Human pharmacology studies with a new, orally active stimulant of cardiac adrenergic beta-receptors

Human pharmacology studies with a new,

orally active stimulant of cardiac adrenergic

beta-receptors

M. Knaus, M.D. B. Pfister, M.D. U. C. Dubach, M.D. P. R. Imhof, M.D. Base& Switzerland

In the management of heart failure, substances that stimulate predominantly the adrenergic &- receptors could be of value as an alternative to, or in combination with, cardiac glycosides and could open up a new therapeutic approach. Such drugs should have a positively inotropic effect without causing any significant acceleration of heart rate. They should not induce arrhythmias, and to be widely applicable they would have to be available in both oral and parenteral dosage forms. The relatively cardioselective /3,-receptor stimulant dobutamine,* though only administrable by intravenous infusion, is the first compound of this type that appears to produce beneficial effects under clinical conditions.2, ll. I6

In investigations in animals, a new experi- mental compound, code-numbered C 50’005/A- Ba or H 80/62,? proved to be a cardioselective p-receptor stimulant satisfying the above conditions.s. 6 In man also it seems to be a selective beta-1-adrenoceptor agonist, which is in addition active by the oral route.16 The results of human pharmacology studies conducted with this preparation, including information on the incidence

From the Research Department, Pharmaceuticals Division, CIBA- GEIGY, Ltd., and the Department of Internal Medicine, University of Base1 Medical Policlinic, Cantonal Hospital, Bawl, Switzerland.

Received for publication Mar. 19, 1977.

Accepted for publication May 9, 1977.

Reprint requests: Dr. U. C. Dubach, Department of Internal Medicine, University of Base1 Medical Policlinic, Cantonal Hospital, Basel, Switzerland. ‘E. Lilly, Research Laboratories, Indianapolis, Ind.: DL-3,4-dihy- droary-N-[3-(4-hydroxyphenyl)-l-methyl-n-propyl]-phenethylam~e hydrochloride.

TCIBA-GEIGY, Ltd., Bawl, Switzerland,: C 50,005/A-Ba; AB H&ale, MGlndal: H @O/62 1-isopropylamino-3-(p-hydroxy-phenoxy)-2-propan- 01 hydrochloride, hereunder referred to as C 50,005/A-Ba.

602 May, 1978, Vol. 95, No. 5

and dependence on dosage of disturbances of cardiac rhythm, are described in the present paper.

Methods

Eight male volunteers free of cardiovascular disorders, who had given their informed consent to the study in writing, each received C 50,005/A- Ba in 5 mg. tablets in doses of 5, 10, and 20 mg. and a placebo, single-blind and in random sequence, at intervals of one week.

To make allowance for the known difference in the incidence of effort-induced arrhythmias due to age,21 the subjects were divided into two groups, one consisting of the four younger subjects, aged between 23 and 26 years (average 24 f 0.6 years) and the other of the elder subjects, whose ages ranged from 49 to 55 years (average 52 * 1.5 years).

In preliminary tests on a bicycle ergometer (Elema Schonander EM 369), the individual workloads producing an increase in heart rate of 160 beats/minute in the younger group and 140 beats/minute in the elder group were determined. These figures correspond to about 80 per cent of the maximum attainable heart rates in the respective age gro~ps.‘~ In the morning, before the preparations were taken, recordings were made of heart rate and the E.C.G. and blood pressure was measured by the cuff method, after the subjects had lain quietly for 15 minutes. The E.C.G. tracing, carotid pulse wave, and phonocardiogram were recorded simultaneously on a three-channel writer (Cardiopan 3 T, Type 703, Philips, Zurich) for subsequent evaluation of the systolic time intervals according to the method of Weissler and

0002-8703/78/0695-0802$00.90/0 0 1978 The C. V. Mosby Co.

A new adrenergic b-receptor stimulant

associates.2” After taking the preparations, the subjects were given a light, standardized break- fast. The same parameters were then registered again 30 minutes later, and thereafter at hourly intervals throughout an observation period of five hours. In addition, after 1,2, and 5 hours, exertion tests of five minutes’ duration were performed on the bicycle ergometer at the previously determined individual workloads. During exercise and during the recovery phase, the E.C.G. was moni- tored continuously on a direct writer.

Starting 30 minutes before the administration of the preparations, continuous E.C.G. recordings were made over an average period of 5% hours on a single-channel, battery-powered, portable tape recorder (Holter Avionics Model 400 Electrocar- diocorder).14 The self-adhesive electrodes were fixed on the midclavicular line at the fifth right intercostal space, on the manubrium sterni and in the V, (exploratory electrode) position. The running speed of the recorder was checked to make sure that there were no fluctuations. The E.C.G. tapes were scanned on an Avionics Model 650 Electrocardioscanner at 60 times the record- ing speed. Any significant morphological alterations appearing on the oscilloscope and any abrupt changes in heart rate were examined at normal speed and simultaneously traced out for detailed analysis at a paper speed of 25 mm/set.

In a second series of tests, C 50,005/A-Ba was given in a dose of 15 mg. thrice daily on two consecutive days to four young volunteers aged 23 to 27 years (average 25 years) and the effects were compared with those observed after the administration of placebo on a previous occasion. E.C.G. tracings were recorded continuously for nine hours daily. The subjects were instructed to pursue their normal everyday activities throughout the study.

