Reprinted from CrrcuLatTion Vol. XIII, No. 6, June, 1956 Printed in U.S.A, Results of Prolonged Treatment with Pentolinium Tartrate with Special Reference to the Addition of Rauwolfia, Hydralazine or Both By Evwarp D. Freis, M.D., anp Inst M. Witson, 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 combinations of hypo- tensive agents were tested and it was concluded that in general the combination of pentolinium tartrate, Rauwolfia and hydralazine resulted in the greatest reduction of blood pressure with the least degree of side effects due to ganglionic “blockade.” OON 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 duration of action. Preliminary clinical results were re- ported by Campbell and Maxwell,’ Smirk? and from this clinic. These reports indicated that pentolinium tartrate was an orally effective, potent, antihypertensive drug that 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 pentolinium tartrate both alone and in combination with certain other hypotensive agents is presented. MaTERIALS AND MeErnops The treatment group consisted of 96 patients 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 National Heart Institute, U. 8. Public Health Service, the Squibb Institute for Medical Research, New Bruns- wick, N. J. and Irwin, Neisler and Company, Decatur, Il. Pentolinium tartrate (Ansolysen) was generously supplied by Daniel LL. Shaw, Jr., M.D., Wyeth Laho- ratories, Philadelphia, Pa. 836 with an average age of 47 years. All except 15 of these patients were hospitalized prior to or during the initiation of treatment with pentolinium. Prior to therapy, 56 per cent exhibited grade III or more changes in the optic fundi and 39 per eent had some degree of nitrogen retention. Electrocardiograms were taken of 83 patients and 66 exhibited the pattern of left ventricular hyper- trophy. Frank congestive heart failure was diagnosed in 13 of the patients, although lesser degrees of cardiac decompensation as manifested by exertional dyspnea were common. Cardiac enlargement was present in 58 of 76 patients who had roentgenograms taken prior to treatment. The method of adjusting dosages of pentolinium tartrate has been described in previous communica- tions.*8 The duration of treatment ranged from 3 to 27 months, with a mean of 12 months. Seven were treated for 24 months or longer, 44 were treated from 12 to 24 months, 26 from 6 to 12 months, and 18 from 3 to 6 months. In the majority of the cases, various other hypotensive agents were added to pentolinium tartrate for periods of time as are descrihed below. RESULTS Over-all Results of Treatment Mortality There were 17 deaths in the entire series. Of these, 10 exhibited grade IV fundi; 4, grade III; and 3, grade IT fundi prior to therapy. The survival from beginning of treatment to death in this group averaged 11 months, and in the malignant group, 13 months. The causes of death were as follows: nephrosclerosis with uremia in 11, cerebral hemorrhage in 4, rup- Cireulation, Volume NUT, June, 195€ FREIS AND WILSON 857 Tare 1.—Severity Indices of Patients Prior to Treatment with Pentolinium Tartrate Parameter No. of nD of Male... 00.02 eee 71 74 Female....0000. 0.0002 ees 25 26 Optie fundi: grade IV... ......0..---. 34 35 grade II]................ 20 2) grade II................. 40 42 grade 1.2.0.0... 2. 1 ] Unelassified* 0.000.002. 1 1 Elevation of blood urea nitrogen or nonprotein nitrogen................/ 38 40 Albuminuria: 2 to4 +................ 37 39 trace tod +............ 27 28 total... ................] 64 67 15 min. excretion phenolsulfonphthalein (55 cases) under 15 per cent........| 35 Electrocardiogram (83 cases) LVH pattern... 00.0.2... eee eee 66 Increased transverse diameter of heart (76 CASES). 