Hemodynamic studies and clinical experience with nethalide, a beta-adrenergic blocking agent

Hemodynamic Studies and Clinical Experience with Nethalide, a BetaAdrenergic Blocking Agent* GUSTAV SCHROnER, M .D .

and LARS WERKO, M .D .

Gbteborg, Sweden

URING recent years a new approach to the treatment of some cardiac disorders has

treated atrial fibrillation were also studied but only at rest .

been explored . According to the theory put forward by Ahlquist,t two different kinds of

METHOD Nethalide was administered orally to all subjects . The doses were increased gradually to 0 .2 to 0 .3 gm ., given three to four times daily . In those with untreated atrial fibrillation the first dose was 0 .3 gm . The last doses were given one to two hours before the circulatory recordings started . Before and during treatment with nethalide, hemodynamic studies were performed in the postabsorptive state in the morning except in 1 patient (Case 8), who was studied at noon after a light breakfast . Catheters were placed percutaneously according to the method of Seldinger'I after carbocaine hydrochloride anesthesia in the brachial artery and into the right atrium or a central vein . Pressures were recorded by means of variable inductance transducers and a multichannelled photographic oscillograph ; an electrocardiogram was recorded simultaneously . Cardiac output was determined by a dye-dilution technic, using sulfobromophthalein sodium as an indicators Expired air was collected simultaneously by means of a low resistance system for about five minutes during rest and for about two minutes during exercise . One set of determinations was made at least 30 min. after the catheter insertion in the recumbent position and another set at least 30 min . later, with the patient sitting in a chair . The patients with atrial fibrillation and 1 patient with arteriosclerotic heart disease (Case 11) were studied only in the recumbent position . After a similar rest period, exercise was performed for 11 minutes with the patient sitting on an electrically braked bicycle-ergometer . The cardiac output was determined after nine minutes of work in the middle of the period of expired air collection . Pressures were recorded every second minute . The pressure recording preceding the cardiac output was used for calculations . The workload was of a

adrenergic receptors exist in the circulatory system : alpha- and beta-adrenergic receptors . The beta-receptors are responsible for the adrenergic drive of the heart and also for adrenergic vasodilatation, while adrenergic vasoconstriction is mediated by alpha-receptors . The development of drugs with specific activity against one of those receptors presents an opportunity to influence the heart and peripheral vessels selectively . The beta-adrenergic receptor antagonist first introduced, dichloroisoproterenol,' unfortunately cannot be used clinically because it has sympathomimetic activity, which disturbs its beta-adrenergic blocking activity . Several compounds have recently been synthesized with similar blocking properties . One of them, naphthyl-isopropylaminoethanol (nethalide), has the advantage of having an almost negligible intrinsic sympathomimetie action' The therapeutic possibilities of this drug have therefore been explored in patients with ischemic heart disease 4 's and in those with various cardiac rhythm disturbances! Clinical trials in a few small groups of patients indicate that the approach is worthh pursuing, even though this compound has side effects° and probably never will be widely used . In view of the important contribution of adrenergie regulation of the circulation during stress, we have studied the effect of nethalide on the circulation during exercise as well as during rest in normal volunteers and in patients with hypertension, ischemic heart disease or rhythm disturbances .

Some patients with recent un-

* From the First Medical Service, Sahlgren's Hospital, University of Goteborg, Sweden . 58

THE AMERICAN JOURNAL OF CARDIO7 .OGY



59

Hemodynamic Studies with Nethalide TABLE I

Hemodynamic Data in Eight Normal and Ten Hypertensive Subjects Before (B) and During (D) Nethalide Treatment -HRH (beats/min.) B D

_BA,_ (mm. Hg) B D

Oxygcn Cons . (ml./misr) B D

-LVW (kg. M ./min.) R D

_RQB D

A. Eight Nuns?Subjects

Rest Mean S .E . p Exercise Mean S .E . p

63 .0 2 .1

60 .6 2 .6

147 .4 117 .1 7 .0 4 .5 <0 .001

92 .4 4 .2

89 .6 4 .0

6 .52 0 .42

115 .8 108 .9 6 .1 6 .2 <0 .001

77 .6 66 .0 5 .1 3 .3 <0 .005

134 .4 122 .1 4 .7 4 .9 <0 .05

151 .3 118 .5 4 .0 3 .6 <0 .001

160 .1 142 .6 7 .8 6 .8 <0 .001

286 .8 14 .1

16 .1 14 .9 0 .3 1 .3 <0 .10

B.

