (range 9 days t,o 2:: months). The average dose of pentolinium was 458 mg. (range 90 to 1700 mg.). The average dose of hydralazinc was 144 mg. (range 50 to 500 mg.). Daily dosage of reserpine varicad b&ween 0.25 and 1 .O mg. per day. The average pretreat,mcnt blood pressure was 230/1X6 (range 19O:/llO t,o 270/170) mm. Hg. After treatment. the a\-cr- age blood pressure in t,hc supine position was 171/106 (range 140/90 to 200/1%0) mm. Hg and in the erect position was 160/99 (range 130/88 to 200/115) mm. Hg. The reduction of "mean" arterial pressure averaged 25 per cent in the supine position and 28 per cent in t,he erect. The incidence of side effects is shown in figure 3. Rauwolfia side effects mere: nasal stuffiness in 20 per cent,, mental depression in 4 per cent, weight gain in 20 per cent, increase in appetite in 24 per cent, nightmares in 2 per cent, gast)rointestinal bleeding in 2 and diar- rhea in 4 per cent. Hydralazine side effects were headache in 16 per cent, palpitation in 10 per cent, and dyspnca in 1. In 27 patknt,s, hydralazinc and ltauwolfia were added almost sitnult~atleously (interval of 3 we&s or less). The results are shown in table 6. In 19 of the 27 patients the dosage of pettto1itlium could he rcduwd. In 9 of the pa- tients tbe additional rcdwtion of blood pres- sttrc a\wagcd 10 per wnt or more. `l'hc developmcttt of "toleratt(*e" was (:A- mated by ceomparittg t(he dosagcl requitw~ettt. and blood pressure reduc*tion at, the initiation of treatment wit)h that required at t,hc end of the period of t,his study. The initial effective daily dosage averaged iSi' mg. and the most. rec~~t~t effective dosagta X0 mg., an awrzgSc~ in- vreaw of :I(i per cwt. 111 the early t,reat,tnctttt period there was a 22 per vent, reduction of supitte and 26 per cent in erect, blood pressure attd at t,hc end of st,udy, 2 I per cent supine and 28 per cent, erect. It should be poittt'ed out, t.hat in most ittstanws Iiauwolfia and hydralazine had been added. Thus, these figures do not, acwrat'ely reflect t,he development of tolcranc~e to prtttolinium tartrat)e alone but rat,hcr to out twatmetit~ regimen. The symptoms t,hat are rolat~ed t,o hypw- t.cttsion or to associated cardiac derompensa- tiott often were reliewd following t,reatmettt. Thus, t,hc symptoms of headache, dizziness, dyspttaa and palpit,atiott were improved in more t,hatt t,mo thirds of t,hc ittdividuals who suffered from these c~omplaint~s. ( )I~ the ot)hct hand, now of the patients with sympt,oms re- sulting from residuals of old cerchrovawular acvidrttts showed improvemettt. and itt some, reduc? ion of blood pressure aggravakd t,hesr symptoms. Similarly, less t,han half of the pa- tients with angina noted itnprovcmc~ttt and att qua1 number complained of irwreased diwom- fort. It would appear t,hat, "hyperkttsive" syrnpt,oms and those t'hat arise from cardiac* "strain" frequently will be improved, whereas those due t#o vascular sclerosis oft,en do not, improve and may becotne worse. In regard t,o objective signs of improvctnetttJ ot)her than blood pressure, regression was noted itt the optic fundi in mow than four fifths of the paticwts with grade III and IV c,hattgw and in slightly less t,hatt half of thck paticttts with grtadc II changes. Thus, the most marked efferts ww ott the hr:morrhagt>s, exudates, and papillcdema, although diminution in thv dc- gree of artwiolar