0 eee 58 ture of an aortic aneurysm in 1, and myocar- dial infarction in 1. Twenty-four of the grade IV patients still survive, 9 have been under treatment for periods varying from 19 to 27 months, 7 from 12 t0 18 months, and 8 from 3 to 10 months. Morbidily Myocardial infarction occurred in only one case listed above. Two patients developed per- sistent angina with electrocardiographie evi- dence of myocardial ischemia. In these two and in one other patient with electrocardio- graphic changes, it was necessary to discon- tinue pentolinium tartrate because of angina. In one other patient the routine “check-up” electrocardiogram revealed the development of a pattern consistent with an old myocardial infarction although the patient had experi- enced no symptoms. In addition to the four who died with cere- brovascular hemorrages, two patients developed cerebrovascular accidents of slight degree while under treatment. Only one patient required hospitalization. Liffecl on Symptoms The results (table 2) indicate that the symp- toms of headache, dizziness, palpitation and dyspnea usually improved, whereas in the case of angina a few improved but an equal number were made worse. Nocturia usually decreased but in some it increased, particu- larly in those who exhibited considerable pos- tural hypotension, the latter tending to pro- duce oliguria during the day. Seven patients had cerebral vascular acci- dents with residuals prior to treatment. None showed any striking improvement, and there TaBLe 2.—Changes in Symptoms Following Treatment Unim- . Com- fo Symptom tad RS | proved More TM } uy t Headache..... ...| 53 | 4 | 30 | 9 | 8 Exertional dyspnea.; 23 2 | 17 6 | 76 Dyspnea at rest... | 15 7 6 | 2) &F Paroxysmal — noc- | ' turnal dyspnea...) 4 2 3 1 0 | 100 Palpitation........ 6) 2) 2 | 2 | 67 Angina............. | 5 | 0 | 2 | 3 | 40 Nocturia,.......... ' 70 | 2) 2 | Ml | 7 Dizziness.......... 15 5 | 10 0 100 CVA residuals. .... 7 7 0 Tasie 3.—Changes in the Optic Fundi Following Treatment with Pentolinium in Ninety-Five Cases No. of Patients in Each | Grade | Patietts Corade After Treatment Improved | Wout | a I | IV | Bb | 2 6) 2] 4 | a4 mW 20) | 0 8 | 1B) 4 8 | 40 0 0 | 22 Is | 45 1} 1 0 0 0 1 | 0 TaBie 4.—Changes in Cardiac Diameter as Meas- ured foentgenographically and Electrocardiograms Following Treatment with Pentoliniwn Tartrate | After Treatment | No. of Cases in I Each Grouping | a No. of |-———- Reef Parameter Pretreatment an ae ; Im- Cases _ S & proved ° Ss \ & Oo “| 8/5 le Cardiac diameter....| 76 | | fnlarged.......... 58 2 | 33 | 19 | 6 | 57 Normal...........| 18 | 4 4 | Eleetrocardiography .| 75 | | LVH pattern...... 65 4), 8) 56/1 12 | Normal. ........-. 11 | 10 | l 858 RESULTS OF PROLONGED TREATMENT WITH PENTOLINIUM TARTRATE Fra. 1. Photographs of the left optie fundus in W. A., 2 32 vear old merchant seaman who entered the hospital with an accelerated hypertension. This could not be arrested by his family physician who had tried reserpine and hydralazine. The patient was treated with pentolinium tartrate and after 3 months returned to work as a carpenter. The upper left photograph taken prior to treatment reveals typical neuroretinitis with papilledema, a large macular “star? and a hemorrhage above the disk. The upper right photograph taken 1 month after treatment with pentolinium shows resorption of the hemorrhage und diminution in the papilledema and exudates. The lower left photograph was taken 3 months and that on the right 9 months after treatment. The fundus has reverted to grade II with residual sears in the macular area. was a temporary return of paresis or difficulty in speech in four of these cases during periods of marked hypotension. Effect on Objective Findings 1. Optic Fundi. As shown in table 3 in the total series, 67 patients, or 71 per cent, ex- hibited improvement in the optic fundi (fig. 1); 28 cases, or 29 per cent, remained unchanged. 2. Transverse Diameter of the Cardiac Sil- houette. Roentgenograms of the chest were taken before and after treatment in 76 of the patients (table 4). Fifty-eight were believed to show cardiac enlargement. Thirty-three exhib- ited a decrease in cardiac diameter, averaging 1.3 em. (range 0.5 to 4.5 em.), 19 were un- changed and 6 showed an increase averaging 1.0 cm. The cardiac diameter was considered normal prior to treatment in 18 patients. Fourteen of these exhibited no significant change, while in four there was an increase in size, averaging 1.2 em. 3. Llectrocardiographic Changes. The clectro- cardiogram was recorded in 75 patients before and after treatment (table 4). Sixty-five ex- hibited the pattern of left ventricular hyper- trophy. After treatment, 4 reverted to normal, 4 showed improvement toward normal, 56 were unchanged and 1 exhibited further pro- gression. Of 11 patients whose electrocardio- FRLEIS AND WILSON 859 TaB.E 5.