Rest Mean S.E . p Exercise Mean S.E. p

6 .14 0 .37

1723 143

266 .4 10 .1

8 .23 0 .77

1633 137 <0 .025

7 .51 0 .60

0-806 0 .023

0 .804 0 .030

25 .5 21 .7 2 .2 2 .6 <0 .02

0 .890 0 .015

0-904 0 .018

11 .68 8 .74 0 .79 0 .64 <0 .001

0 .756 0 .643 0 .013 0 .036 <0 .02

25 .8 21 .7 1 .6 1 .8 <0 .005

0 .929 0 .964 0 .016 0 .015 <0 .05

Ten Hypere nice Patients

6 .34 5 .25 0 .41 0 .24 <0 .01 11 .8 3 .4

277 .7 259 .8 8 .6 10 .1 <0 .10

11 .4 3 .6

1183 82

1179 97

HR = heart rate ; BA„s - brachia! arterial mean pressure ; CO = cardiac output ; Cons . = consumption ; LV W - left ventricular work ; and RQ = respiratory quotient,

moderate degree for each subject, usually 600 kg .M/ min . Standard technics were used in determination of dye concentrations and in gas analyses . Standard formulas were used for calculation of stroke volume and left ventricular work, as were standard statistical methods . The significance of differences was determined by Students' t test . In a few patients with ischemic heart disease and rhythm disturbance, only cuff blood pressures and electrocardiograms were recorded before and during exercise on the bicycle ergometer . Coronary angiograms were made in the patients with ischemic heart disease ; 30 to 50 ml . of 75 per cent Urografin ® was injected through a specially designed intra-arterial catheter, the curved end of which was placed just above the aortic valves . Repeated exposures followed . The details of the technics used have been described earlier .° ,10

ventricular work were unchanged during rest and were lower during exercise . Cardiac output and respiratory quotient were unchanged at rest as well as during exercise . The subjective working capacity was unchanged . The orthostatic hemodynamic reaction was not altered during treatment with nethalide .

BASAL

202

sJ

a 0

Q

55:

150

50

ICES'

E11111Jr

s'i V

90 .:

f0

o

536 100

501

500

I

0

0 S

1 _u

T1

0cons .

•

RESULTS

uNw

NET HALIDE

ErEVCSE

eES

:c n

2502-

25

2000

2f

200

10

110

5V

t

NORMAL SUBJECTS 1KI

An average dose of 0 .61 gm . of nethalide daily for 7 .4 days was given to 4 volunteers and 4 hospitalized subjects without signs of circulatory disease . Their ages ranged from 26 to 40 years . Some hemodynamic data before and during treatment are presented in Table IA and Figure 1 . On nethalide treatment, heart rate, brachial arterial pressure, oxygen consumption and left VOLUME

15,

JANUARY

1965

1 :00 500

5o

T

FIG. 1 . Hemodynamic data on a 29 year old healthy man given 0 .3 gm . of nethalide three times a day for six days between the studies . Exercise is expressed in kg .M/min ., SV = stroke volume in milliliters . For further abbreviations, see Table I .





60

Schroder and Werko BASAL

NETHALIDE

REST EXERCISE .nt"s 300 600

swiia

REST

EXERCISE

srtI .y

SUP! ..

300

600

7

is 0

C C

O

C

oL 0 -cans Co EV 1500r 15 150

1000- 10 100 A

500-

5

Z1 .

50-

Coronary angiogram of a 44 year old man showing total occlusion of left anterior descending branch . Fxe . 4 .

Hemodynamic data on a 64 year old hypertensive man given 0 .3 gm . of nethalide three times a day for six days between the studies . For abbreviations, see Figure 1 . FIG . 2 .