tiarro\\-itig also \vas sew it\ some of t)he (`ases. In t,he patiettt,s wit,h vardiomcgaly dimittw tiott of cwtliac~ size was observed in approxi- matc4y otte half of the cases. Sinw t,hc majorit) of these vases had t,he usual t,herapy for wtt- gestivc heart failure prior to being plaved ott pentolinium tartrat,e, the improwment ap- pear4 to wsult frotn the attt ihypert~ettsi~~c therapy pclr SC. In fact, itt tuatty of thcscl pa- tiettt)s t,he INW~ for salt, rest,rictiott or diurrtiw was reduwd or e\-cn abolish(bd. In contrast to these evidrnws of improvrmetrt~ in cardiacs statSus only 12 per vettt of patiettts showed partial or votiipletc reversal of the c4ec+roc*at.- diographica pattertt of left vctttricsttlar hypcr- trophy. The cstc~~t of improvettwtrt in the kidtwys was less itnprcssivc than it1 t,he futtdi and the heart,. In t,he pat,irttt)s with ttitrogett retctttiott, as many showed increasing uremia as she\\-cad clearing, attd five pat,iettts de\-eloped elevations of blood utva ttitrogctt or ttottprotcitt nitrogen from normal t,o abnormal while under tJroat- merit,. The dcgrec of albuminuria itt general tended to lessen under t,herapjr. Ott the othct hand the ability of the patients to ex(vtv phetwlsulfottphtha.leitt dye dwreased more of- ten than it itnproved. It seems possible that the dwrcasc in al- humitturia and improvement, in nitrogen rthtctt- t)iott seen in some of the cases might) be expected in part, on the basis of impro\-ement itt latent or overt cwtliac~ dwompensat iotr. The sw1iv might be said for the decrease it1 ttocturia that was frequently noted. The appearattw or morscnittg of nitrogen retention in other pa- t,iettts while under therapy and the frequent obswvaLtiott of reduced ability to excwte phe- ttolsulfonphthaleitt dye may be acwuntcd fot ott the basis of tn,o facators: (1) rffcvt of gatt- glionic bloc~king agents on renal hemodynam- its" atrd (2) further progwss of the renal Iesiotts despite attt,ihypertensive t!herapy. The favt that the majority of the deaths itt this scriw mere due t,o renal failure tends t,o sup- port t,his thesis. It would appear, therefore, that treatment with pentolinium tartxatc is lcast effective against t,he renal complicat,iotts of wvere hypertension. If twphrosclerosis re- sttlts from sust,ained hypertension t,hese ob- wrvatiotts provide an argumettt for bcgittnittg trwtmettt~ earlier, before t,hc renal arterioles lia\~ become irreparably sc~lrroscd. (`o~lfirrnittg our previous esperiettc*clo and those of othersL' 1 I2 the additiolt of rcsctrpi~te ttot ottly produces a further rcdurtiott of blood pwssure in matty patients bitt also may per- mit reduction of t,hc dosage of petttolittiurtt attd, hence, lessen t#he ittc4dcttw of disabling side cffcvts produced by gangliottic "hloc+kade." This romhittation while c~ff'crtivc attd gcwerally twttcr t,oleratJrd by the patieitt must, be insti- tuted with att awareness that serious mental dcprcssion ran owur in patiwits t,rcatc:d fol long periods wit)h Itauwolfia preparatiotts.