—Changes in Blood Nonprotein Nitrogen or Urea Nitrogen Levels, Degree of Albuminuria and Fifteen-Minute Excretion of Phenolsulfonphthalein Following Treatment with Pentolinium Tartrate ~ ~ I After Treatment No. of Cases in Each Grouping a Ww — . nse . . No. of _ z a Parameter Pretreatment; Cases - : Z ! . proved 2, 5.8 Blood nonprotein nitrogen or urea , nitrogen.........; 64 Blevated........... 381 ' 8] 14) 3] 145 46 Normal. .......... . 38 28 5 Albuminuria......... 76 4phus...0.00.000.. ' 10! 10 100 3 plus............. | 13 2/7) 5: 1] 54 2plus............. 7 3] 6. 1: 8&6 1 plus............. 8 1) 4 | 2/ 1 62 trace... ee. 21 4) 4] 8 9) 19 negative........... 17 12 PV2) 6) Excretion of phenol- | sulfonphthalein..| 45 Less than 15%.....) 19 7) 4] Si 37 4) 3419] 1 15 to BWM. ........ 26 grams were normal before treatment, 10 remained normal while 1 developed changes characteristic of left ventricular hypertrophy. 4, Renal Function. The blood nonprotein nitrogen or urea nitrogen was estimated in 64 cases before and after treatment. The results (table 5) indicate no consistent trend, some showing improvement and an equal number increasing azotemia. The presence of albuminuria was estimated semiquantitatively using the heat and’ acctic acid method on freshly voided specimens of urine in 76 patients. The results (table 5) indi- cate that 73 per cent of the 38 patients with 1 plus or more albuminuria showed improve- ment. The percentage of phenolsulfonphthalein ex- creted 15 minutes after injection was deter- mined in 45 cases before and after treatment (table 5). In 26 of the cases prior to therapy, the 15 minute excretion ranged between 15 and 25 per cent of the injected dye. After treatment there was an increased excretion averaging 7 per cent above control values in + of the patients, no essential change in 3 cases, while in 19 patients there was a de- creased excretion averaging 10 per cent below the pretreatment level. In the remaining 10 cases the control excretion was less than 15 per cent of dye in 15 minutes; of this number 7 showed an increase following therapy aver- aging 8 per cent of the injected phenolsulfon- phthalein, + were unchanged, and 8 exhibited a further decrease averaging 5 per cent. Treatment with Pentolinium Alone Fifty-four patients were treated initially with pentolintum for an average period of 2 months (range 2 days to 19 months, fig. 2). The average pretreatment blood pressure was 222/137 mm. Hg (range 190/110 to 270/155). Following treatment, the average pressure in the supine position was 174/106 mm. Hg (range 145/95 to 208/135), and 161/101 mm. Ag erect (range 130/88 to 200/125). This represented a reduction of “mean” arterial AVERAGE DAILY DOSE OF PENTOLINIUM TARTRATE CO PEATOLINNM ALONE 6 soos. GR PENTOLINIUM AND RAUWOLFIA PENTOLINIUM AND WYDRALAZINE 200 ISS PEN TOLINIUM,HYDRALAZINE AND RAUWOLFIA 0 400 200 PER CENT REDUCTION OF BLOOD PRES SURE~SUPINE 30 40 20+ 34 7 20 so cases Fic. 2. Chart showing average daily dosage of pentolinium (above) and mean per cent reduction of blood pressure (below) in the group of patients treated with pentolinium tartrate alone as compared to the groups treated with the various combinations. of hypotensive agents. The combination of pento- linium, hydralazine, and Rauwolfia resulted in the greatest reduction of blood pressure and the lowest dosage requirement of pentolinium tartrate. 