BASAL

Rest

HR

BA

200- •°

; .. .. t ,

NETHALIDE

Exercise

I 100 LVW

1 o

Rest

Exercise

iTs

~] ~C 0

20x o,-eons 10 1500

0

0 1

0o

CC sv n fo r- 100

G 0

SOO-

,

50

i Hemodynamic data on 49 year old man with coronary heart disease and moderate anginal pain on effort (Case 1) given 0 .3 gm. of nethalide three times a day for six days between the studies . For abbreviations, see Figure 1 .

HYPERTENSIVE PATIENTS

Ten patients hospitalized for evaluation of hypertension were given approximately 0 .56 gm . of nethalide a day for 5 .6 days . Their ages ranged from 43 to 64 years . One had slight papilledema ; the others had only minor changes in the ocular fundi . None had renal insufficiency or cardiac enlargement (cardiac volume not over 470 ml ./Ms . body surface area) . Some data before and during treatment are presented in Table is and Figure 2 . On nethalide treatment, heart rate, brachial arterial pressure and left ventricular work were lower than before treatment . This was most evident during exercise . The respiratory quotient increased . Cardiac output decreased only during rest and oxygen consumption was unchanged . Peripheral resistance was unchanged during rest but was lower during exercise (13 .9 to 12 .7 peripheral resistance units ; p < 0 .01) . Stroke volume was the same during rest on nethalide treatment and increased during exercise (78 .6 ml . before treatment and 96 .9 ml. when nethalide was given ; p < 0 .001) . The subjective working capacity was the same on nethalide treatment, and the orthostatic adaptation was not altered .

FIG . 3 .

ISCHEMIC HEART DISEASE

Six male patients with typical severe anginal pain on effort were followed before and during THE AMERICAN JOURNAL OF CARDIOLOGY



Hemodynamic Studies with Nethalide

61

TABLE R

Hemodynamic Data in Seven Patients with Coronary Artery Disease, Arrhythmias and Toxic Goiter

Case No .

State

.-HR_ (beats/min .) B D

_BAy- , (mm, Hg) B D

CO(L,/min .) B D

.-Oxygen, Cons. (ml /min .) B D

.-LVW. (kg.M ./min .) B D

-Rfr. B D

A . Coronary Artery Di.,enrc

Rest Sitting 300 kg M.

68 70 100

65 62 88

118 121 130

95 89 106

6 .22 5 .33 996

5 .64 5 .12 9 .01

394 396 1204

361 318 1245

10 .0 8 .8 16 .6

7 .3 6 .2 13 .0

0 .67 0 .77 0 .83

0 .81 0 .82 0 .97

Rtst Sitting 600 kg .M.

54 50 103

49 49 95

76 72 114

82 71 108

7-13 5 .71 17 .1

6 .00 5 .69 14 .3

284 261 1750

257 245 1691

7 .4 5 .6 26 .6

6 .7 3 .5 21 .0

0 .74 0 .73 1 00

0 .78 0 .74 1 .02

B . Amhythmlas

5

Rest Sitting 600 kg .M.

65 66 180

59 59 124

93 90 103

91 85 98

7 .91 6 .63 12 .2

7 .61 6 .50 14 .0

368 361 1975

348 341 1904

10 .0 8 .1 17 .1

9 .4 7 .5 18 .7

0 .76 0 .79 0 96

0 .76 0 .82 0 .98

Real Sitting 600 kg . M .

54 92 170

67 155* 138

93 95 107

96 10o* 106

8 .35 8 .72 14 .2

7 .27 5 .87* 11 .3

283 338 2003

280 306* 1941

10 .6 11 .3 20 .6

9 .5 8 .0* 16 .3

0 80 0 .80 1 .03

0 .78 0 .82* 0 .95

Rest 600 kg .M .

108 192

118 168

95 98

98 106

8 .63 17 .6

6 .79 12 .5

294 16,76

276 1602

11 .1 23 .4

9 .0 1A 0

0 .76 .95 0

0 .73 0 .99

C . ra.xie Golfer

6

Rest 600 kg .M .