`:3 The addit,ive hypotensive effec+t of hydrala- xittca alone was &died in ottlg a small ttumbei of patients and t,he dosages used wct~c smallc~ than t>hose employed by Perry attd Schroedw in a similar study. I4 Xwertheless, the present results caontirm t,heir observation that t,hc addi- tioit of hydralazine produwd a further lower- itlg of blood pressure. It' is ittt,clrestittg t,hat, in ottr vases, where the dosages of hydralazitre \vcrc small, the devclopmetrt of the sytrdron~c~ twcmbling disseminated lupus erytltematonus did not occur; whereas it, was ttot, art infreclucnt vomplic~ation in Perry and Srhroeder's series. ( )II the basis of t)hc variotts observations on small doses of hydralazittc and of l~attwolfia \w haryo cowluded t,hat therapy cwntbittittg all 3 agcttts produces the greatjest, redtwtiott of blood prcwtuc and the smallcxt dosage rcqttiremettt~ of t,he blocking agent. We believe, bon-wer, t)hat each drug be added wpatately itt order to jttdgv it,s effcct,s in t,hc particular case. It, is inCerest,irtg that all of the "toxir" reac- tiotts to pent,olinium tartrat,e seemed to be due to t)he acut,c effec%s of ganglionic "hloc~kade." ITttlike hexatttethortiltln~~' tti tto cases of cshrortic itttcrst,it,ial ptreumonitis occurred in this series, Thor t,o our kno\vledge have thcrc been an? wport.s of t,his complic.ation itt t)hc litwatttrc~ on pc~t~toliniuni tartratc. The proof of the effectiveness of atty form of trcatmcnt~ ill hypertension is its ability to prevent morbidity xnd mortality. The dura- t,iott of trcat~mettt in this series AlI is too short t>o draw arty wttc~lusions in regard to mortalit,y. In regard to morbidity, howrvclr, it is itnpor- tant to note that, the majority of t,hr patiettts who had lost their jobs because of srvcre hyprr- tettsion were able to retStint to sonic sort of gaittful owupat~iott. This WLS also the GLSC in matly of the patients who eventually died but who wcrc able to \vork until shortly before exitus. The clearing of sympt,otns of rartliw decwmpettsntiott or hypertensivr rttwphalopa- t)hy produwd considerable subjective intprovcb- tttetlt in these severe cases. 111 additiott, dw to the postural hypotetisioti produced by pvttto- linittm tartrat{>, thr rotttrol of blood pressuw was as good or better whett thr paticwt \vats up and wti\,e thatt n-hen he was ittactivc. l'hc atwst and scrming reversal of e\-ct. \rorsettittg symptoms in thesr most severe cases provided a tremendous boost to thr patient's morale, and as such was an impor- tattt additiottal therapeutic dividend. In Iws dcspcratc situatiotts and particularly itt the asymptomatic* hypertensiw, th(l side eRcrts resttltittg from t,herapy blunted thtl paticttt's desire to continue with treatment. III stwlt cases Lrarious twhnicas were used to assure the patient's voopvratiott. These ittc~ludetl (1) gradual elevation of dosage to t)he effcrtivcl level, (2) cxplanat,ion of side effwts and itt- strrtctiotts in mittimizittg thrir scvwity" ailtl (3) the use of home blood pressure rwotdit~gs. -1 scrics of' !Hi patients with severe, fiscd hypert#ettsion was txrated with pent,olittirtm tar- trate alone: or in c*ombitta,t)ion with Rau\\-olfia or hydralazitte, or both, for prriods varying front 3 to 27 nnont)hs (average 1% mottt,hs) \vith the followittg results: 1. Ten of t,he 34 patiettt,s Jvith grade I\- changes it1 t)hc optic fundi and 7 of the rcmaitt- ing pases hnw died. In addition, 1 wse drvel- oped a myorardial infarction attd 2 devrloped mild wrebrovascular awidcttts while uttdcl trratmetit. 2. Typichal hypcrtcttsive symptoms swh as 864 RESULTS OF PItOI,OKGJ~:I) TItI~ATMENT WITH I'I~:h'TOI,INIUhl T:1I~`IX.