860 RESULTS OF PROLONGED TREATMENT WITH PENTOLINIUM TARTRATE OC] PENTOLIAIUM ALONE MB PENTOLINIUM AND RAUWOLFIA PENTOLINIUM AND HYDRALAZINE PENTOLINIUM,HYDRALAZINE AND RAUWOLFIA IMPAIRED VISUAL ACCOMMODATION SSS SS SSS SSS WET ELLE ELLA DRYNESS OF MOUTH CONSTIPATION CONSTIPATION CONTROLLED WITH LAXATIVES AND/ OR NEOS TYGMINE ESS PH OOH HHH HAD RLADAg PLL TLL POSTURAL HYPOTENSION SYNCOPE IMPOTENCE o lo 20 30 40 30 «60 7o PER CENT Fig. 3. Chart showing incidence of side effects of ganglionte “blackade”’ experienced with pentolinium tartrate alone and with the various combinations of hypotensive drugs. The incidence of such side effects appeared to be somewhat reduced with all of the combinations 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 were obtained from the average of many hospital, home and office readings; in each patient individual read- ings may have ranged considerably above or below the average reading. Dosages were administered 3 times daily at approximately 8 hour intervals. The average total 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 the 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 tbe 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 pentolinium with reser- pine or hydralazine or both. Pentolinium Tartrate and Rauwolfia There were 71 cases in this group, the aver- age duration of treatment with Rauwolfia serpentina heing 6 months (range 9 days to 19 months, fig. 2). Dosages of pentolinium aver- aged 492 mg. (range 60 to 1800) as contrasted to 867 mg. on pentolinium alone. Rauwolfia was administered to 61 patients as reserpine in doses of 0.25 to 1 mg. per day, and as an extract of the crude root (Rauwiloid) in doses of 2 to 4 mg. daily in 10 cases. The control blood pressures averaged 228/ 135 (range 200/115 to 300/170) mm. Hg. After treatment the mean supine pressure was 197/109 (range 142/92 to 250/150) mm. Hg and in the erect position 163/101 (range 130/80 to 240/145) mm. Hg. The reduction of “mean” arterial pressure averaged 16 per cent in the supine position and 26 per cent in the erect position. The side effects of ganglionic blockade on this combination are shown in figure 3. Side effects due to the addition of Rauwolfia were nasal stuffiness in 18 per cent, 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 pentolinium after, as compared to before, the addition of Rau- wolfia (table 6). The average daily dosage of pentolintum when used alone was 550 mg., which produced an average blood pressure fall of 18 per cent in the supine position and 22 per cent in the erect position. After addition of Rauwolfia, the average daily requirement of pentolinium was 422 mg. and the mean 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 patients 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 reduction of 5 per cent FREIS AND WILSON 861 Tanne 6.— The Effect of Added Rauwolfia or Hydralazine or Both on Blood Pressure and Dosage Requirement of Pentolintum Tartrate m the Patients with Three or More Recordings of Blood Pressure Datly for Several Weeks Preceding and Following Combined Drug Therapy Pentolinium Alone No. of | Blood Pressure Drug Combination Cases Day Reon Dose: mg. “oe | Supine’ Erect Pentolinium tartrate and Rauwolfia............... 43 550 18 22 Pentolinium tartrate and hydralazine... ......... 13 671 18 24 Pentolinium tartrate, Rauwolfia and hydrala- BNE eevee | 27 642 19 23 Pentolinium Combined Blood Pressure Cases in Which Average Daily = |——-——~——____.—— ..--. - -- Pentolinium Dose Av. % Additional % Was Reduced Reduction Reduction % M Per cent | oui Erect | Supi E Mg. reduction | * upine trect | Supine rect 422 23 25 29 7 7 4 610 9 24 28 6 4 54 | 1 418 35 27 31 8 | 8 70 or more of ‘‘mean” arterial pressure after addi- tion of reserpine. Pentolinium Tartrate and Hydralazine Twenty patients were given this combina- tion (fig. 2). The average duration of treat- ment with hydralazine and pentolinium tar- trate was 4 months (range 3 days to 8 months). The average daily dose of pentolinium tartrate 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 hydralazine were de- liberately maintained at a low level because of the reported serious reactions that may occur on long term use. The pretreatment control blood pressure averaged 227/135 mm. Hg. (range 210/120 to 250/160) in this group of cases. After treat- ment the average blood pressure was 173/104 mm. Hg (range 158/96 to 200/120) in the supine position. In the erect position the average blood