71 183

60 128

89 113

75 109

7 .82 14 .4

7 .47 15 .2

349 1798

307 1751

9 .5 22 .1

7 .6 22 .5

0 .75 1 .03

0 .76 1 .00

7

Rest 600 kg .M .

59 165

55 128

119 159

104 145

6 .50 14 .8

5 .70 15 .0

312 1627

296 1648

10 .5 32 .0

8 .1 295

0 .71 0 .91

0 .74 0 .98

* Atrial fibrillation.

nethalide treatment on a dosage schedule of 0.3 gin . three times daily . Two patients (Cases 1 and 2), aged 49 and 50 years, one with occlusive coronary disease according to the angiogram and the other with a myocardial infarction two years earlier, were studied during rest and exercise (Table ii, Fig . 3) . Their hemodynamic reaction to nethalide was similar to that of the normal subjects . The heart rate during exercise was lower on nethalide, as were brachial arterial pressures, cardiac output and left ventricular work . The respiratory quotient was somewhat higher . When untreated, they experienced chest pain during work which did not appear while under treatment with nethalide . Their ordinary daily working capacity was also increased . Three patients with occlusive coronary disease (Fig . 4) and anginal pain on effort were given nethalide for several weeks in a dosage of 0 .3 gm. three times daily . In repeated exercise tests, the heart rate and blood pressure were obviously lower during nethalide treatment . VOLUME

15,

JANUARY

1965

In every patient it was possible to increase the workload before pain developed . Figure 5 illustrates a typical response . A 40 year old man with hypcrlipemia (Case 11), a nine month old myocardial infarction and extensive occlusive changes demonstrated in the coronary angiogram was given nethalide . Before treatment he had severe anginal pain at rest and frequent ventricular extrasystoles . During treatment the pain disappeared, and the number of extrasystoles decreased somewhat . The heart rate and cardiac output were lower and the arterial pressure higher during treatment with nethalide . ARRHYTHMIAS

Two subjects, 1 woman aged 23 years and 1 man aged 37 years (Case 3, Table n), with sinus tachycardia, were treated with nethalide that lead to lower pulse rate and blood pressure . A side effect (nausea) of the treatment caused withdrawal of the drug in the woman . The effect of nethalide treatment in a 39 year old woman with paroxysmal atrial fibril-



62

Schroder and Werkb BEFORE TREATMENT 200

EXERCISE lro Xpm I RECOVERY REST

NETHALIDE I EXERCISE 200 Mpm I RECOVERY REST

NETHALIDE II EXERCISE EXERCISE 200 kpm IOC kpm I 7 RECOVERY REST

150 BA 100 50 120 100 HR

Pains

Slryht pmc5

0 P

0 0

80 60

0

O 0

0

c0FIG . 5 . Data from three studies on a 44 year old titan with occlusive coronary disease and angina on effort, given 0 .2 gm . of nethalide for 3 and 30 days, respectively, before the second and third study . For abbreviations, see Figure 1 . lation which was not responsive to digitalis and to nethalide was similar to that found in the quinidine (Case 4) and in a 20 year old man normal subjects . In both patients it seemed with supraventricular tachycardia (Case 5) is that treatment with nethalide caused diminished frequency of attacks of abnormal shown in Table It . The circulatory reaction rhythm during the first weeks of treatment, BASAL N E T HA LID E Thereafter, no effect on the abnormal rhythm was noticed . HR REST EXERCISE REST EXERCISE 11300300 600 300 600 TOXIC GOITER 9A Two hyperthyroid patients, a woman aged 49 years (Case 6) and a man aged 52 years • 200 (Case 7), were given 0 .3 gin . of nethalide three times a day for a week (Table n and Fig . 6) . During treatment, heart rates and brachial arte100 rial pressures became lower both at rest and during exercise . Cardiac output, left ventricular 0Z cons work and oxygen consumption decreased some2000 what during rest . In another woman, aged 29 oL years, with toxic goiter, side effects (nausea) front CO SV nethalide necessitated withdrawal of the drug . n 150A 1500 15This patient had lower blood pressure and heart rate during rest and exercise . 1000

10 - 100

500

5 - 50

A

Fin . 6 . Hemodynamic data of a 52 year old man with toxic goiter (Case 7) given 0 .3 gm . of nethalide three times a day for a week between the studies . For abbreviations, see Figure 1 .