\TI~: headache, dizziness and those relating to car- diac decompensation often mere relieved; whereas those due to vascular sclerosis, suc*h as angina or residuals of old cerebrovascular acci- dents, usually did not improve or wrre made worst. 3. Improvemcttt in the optic fundi was ob- served in more t,han 80 per cent of t,he pat,ients with grade III and grade IV changes and in slightly less than half of the pat,ients with grade II changes. 4. Decrease in cardiac size frequettt,ly was observed. Improvement in t'he elec%rorardio- graphic pattern of left ventricular hypcrtrophy also owurred but less frequently thart t.hc former. 5. The degree of albuminuria usually t,t:nded to lessen during treatment,. Approximately half of t,he pat,iertt,s nit,h nitrogen retention showed clearing, whereas t,he other half devcl- opcd increased retention. The abilit,y of the patiettt,s t,o excrete phenolsulfonpht-halein de- creased more often than it increased following treatment. The reasons for these apparettt, dis- crepancies are discussed and it is (Lottcluded that t,raatnient, was more cffect,ive in arrest,ing or reversing chattges in the optic fundi and in the heart than in the kidneys. ti. Data are presented to demottst,rat(x the additive effects of Iiauwolfia or hydralazittc, or bot,h, to the regitnen. Combining all three agentas generally resulted in t,he greatest reduc- tion of blood pressure with the least degree of sympt,oms rcsult,ittg from gattgliottic "block- ade." 7. In \-icw of the scverit'y of the hypcrten- sion in the prcscnt series, it is concluded t,hat this method of treat,tnent is beneficial. It xas especially effective in restoring semi-invalided or irtvalided hypertensive patients back to more useful and active modes of living. Un serie de !N paticntes de sever hyperten- sion fixe csseva tractate durante periodos de inter 3 e 27 mettses (durantia median 12 ntcnses) con tartrat, de pcnt'olinium sol o in combina- tion con Rauwolfia o hydralaeina o ambes. Le resultat,os esseva le scquente : 1. I)ece de1 3 pat,icwtes cott :~ltct~at.iottes de grado IV in lc fundos optic c `T del alt'ere pa- tientes ha morite. In plus, un pat,iettttr dis- veloppava url ittfarcimtnto myocardiac t! duo disveloppavn levc accidentes cwcbrovascular quando illcs esseva sub ttwtamettto. 2. Typic sytnptomas hypcrtettsivc ~ntal de capite, \-ertigine, sympt,omas pert,incttte al dis- compensation cardiac, etr. csscva allcviatcl in multe cases. Sympt~otiias dcbite a sclerosis vascularPattgitta, residues at) anriatt acci- derttcs ccwbrovascwlar, d (8. ttott se meliora\-a in general, e in wrtc cases illos devcttiva pcjor. 3. Melioration itt Ic futidos optic csseva ob- serrate itt plus qtte X0 pro wttto de1 patientw con alterat,ioties dcl gtxlos III (: IV e in lcvc- mcntc minus qtte 50 pro wtit~o de1 cases dc grade II. 1. Reduction dcl dintcnsiottcs cwdinc ws~va obscrvate. Melioration de1 figuration electro- cardiographic: dc hyprrt rophia sinistro-vent ri- cular essc~3 etiam obscrvatc~ scd ill0 ocrurre'va minus frec~iictitet~ietttc clue Ic i~cductioti de1 dimcnsiottes c~ardiar. 