pressure after treatment was 162/100 mm. Hg (range 140/80 to 190/110). The reduction of ‘mean’ arterial pressure averaged 23 per cent in the supine position and 26 per cent erect. The side effects due to pentolinium tartrate 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 arthritis or dermatitis. In 13 patients it was possible to compare dosage requirements and blood pressure re- sponse before and after addition of hydralazine. The results are shown in table 6. In seven patients it was possible to reduce the dosage of pentolinium. Pentolinium Tartrate plus Rauwolfia and Hydralazine There were 50 patients in this group (fig. 2). The average length of treatment was 4 months (range 9 days to 23 months). The average dose of pentolintum was 458 mg. (range 90 to 1700 mg.). The average dose of hydralazine was 144 mg. (range 50 to 500 mg.). Daily dosage of reserpine varied between 0.25 and 1.0 mg. per day. The average pretreatment blood pressure was 230/136 (range 190/110 to 270/170) mm. Hg. After treatment the aver- age blood pressure in the supine position was 171/106 (range 140/90 to 200/120) 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 the erect. The incidence of side effects is shown in figure 3. Rauwolfia side effects were: 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, gastrointestinal 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 dyspnea in 1. 862 RESULTS OF PROLONGED TREATMENT WITH PENTOLINIUM TARTRATE In 27 patients, hydralazine and Rauwolfia were added almost simultaneously (interval of 5 weeks or less). The results are shown in table 6. In 19 of the 27 patients the dosage of pentolinium could be reduced. In 9 of the pa- tients the additional reduction of blood pres- sure averaged 10 per cent or more. Development of “Tolerance”? The development. of “tolerance” was esti- mated by comparing the dosage requirement. and blood pressure reduction at the initiation of treatment with that required at the end of the period of this study. The initial effective daily dosage averaged 374 mg. and the most recent effective dosage 520 mg., an average in- crease of 36 per cent. In the early treatment period there was a 22 per cent reduction of supine and 26 per cent in erect, blood pressure and at the end of study, 21 per cent supine and 28 per cent erect. It should be pointed out that in most. instances Rauwolfia and hydralazine had been added. Thus, these figures do not. accurately reflect the development of tolerance to pentolinium tartrate alone but rather to our treatment regimen. Discussion The symptoms that are related to hyper- tension or to associated cardiac decompensa- tion often were relieved following treatment. Thus, the symptoms of headache, dizziness, dyspnea and palpitation were improved in more than two thirds of the individuals who suffered from these complaints. On the other hand, none of the patients with symptoms re- sulting from residuals of old cerebrovascular accidents showed improvement and in some, reduction of blood pressure aggravated these symptoms. Similarly, less than half of the pa- tients with angina noted improvement and an equal number complained of increased discom- fort. It would appear that “hypertensive” symptoms and those that arise from cardiac “strain” frequently will be improved, whereas those due to vascular sclerosis often do not improve and may become worse. In regard to objective signs of improvement other than blood pressure, regression was noted in the optic fundi in more than four fifths of the patients with grade III and IV changes and in slightly less than half of the patients with grade II changes. Thus, the most marked effects were on the hemorrhages, exudates, and papilledema, although diminution in the de- gree of arteriolar narrowing also was seen in some of the cases. In the patients with cardiomegaly diminu- tion of cardiac size was observed in approxi- mately one half of the cases. Since the majority of these cases had the usual therapy for con- gestive heart failure prior to being placed on pentolinium tartrate, the improvement ap- peared to result from the antihypertensive therapy