ATRIAL FIBRILLATION The 3 patients (Cases 8, 9 and 10), aged 74 58 and 70 years, respectively, with recent atrial fibrillation without obvious heart failure, reacted to nethalide with a marked and consistent decrease in heart rate (Table III) . In the doses used, this decrease was not comparable to that seen after full digitalization . The administration of lanatoside C caused a further decrease in rate when given during continuous nethalide treatment . THE AMERICAN JOURNAL OF CARDIOLOGY



Hemodynamic Studies with Nethalide

63

TABLE In

The Effect of Nethalide and Nethalide Plus Lanatoside C in Three Patients with Untreated Atrial Fibrillation Patients with Atherosclerotic and One with Hypertensive Heart Disease) .

Control CO

HR

(L ./min .) (per min .)

Stroke volume (ml .)

BA, (mm. Hg)

Nethalidc First Day After N, N, N,

(Two

1

Week N,

Lanatoside C Dig ., Dig .t

Case

B,

B,

8 9 10

3 .06 6 .11 6 .60

2 .78 5 .10 7 .24

2 .41 5 .60 6 .24

2 .55 4 .92 6 .03

2 .43 6 .40 5 .07

6 .65 5 .47

3 .66 5 .79 5 .39

3 .31 5 .83 5 .34

8 9 10

174 106 81

150 110 85

136 106 79

130 92 74

113 80 77

82 72

103 70 62

80 71 64

8 9 10

18 58 82

19 46 85

18 53 79

20 57 82

22 80 66

.. 81 76

36 83 87

41 82 83

8 9 10

104 143 80

90 139 75

95 135 77

94 130 70

96 126 122

123 121

114 128 113

107 120 114

B, and B, basal studies and N, and N s post-nethalide (0 .3 gm.) studies all made at an interval of an hour on the first investigation day. N, and N, studies after one week of nethalide treatment with the last dose (0 .3 gm.) given two hours before . Dig ., and Dig., studies one and two hours after administration of 1 .2 mg . lanatoside C, intravenously . For other abbreviations see Table I .

In 2 of the 3 patients (Cases 9 and 10) the cardiac output was normal, and the stroke volume was borderline normal . Neither nethalide nor digitalization caused any alteration in cardiac output in these subjects . In the third patient (Case 8) the cardiac output was extremely low when fibrillation began . Nethalide decreased the output further, while digitalization increased the output . The stroke volume was largely unaltered by nethalide in all patients and was increased by digitalis . The arterial pressure was the same during nethalide treatment . After lanatoside C was added, the pressure increased in Case 8, paralleling the cardiac output increase . SIDE EFFECTS

In all, nethalide has been given to 46 subjects, 7 of whom complained of such side effects as nausea (5), vomiting (2), diarrhea (1) and paresthesia (1) . In 3 of these subjects the symptoms necessitated withdrawal of the drug . The paresthesia was of a mild type and was described as numbness or as a creeping sensation in the skin . One 65 year old woman with mitral valvular disease was being treated with nethalide when quinidine was added to maintain sinus rhythm. Signs of left ventricular failure with dyspnea and moist Tales over her chest followed . When quinidine was withdrawn, the symptoms vanished . VOLUME

15,

JANUARY

1965

Due to these side effects and the possibility of carcinogenic effect, the drug has been given for only one or two weeks to each patient except for 4 with anginal pain and severe ischemic heart disease who have shown much improvement on treatment and have had no side effects . They have been under continuous treatment for several months . DISCUSSION