5. In getteral, Ic grad0 tic alt~utiiitittria mottstrava uti tcndetitia a rcdwcr se durattt'c le tra&mettto. Circaa ttti tiicdic%atc clcl pa- tientcs con rctentiott de ttitrogctto hubeva utt augment,0 dcl clearing; le alt we tttedietat,c> dis- veloppava tin augmetttatc grad0 de retetttiott. Le c+apacitnte de- excrrticr pltettolsttlfotiptitha- leina essevn plus frecjt~etitctiic~ttt~~ redttcit t' post, le trac+atnettto que augmctlt~atc. Kos diwute le rat,iottes pro istc app:tr(:tit(~ discrepant ias (' conclude qttc Ic trwtantcttto PSSCW plus cfficaw in arrestar 0 revcrter alteratiottw itt lo fttttdos optic e in lc cordr clue itt IV rcncs. (i. Es presentat~c~ dntmos pro demotistrar le effect,os addit,ivo de liauwolfia o ltydralazinn 0 ambes. Lc ~ombitiation de omttc t,res agcntcs resultava gencralmcnt.e in le plus grande wduc- tion de1 pression sartgttinee, rot1 le minus grnnde grado de symptomas rcsultattt,c ab L%lo(xg(~O gangliotiic. 7. Considerante le scvcritutr: del hylwrteti- sion iii lc preseiit)e seric de putientrs, ties con- cludc que iste methodo t herapctttic rs hmcfic. 1110 csseva specialmctitc t#ic:aco in rcstaurat semi-inralidat,o o inr-alidatc: pai ientcs ttyper- t,ctisive a plus utile: e ac+ti\-(b fortiias tl~ lita. ' r.rI3.uAN, I ). I)., PAIN, I>. L., ASD SLACti, Ii.: Some bisqu:tternur~- salts. -1. (`hem. SOV. 430: 2305, 1952. ? \\-BIN, It., .GVD _\koN, 1). IT. ,J.: I%:~rn~:rc~~log~- of 11 R- 1% 2050. 1,:1ncrt 1: 4M, 1953. 3 ~IAXWICLL, 11. 1). If., AND (:.~MPBI:LL, .\. .J. 31.: Ken- s)-mpathol~:tic agents. Lancet 1: 145, 1953. 4 kqMIRK, F. H.: Ait*tlon of a new methonium coni- pound in arterial hypertension, I'ent:triietllSlene 1 :.i-l)is-S-(S-xliet'llvl-p~rrolidiIiiu~u I)it:rrtrate) (MC% IS 2050 -1). Lancet 1: -157, 1953. " FRl:IS, 1':. I)., ~`.4RTIXOIJ1~:, 1% .I., ~,ILIl~:h-FIELD. I,. S. .1xn Itosl~:, .I. (1.: :1 c*liniwl appraisal of l~ental~~i~rolicli~iiulli~ (hI h I3 2050) in Ilyper- tcnsi\.c l)atients. ("ir(ulation 9: 510, 1954. fi --~: Hyl~rrtcnsion; mcthotl of trcat,ment. 171 (`onn, II. I'., (`urrent, Therapy. I'l~il:~clrll~l~i:t, I\`. n. S;:lllIl~lfl.S ( 30., 19%. ,,. 12-k. 7 --- -: The dircrcl~anc~~- between home and office rccwtling of Moot1 lnwsure in patients under treatment \vitli l)erit:11,~rrolitliniuln. Importance of llome rrcw~rlings in acljusting tlOSitgf3. .Znn. I)istrict of CX~l~uul~i:~ 23: 363, 195-1. 8 ----: Let~ter to the editor. .J..\..\I.A1., 158: 1390, 1955. 9 -, ROSE, J. C., PARTENOPI~:, P:. A., HIGGINS, T. F., SCHNAITR, H. \V., AND .JOHNSON, R. I,.: The Iieniody~~:~~ni~ cffccts of hypotensivct clrugs in man. III. Hesamethonium. .J. Clin. Invest. 32: 1285, 1953. I0 -: Combinations with ganglionic blocking agents. Symposium on hypotensive drugs. Elvans Me- morial Research Conference, Sept. 15, 1953, p. 126. I1 SMIRK, E`. H., DOYLE, .\. E., AND ;\~@JwN, E. G.: Control of blood pressure by combined a&on of reserpine and pentapfrl'olidinium. Lancet 2: 159, 1954. I2 BAIN, c. I?-. c., i\SHTOX, F., .4ND JONES, n. I'.: The treatment of essential hypertension with pentolinium tartrate combined with Rauwolfis alkaloids. Brit. 31. ,J. 1: 817, 1955. I8 FREIS, I:. I>.: I\Iental depression in hypertensive patients treated for lone ueriode wit'ti large doses of reserpine. Kcm &&land .J. RIed. 25% 1006. 1954. I4 PICRHY; 1% 51 , .JR., AIYD SCHROEDER, H. A.: The use of pentolinium tartrate with and without hydralazine in the treatment of severe hyper- tension. New England J. Med. 252: 1057, 1955. I5 MORRISON, 13. : Parenteral hexamethonium in hypertension. Wt. II. J. 1: 1291, 1953. I6 MORROW, J. Il., SCHROEDER, H. A, AND PERRY, 1~. M., JR.: Studies on the control of hyperten- sion with Hyphex. II. Toxic reactions and side effects. Circulation 8: X29, 1953.