per se. In fact, in many of these pu- tients the need for salt restriction or diurctiex was reduced or even abolished. In contrast to these evidences of improvement in. cardiac status only 12 per cent of patients showed partial or complete reversal of the electrocar- diographic pattern of left ventricular hyper- trophy. The extent of improvement in the kidneys was less impressive than in the fundi and the heart. In the patients with nitrogen retention, as many showed increasing uremia as showed clearing, and five patients developed elevations of blood urea nitrogen or nonprotein nitrogen from normal to abnormal while under treat- ment. The degree of albuminuria in general tended to lessen under therapy. On the other hand the ability of the patients to excrete phenolsulfonphthalein dye decreased more of- ten than it improved. It seems possible that the decrease in al- buminuria and improvement in nitrogen reten- tion seen in some of the cases might be expected in part on the basis of improvement in latent or overt cardiac decompensation. The same might be said for the decrease in nocturia that was frequently noted. The appearance or worsening of nitrogen retention in other pa- tients while under therapy and the frequent observation of reduced ability to excrete phe- nolsulfonphthalein dye may be accounted for on the basis of two factors: (1) effect of gan- glionic blocking agents on renal hemodynam- ics’ and (2) further progress of the renal lesions despite antihypertensive therapy. The fact that the majority of the deaths in this FREIS AND WILSON 863 series were due to renal failure tends to sup- port this thesis. It would appear, therefore, that treatment with pentolinium tartrate is least. effective against the renal complications of severe hypertension. If nephrosclerosis re- sults from sustained hypertension these ob- servations provide an argument for beginning treatment. earlier, before the renal arterioles have become irreparably sclerosed. Confirming our previous experience!’ and those of others!" the addition of reserpine not only produces a further reduction of blood pressure in many patients but also may per- mit reduction of the dosage of pentolinium and, hence, lessen the incidence of disabling side effects produced by ganglionic “blockade.” This combination while effective and generally better tolerated by the patient must be insti- tuted with an awareness that serious mental depression can occur in patients treated for long periods with Rauwolfia preparations.” The additive hypotensive effect of hydrala- zine alone was studied in only a smal! number of patients and the dosages used were smaller than those employed by Perry and Schroeder in a similar study.“ Nevertheless, the present results confirm their observation that the addi- tion of hydralazine produced a further lower- ing of blood pressure. It is interesting that in our cases, where the dosages of hydralazine were small, the development of the syndrome resembling disseminated lupus erythematosus did not occur; whereas it was not an infrequent complication in Perry and Schroeder’s series. On the basis of the various observations on small doses of hydralazine and of Rauwolfia we have concluded that therapy combining all 3 wgents produces the greatest reduction of blood pressure and the smallest dosage requirement of the blocking agent. We believe, however, that each drug be added separately in order to judge its effects in the particular case. It is interesting that all of the “toxic” reae- tions to pentolinium tartrate seemed to be due to the acute effects of ganglionic “blockade.” Unlike hexamethonium!®: !