According to its pharmacologic properties,' nethalide should have a suppressing or inhibiting effect on almost all adrenergic actions on the heart ; the finding that it decreases heart rate, especially during exercise, in subjects with sinus rhythm is well in line with this presumed effect . The occasional decrease in cardiac output observed during nethalide treatment is also consistent with its adrenergic myocardial blocking action . The negative inotropic effect of nethalide, recorded after intravenous administration in man as a diminished rate of increase of isometric pressure in the right ventricle," was not evident as a decrease in stroke volume, which was unaltered or even increased . The same effect on stroke volume was noted in the present study after prolonged oral use . The increase in stroke volume on nethalide may be due to the better ventricular filling that occurs when the heart rate is slower . The decrease in outflow re-



64

Schroder and Werko

sistance due to lower arterial blood pressure, which was most obvious in the patients with arterial hypertension, may also contribute to some augmentation of the stroke volume . An increase in the end-systolic volume, due to the negative inotropic action that is likely to occur, must be obscured by the other heart effects induced by nethalide . The arterial blood pressure was lower during nethalide treatment, especially in patients with hypertension during exercise . As the cardiac output usually was unaltered, the peripheral resistance decreased on nethalide . Beta-adrenergic blocking should, rather, cause an increase in total peripheral resistance and blood pressure when the active adrenergic vasodilatation is blocked, as has been shown regarding the forearm circulation in man after infusion of nethalide 4 Intrinsic, perhaps sympathomimetic, properties of the drug may instead be responsible for the drop in pressure thus obscuring the loss of local active vasodilatation . Regarding glucogenolysis and release of free fatty acids, such intrinsic sympathomimetic effects of nethalide have been reported . The finding that the same exercise-load was performed with a lower oxygen consumption may, similarly, be due to some metabolic effects of the drug ; this interpretation is supported by the increase in respiratory quotient, indicating that a shift to less oxygen-consuming carbohydrate metabolism had taken place . This change is also reflected in alterations in the metabolism of free fatty acids and in triglyceride and glucose concentrations in the blood ." An explanation of the lower cardiac output on the same exercise-load that was sometimes seen during nethalide treatment could be a different distribution of blood flow, due to changes in vessel tone induced by the drug . Such interference with the regulation of peripheral blood flow, in conjunction with the negative inotropic effect, may be responsible for the signs of left ventricular failure seen in some older patients with weak myocardium,' as well as for the failure to increase the stroke volume in patients with arteriosclerotic heart disease and recent atrial fibrillation when their heart rate was slowed by nethalide . In contrast to this adverse effect of nethalide, it has been found that patients with severe anginal pain and ischemic heart disease often get relief of symptoms' and may increase

exercise tolerance . The present finding of reduced demand on the heart by the slower heart rate and attenuated increase in blood pressure and sometimes in cardiac output that nethalide induced during exercise gives a reasonable background for this improvement . The decrease of left ventricular work, together with longer diastolic time, should bring about a better nutritional state in ischemic myocardium, leading to increase exercise tolerance . Nethalide seems to be of little value in the treatment or prophylaxis of ectopic arrhythmias, an experience also reported earlier .' The only exceptions to this conclusion seem to be patients with digitalis intoxication and the occasional patient with atrial fibrillation whose heart rate is difficult to control with digitalization only .' The possibility remains, however, that other beta-adrenergic blocking drugs may be more useful in arrhythmias . From a theoretic point of view, the effect in hyperthyroid patients is interesting . The decrease during nethalide treatment in heart rate, cardiac output and oxygen consumption at rest indicates an increased adrenergic tone in this state partly responsible for the symptoms . However, nethalide has no place in the therapy of these patients because other effective specific treatments are available . In a few patients, side effects appeared that necessitate withdrawal of the drug. Rather mild ones, such as nausea, vomiting and paresthesia, usually disappeared after a few days of continuous treatment . The only serious side effect observed was the development of left ventricular failure, but in our patient this was certainly due to the additive depressive action of both quinidine and nethalide on the myocardium . These side effects and the possible carcinogenic action (according to long term toxicity studies in mice, in which lymphosarcoma sometimes developed) make the drug unsuitable for wide clinical use . The present results, however, indicate that the principle of beta-adrenergic blocking could be used in the treatment of some clinical disorders of the cardiovascular system, notably anginal pain and tachycardias . Further development of drugs with these properties may be rewarding . SUMMARY

