apyright, 1947, by the Sociotp for Experimental Biology and Medicine Reprinted from PILOCEESINGS OF THE SOCIETY MB EXPERIMENTAL BIOLOGY ANJ MEDICINE, 1~947,61,455-458 15829 Effect of Pentaquine in Patients with Hypertension.* EDWARD D.FREIS &D ROBERT W. WILKINS. From thg Evans i&mmial,Xassaehuaetts dk-mmid Hospitals, and the Departnwnt of iVediciae, Boston University Sclwol of iWedicine. The recent observation that pentaquine [6-methoxy+( S+opropylaminoamylanGmo)- quinoline], a new antimalarial agent, pro- duces postural hypotension in normal maG4 raised the question of its usefulness in treat- ing hypertensive patients. The purpose of the present report is to summarize briefly the results of a clinical trial of this compound in a random group of 17 patients with long standing essential ,hypertension including 3 in the malignant phase of the disease. Pricedwe and Results. Pentaquine was administered orally in amounts varying from 120 to 240 mg of the ,base per day, given in equally divided doses every 4 hours. Arterial pressure was measured in the arm by the standard auscultatory method using a mercury manometer. Measurements -were made with the patient resting comfortably in the supine position, and also, during and after 5 minutes (or less if syncope intervened) of motionless standing. Mean arterial pres- sure was .calculated as one-half the sum of o This investigation was supported in part by the Squibb Institute for Medical Research, New Brunswick, N.J. The pentaquine used was supplied by James. A. Shannon, M.D., of the Squibb Insti- tute. ILoeb, R. F., J. 8.111. rl., 1946,1358, 321. 4 Craige, B., Jr., Jones, R., Eiohelberger, L., Altig, A., Pullman, It. N., and Wborton, C. M., to be published. the systolic' and diastolic blood pressure. The pulse rate was palpated at the. wrist or auscultated at the cardiac apex. Patients were *hospitalized for at least 3 days prior to treatment, and were maintained on es- sentially the same regimen before, during and after the period of drug therapy. In the majority of. cases (Table I), after 2 to 7 days of treatment at dosages of 120 to 240 mg per day, a reduction of systolic and diastolic blood pressure occurred, vary- ing from 10 to 40% of the mean arterial ,blood pressure. At the same time there was usuatly a further fall in bIood pressure in the erect position associated with narrowing of pulse p&sure. The pulse rate remained unchanged, or actually decreased in the supine position, and in the majority of pa- tients failed to rise abnormally in the upright position even during marked hypotension. The development of post&l hypotension was not observed in all cases. Four patients exhibited a definite fall in resting blood pres- sure without the development of a further hypotension when erect. Others maintained a lower resting blood pressure for several weeks after the disappearance of the postural effect. However, one patient exhibited a re- duction of blood pressure only in the upright position. In a few patients the depression of arterial pressure first appeared several days after the medication had been discon-. tinued because of toxic reactions. PENTAQUINE IN H&RTENSWE PATIENTS TABLE I. Summary of Cases. Ses Blood pressure Dosage Supine blood prior to pressure at - Postural pentaquine, Dars to return time of max. Age treatment mg/day to pretreatment fall blood pressure hypo- Toxic tension effects F. M. F. F. Y. F. F. F. GI F. F. M. F. M. F. M. 50 220/120 41 210/130 36 240/140 48 180/110 46 2.00/100 46 230/130 41 230/130 41 220/120 46 170/110 34 .l70/120 46 220/140 49 240/150 51 200/130 49 260/135 47 34 45 `250/U@ 240/140 230/160 120-2 clays MO-3 " 180-2 " 240-l " 120-3 " 120-3 " 180-4 " 180-2 " 240-2 " 120-2 " MO-3 " l20-3 " 180-3 " 120-14 " 120-Z " 120-2 " 180-4 " 240-4 " 120-4 " 60-6 2' 120-3 " 180-4 " 120-3 " 90-7 " 120-2 " 180-4 " 60-11 " 120-3 " 90-11 `3, 120-6 " 120-2 " 150/90 180/118 Discontinued 140/90 c `No response 125/88 150/100 No response 140/90 135/110 180/120 240/150 170/90 , 190/100 1.. , l&/70 140/90 160/100 12+ +++ ++++ 2 + +++ Serere vomiting and pain 3+ + ++ ++ 6 ++++ +++ 20 ++ ++ 20+ 7+ Agranulocytosi$ +0+ +-s 4 0 ++ Postural hypotension 3 days + 3Of 0 + 15 0 ++ Terminal uremia 20 +-IT+ +-i- 12 -I=++ +++ The last 3 patients mere in the malignant phase of essential hypertension. PULSE `z- t $. - + 5 IO OAYS? 30 FIG. 1. 2 days, while several failed to respond to doses as high as 240,mg given for 5 days. Fig. 1 illustrates the `typical response of a patient with essential hypertension. The lowering of blood pressure was often preceded and accompanied by abdominal pain and tenderness, back and. chest pain, frequently girdle in character, facial pallor, anorexia, nausea and vomiting, constipation or diarrhea, loss of weight in a few patients, and rarely by fever. Nausea and vomiting and/or abdominal pain were occasionally suf- ficiently severe to necessitate discontinuation of treatment. Impotence was noted in 2 male patients. Methemoglobinemia and moderate hemolytic anemia occurred in earlier cases but were later successfully controlled Typical response to pentaquine. The vertical broken lines represent arterial pressure readings after 2 minutes in the upright position. The effective dose varied markedly, one by the simultaneous administration of 1 grain of methylene blue with. each dose of penta- patient requiring 120 mg per day given for quine. Cyanosis without