® no cases of chronic interstitial pneumonitis occurred in this series, nor to our knowledge have there been any reports of this complication in the literature on pentolinium tartrate. The proof of the effectiveness of any form of treatment in hypertension 1s tts ability to prevent morbidity and mortality. The dura- tion of treatment in this series still is too short to draw any conclusions in regard to mortality. In regard to morbidity, however, it is impor- tant to note that the majority of the patients who had lost their Jobs because of severe hyper- tension were able to return to some sort of gainful occupation. This was also the case in many of the patients who eventually died but who were able to work until shortly before exitus. The clearing of symptoms of cardiac decompensation or hypertensive encephalopa- thy produced considerable subjective improve- ment in these severe cases. In addition, due to the postural hypotension produced by pento- lintum tartrate, the control of blood pressure was as good or better when the patient was up and active than when he was inactive. The arrest and seeming reversal of ever worsening symptoms in these most severe cases provided a tremendous boost to the patient’s morale, and as such was an impor- tant. additional therapeutic dividend. In less desperate situations and particularly in the asymptomatic hypertensive, the side effects resulting from therapy blunted the patient’s desire to continue with treatment. In such cases various technics were used to assure the patient’s cooperation. These included (1) gradual elevation of dosage to the effective level, (2) explanation of side effeets and in- structions in minimizing their severity’ and (3) the use of home blood pressure recordings. SUMMARY AND CONCLUSIONS A series of 96 patients with severe, fixed hypertension was treated with pentolinium tar- trate alone or in combination with Rauwolfia or hydralazine, or both, for periods varying from 3 to 27 months (average 12 months) with the following results: 1. Ten of the 34 patients with grade IV changes in the optic fundi and 7 of the remain- ing cases have died. In addition, 1 case devel- oped a myocardial infarction and 2 developed mild cerebrovascular accidents while under treatment. 2. Typical hypertensive symptoms such as 864 RESULTS OF PROLONGED TREATMENT WITH PENTOLINIUM TARTRATE headache, dizziness and those relating to car- diac decompensation often were relieved; whereas those due to vascular sclerosis, such as angina or residuals of old cerebrovascular acci- dents, usually did not improve or were made worse. 3. Improvement in the optic fundi was ob- served in more than 80 per cent of the patients with grade III and grade IV changes and in shghtly less than half of the patients with grade II changes. 4, Decrease in cardiac size frequently was observed. Improvement in the electrocardio- graphic pattern of left ventricular hypertrophy also occurred but less frequently than the former. 5. The degree of albuminuria usually tended to lessen during treatment. Approximately half of the patients with nitrogen retention showed clearing, whereas the other half devel- oped increased retention. The ability of the patients to excrete phenolsulfonphthalein de- creased more often than it increased following treatment. The reasons for these apparent. dis- crepancies are discussed and it is concluded that treatment was more effective in arresting or reversing changes in the optic fundi and in the heart than in the kidneys. 6. Data are presented to demonstrate the additive effects of Rauwolfia or hydralazine, or both, to the regimen. Combining all three agents generally resulted in the greatest reduc- tion of blood pressure with the least degree of symptoms resulting from ganglionic ‘“block- ade.” 7. In view of the severity of the hyperten- sion in. the present series, it is concluded that this method of treatment is beneficial. It was especially effective in restoring semi-invalided or invalided hypertensive patients back to more useful and active modes of living. SUMMARIO IN INTERLINGUA Un serie de 96 patientes de sever hyperten- sion fixe esseva tractate durante periodos de inter 3 ¢ 27 menses (durantia median 12 menses) con tartrato de pentolinium sol o in combina- tion con Rauwolfia o hydralazina o ambes. Le resultatos esseva le sequente: 1. Dece del 34 patientes con alterationes de grado IV in le fundos optic e 7 del altere pa- tientes ha morite. In plus, un patiente dis- veloppava un infarcimento myocardiac e duo disveloppava leve accidentes cerebrovascular quando illes esseva sub tractamento. 