Nethalide (naphthyl-isopropylaminoethanol), a beta-adrenergic blocking agent, has been given orally to 46 subjects in doses of 0 .2 to 0.3 gm . three times daily for one to two weeks . THE AMERICAN JOURNAL OF CARDIOLOGY

Hemodynamic Studies with Nethalide In 8 volunteers without cardiovascular disease, the heart rate, brachial arterial pressure, left ventricular work and oxygen consumption were lower during standardized exercise when on nethalide, while cardiac output was unchanged . In 10 patients with hypertensive disease, the heart rate, brachial arterial pressure and left ventricular work were lower both at rest and during exercise when nethalide had been given. Cardiac output was lower at rest but unchanged during exercise, and peripheral vascular resistance was lower during exercise . Similar effects were recorded in 2 patients with severe ischemic heart disease, in 3 patients with regular supraventricular tachycardia and in 2 with toxic goiter . In 3 patients with recent untreated atrial fibrillation, nethalide caused a decrease in heart rate and brachial arterial pressure, with unaltered cardiac output. In 6 male patients with severe anginal pain, the exercise tolerance increased and anginal attacks decreased in frequency on nethalide treatment . In one patient congestive failure developed when nethalide and quinidine were given simultaneously . Three patients had side effects, including nausea, vomiting and paresthesia, of a degree necessitating withdrawal of the drug . Several other patients had similar side effects that disappeared on continued treatment . In view of possible carcinogenic effects, the drug was used for a short time except in patients with severe, "untractable" angina . It is concluded that drugs with beta-adrenergic blocking properties may be of value in

VOLUME 15, JANUARY 1965

65

some disorders of the cardiovascular system but that nethalide, due to its side effects, cannot be recommended for widespread clinical use . REFERENCES I . AHLQUIST, R . P . A study of the adrenotropic receptors . Am . J. Physiol ., 153 : 586, 1948 . 2 . POwELL, C . E . and SLATER, J . H . Blocking of the inhibitory adrenergic receptors by a dichloro analog of isoproterenol . J. Pharmacol . & Exper . Therap., 122 : 480, 1958 . 3 . BLACK, J . W. and STEPHENSON, .f . S . Pharmacology of a new adrenergic beta-receptor blocking compound (Nethalide) . Lancet, 2 : 311, 1962 . 4 . DORNHORST, A . C . and ROBINSON, B. F . Clinical pharmacology of a beta-adrenergic blocking agent (Nethalide). Lancet, 2 : 314, 1962 . 5 . ALLEYNE, G. A . 0 ., et al . Effects of Pronethalol in angina pectoris . Brit . M. J., 2 : 1226, 1963 . 6 . STOCK, J. P. P. and DALE, N . : Beta-adrenergic receptor blockage in cardiac arrhythmias . Brit . M. J., 2 : 1230, 1963 . 7 . SELDINOER, S . J . Catheter replacement of the needle in percutaneous arteriography . Acta radiol., 39 : 368, 1953 . 8 . WASSEN, A . The use of bromsulphalein for determination of the cardiac output . Scandinav . J. Clin . & Lab . Invest ., 8 : 189, 1956 . 9 . SCHR6DER, G. and WERK6, L . Nethalide, a betaadrenergic blocking agent . Clin . Pharmacal . & Therap ., 5 :159, 1964. 10 . FORSBERG, S . A., PAULIN, S ., VARNAUSRAS, E. and WERK6, L . Coronary angiography in the diagnosis of coronary heart disease. Acta med. scandinav ., 173, 269, 1963 . 11 . HARRISON, D . C . et al . Effects of beta-adrenergic blockage on the circulation with particular refercnce to observations in patients with hypertrophic subaortic stenosis . Circulation, 29 : 84, 1964 . 12 . SCHR&DER, G. and BJbRNTORP, P. The effect of a beta-adrenergic blocking agent (Nethalide) on serum lipids and glucose in man . Acta med. scandinav., 176 :395, 1964.