signs of cardiac PFNTAQUINE IN HYPERTENSIVE PATIENTS failure or `significant metbemoglobinemia ap- peared in a few patients. In addition to these toxic effects, agran- ulocytosis developed in one .patient after 2 weeks of continuous therapy, and prolonged menses appeared in another, accompanied by evidence of increased capillary fragility. Both patients recovered uneventfully following ces- sation of therapy and ,treatment with peni- cillin in the case of agranulocytosis. There were no other severe reactions in the group. Following cessation of full doses of the drug the blood pressure gradually returned to its previous level over a period of several days to several weeks In most cases the hypotensive effect was not prolon,ged by the administration of 50 to 60 mg of pen&mine per day-. The depression of blood pressure and postural hypotension recurred, however, when the drug was. again administered in full doses, The patients with a malignant phase of essential hypertension as manifested by neu- roretinitis, impairment of renal function, high diastolic blood pressure, weight loss and oth- er signs of rapidly progressing disease, re- sponded to pentaquine similarly as patients with uncomplicated essential hypertension, except that they uniformly required lower dosage (120 mg per day). Coincident with the fall in blood pressure there was considera- ble regression of the pathological changes in the fundi, relief of;headaches and cessation of gross hematuria; but apparently no im- provement in renal function as measured by clinical and clearance tests. Hemodynamic studies using Hamilton manometers for recording arterial pressure and the ballistocardiograph for measuring cardiac output, before and after the hype- tensive effect had been achieved, indicated `that pentaquine caused a reduction of sympa- thetic vasopressor reflexes similar to that oc- curring after surgical sympathectomy.2 This lack of responsiveness was most apparent in those cases which exhibited marked postural hypotension. Measurements of the skin tem- perature in the extremities under control con- 2 Wilkins, R. W, and Culbertson, J. W., unpub- lished data. ditions also indicated a depression of sympa- thetic activity.a Pressor responses to epine- phrine and ephedrine were unimpaired, but epinephrine did not prevent collapse in the erect position. Marked postural hypotension and collapse were prevented, however, by the use of a tight abdominal belt similar to that worn following lumbodorsal splanchnicecto- my. There were no consistent changes in either the electrocardiogram or in the cardiac output! lXscussion. The most interesting effect ob- tained with pentaquine in hypertensive pa- tients resembled that found in certain nor- mal subjectsP namely the appearance of postural hypotension. In addition, hyper- tensive patients often exhibited a reduction in resting blood pressure. The frequent .oc- currence of toxic symptoms at first suggested that the hypotensive effect was merely a re- flection of toxic debility. However, there was no uniform relation between the appear- ance of other toxic symptoms and of the hy- potknsive effect. Furthermore, the hypoten- sion was frequently maintained for several weeks after the disappearance of all other toxic symptoms, and in such instances was associated with considerable subjective im- provement. These results indicate that while the drug is too toxic in the dosage necessary to produce a fall in blood pressure, its toxic and- hypotensive qualities may not be in- separable. The preliminary studies suggested that the mode of action of pentaquine upon the vasomotor system is to depress sympathetic nervous reflexes. Its activity differed from that of. certain other sympatholytic agents such as the tetraethylammonium salts in that the depression of blood pressure was more prolonged and was not accompanied. by .a marked quickening of pulse rate. This main- tenance of a normal heart rate indicates that its depressor effects include the cardiac ac- celerator mechanisms. That pentaquine did `not block the reactivity of the vascular sys- tem to pressor agents was shown by the con- tinued effectiveness of epinephrine and ephel 3Mixter, G., Jr., and Freis, E. D., unpnbli&ed data. PENTAQUINE IN HYPERTENSIVE PATIENTS drine, It is of interest that Moe and Seever# reported central impairment of sympathetic reflexes in dogs treated with plasmochin, a closely related b-aminoquinoline. Summary. 1. The administration of penta- quine in high dosage to patients with essential hypertension frequently produced a signifi- cant reduction in resting arterial blood pres- sure, usually accompanied by the develop- ment of postural hypotension. This depres- sor effect occurred abruptly after several days of therapy and receded gradually over 6 &foe, G. K., and Seevers, Y. H., Fed. Proc., 1946,5, 193. a period of several days to several weeks iol- lowing cessation oi therapy. 2. Patients with malignant hypertension exhibited a similar response, but did not re- quiress high dosage. With the fall in blood pressure ihere was some regression cf neu- roretinitis, headache and gross hematuria: but no significant improvement in renal function. 3. Pentaquine appeared to exert its effects primarily through a sympatholytic action. 4. Toxic reactions to the drug were too frequent and severe to consider its use practicable in the treatment of essential hy- pertension.