2. Typic symptomas hypertensive--mal de capite, vertigine, symptomas pertinente al dis- compensation cardiac, etc. esseva alleviate in multe easos. Symptomas debite a sclerosis vascular—angina, residuos ab ancian acci- dentes cerebrovascular, ele. -non se meliorava in general, e in certe casos illus deveniva pejor. 3. Melioration in le fundos optic esseva ob- servate in plus que 80 pro cento del patientes con alterationes del grados IIL e IV e in leve- mente minus que 40 pro cento del cases de grado II. 4. Reduction del dimensiones cardiac esseva observate. Melioration del figuration electro- cardiographic de hypertrophia sinistro-ventri- cular esseva etiam observate sed illo occurreva minus frequentemente que le reduction del dimensiones cardiac. 5. In general, le grado de albuminuria monstrava un tendentia a reduecr se durante le tractamento. Circa un medictate del pa- tientes con retention de nitrogeno habeva un augmento del clearing; le altere medictate dis- veloppava un augmentate grado de retention. Le capacitate de excerner phenolsulfonphtha- leina esseva plus frequentemente reducite post le tractameuto que augmentate. Nos discute le rationes pro iste apparente discrepantias e conclude que le tractamento esseva plus eficace in arrestar o reverter alterationes in le fundos optic e in le corde que in Ie renes. 6. Es presentate datos pro demonstrar le effectos additive de Rauwolfia o hydralazina o ambes. Le combination de omne tres agentes resultava generalmente in le plus grande redue- tion del pression sanguinee, con le minus grande grado de symptomas resultante ab “blocage”’ ganglionic. 7. Considerante le severitate del hyperten- sion in le presente seric de patientes, nos con- clude que iste methodo therapeutic es benefic, Ilo esseva specialmente efficace in restaurar semi-invalidate o invalidate patientes hyper- tensive a plus utile e active formas de vita. FRIIS AND REFERENC Is ' Lipman, 1. D., Parn, D. L., axp Stack, R.: Some bisquaternary salts. J. Chem. Soc. 430: 2305, 1952. 2 Wein, R., AND Mason, D. F. J.: Pharmacology of AM. & B 2050. Lancet 1: 454, 1953. 3 \[axwei, R. D. H., anp CAMPBELL, A. J. ML: New sympatholytic agents. Lancet 1: 445, 1953. 4sSaurk, F. H.: Action of a new methonium com- pound in arterial hypertension, Pentamethylene 1:5-bis-N-(N-methyl-pyrrolidinium — bitartrate) (M& B 2050 A). Lancet 1: 457, 1953. ‘Pret, 4. D., Parrenopr, EB. A., LanieNnFrecn, L. 8. anp Rose, J. C.: A elinieal appraisal of pentapyrrolidintum (M & B 2050) in hyper- tensive patients. Circulation 9: 540, 1954. 6 —: Hypertension; method of treatment. Jn Conn, H. F., Current Therapy. Philadelphia, W. B. Saunders Co., 1955. p. 124. 7—-: The diserepaney between home and. office recording of blood pressure in patients under treatment with pentapyrrolidinium. Importance of home recordings in adjusting dosages. Ann. District of Columbia 23: 363, 1954. 8 —.: Letter to the editor. J-A.MA., 158: 1390, 1955. 9 —, Ross, J.C., Parvenore, K. A., Hiceins, T. F., Scunarer, H. W., ann Jonnson, R. L.: The hemodyuuinic effects of hypotensive drugs in WILSON 865 man. ITI. Hexamethonium. J. Clin. Invest. 32: 1285, 1953. 10 —_: Combinations with ganglionic blocking agents. Symposium on hypotensive drugs. Evans Me- morial Research Conference, Sept. 15, 19338, p. 126. 1 Smirk, F. H., Doyur, A. E., anp McQuren, E. G.: Control of blood pressure by combined action of reserpine and pentapyrrolidinium. Lancet 2: 159, 1954. 2 Barn, C. W. C., Asutron, F., anp Jones, B. P.: The treatment of essential hypertension with pentolinium tartrate combined with Rauwolfia alkaloids. Brit. M. J. 1: 817, 1955. 8 Frueis, E. D.: Mental depression in hypertensive patients treated for long periods with large doses of reserpine. New England J. Med. 251: 1006, 1954. ‘4 Perry, H. M., Jg., anp ScHroepER, 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. 15 Morrison, B.: Parenteral hexamethonium in hypertension. Brit. M. J. 1: 1291, 1953. 16 Morrow, J. D., ScoroxprEr, H. A, AnD Perry, H. M., Jr.: Studies on the control of hyperten- sion with Hyphex. II. Toxic reactions and side effects. Circulation 8: 829, 1953.