The statistical significance of the differences between any changes observed after placebo and those produced by the test substance was determined by the t test and is indicated in the figures by * = p c 0.05, ** = p < 0.01, and * * * = p < 0.001. All the values quoted are means with the corresponding standard errors (X f s;;).

Results Effects of single oral doses.

Heart rate (Fig. 1). Thirty and 60 minutes after the administration of C 50,005/A-Ba, there was a dose-related increase in heart rate of 8 to 20

AHR b/min

241Tw

-4 I I I I

8-- - --.

12 + 0 30 60 120 180 240 300 min

Fig. 1. Changes in heart rate after single oral doses of C 50,005/A-Ba (n = 8).

beats/minute above the placebo value. The differences were statistically significant at all dose levels up to 120 minutes after administration. The effects of doses of 5 and 10 mg. C 50,005/A-Ba remained demonstrable for three hours and that of 20 mg. for four hours. There was no statistically significant difference between the results observed in the two age groups.

Arterial blood pressure (Fig. 2). The effect of C 50,005/A-Ba on systolic pressure differed in the two age groups. A dose-related increase occurred in both, but the values 30 and 60 minutes after administration at all dose levels were distinctly higher in the younger than in the older subjects (18 to 31 as against 4 to 21 mm. Hg). The increases in systolic pressure 30 minutes after the administration of the drug were all statistically significant, except at the 5 mg. dose level in the older group.

The effect .of C 50,005/A-Ba on diastolic pressure also differed in the two age groups. At all dose levels there was a more marked decrease in the younger group.

The maximum effect on systolic pressure was observed after 30 minutes, except at doses of 5 mg. in the elder and 20 mg. in the younger group. The duration of effect was two hours after a dose of 5 mg. and, in the younger subjects, up to four hours

American Heart Journu2 603

Knaus et al.

ASAP mm Hg llllllllllllllllllllllll 52 2 1.5vrs.

ADAP 60 180 300 0 60 180 300 0 60 180 300 min

Fig. 2. Changes in systolic and diastolic blood pressure in younger and elderly subjects after single oral doses of C 50,005/A-Ba (n = 8).

after 20 mg. The maximum effect on diastolic pressure was noted between 30 and 60 minutes after medication. The decrease was slight and not dose-related, and by comparison with the placebo values only significant at one determination each after 5 mg. (p < 0.05) and 10 mg. (p c 0.01). The duration of effect was 2 to 3 hours.

Pre-ejection period (PEP) (Fig. 3). The changes in the rate-corrected pre-ejection period (PEP,), which serves as an index of myocardial contractility, were not significantly different in the two age groups. An increase in contractility, reflected in a distinct decrease of approximately 10 msec. in the duration of the PEP, and attributable to diges- tion, was observed after placebo medication. Thirty minutes after the administration of C 50,005/A-Ba, there was a dose-related decrease in PEP,. In relation to the placebo values, the reductions recorded after 510, and 20 mg., respec- tively, were -16.9 msec. (p < 0.05), -17.3 msec. (p < O.Ol), and -24.3 msec. (p < 0.001); the corresponding 60-minute values were -8 msec. (n.s.), -17 msec. (p < O.Ol), and -14 msec. (p < 0.05). Up to three hours after doses of 10 and 20 mg., the reductions were significantly (p < 0.05) different from the placebo values. The maximum increase in contractility was reached 30 minutes after 5 and 20 mg. and 60 minutes after 10 mg., and the duration of this effect after 10 and 20 mg. was three hours.

whom the E.C.G. was recorded continuously over an average period of 5 3/4 hours, one ventricular extrusystole (VES) was seen during the first exercise test after placebo medication. After the administration of C 50,005/A-Ba, there was an on the whole slight, non-dose-related and statistically non-significant increase in the frequency of VES; in five of the eight subjects altogether 11 VES occurred-five in three subjects after 5 mg., one in each of three subjects after 10 mg., and one in each of three subjects after 20 mg. Of the total of 11 VES recorded after the administration of the drug, only two occurred during effort.

Supraventricular extrasystoles (SVES) were not observed after placebo, but altogether 17 appeared in five subjects after C 50,005/A-Ba (seven after 5 mg., seven after 10 mg., and three after 20 mg.). Scrutiny of the E.C.G.‘s revealed the combined occurrence of SVES and VES in half of the tracings. Only one of the 17 SVES arose during effort.

Continuous E.C.G. recordings (Figs. 4 and 5; Table I). In each of two of the eight subjects, in

Sinus arrhythmias (SAR) with changes in pulse rate of more than 30 beats/minute within 4 seconds were recorded in seven of the eight subjects after placebo. These changes were mainly observed in the younger group and were in some cases associated with a considerable slowing of sinus rhythm, independently of respiration, and without any conspicuous alteration in the P wave. Prior to the change, heart rate was usually relatively fast (> 90 beats/minute). After the administration of C 50,005/A-Ba, except in a dose

604 May, 1978, Vol. 95, No. 5

A new adrenergic P-receptor stimulant

of 5 mg., the frequency of marked SAR increased slightly during the observation period of, on the average, 5% hours; after 10 mg. the average for all subjects rose from 81 (placebo and 5 mg.) to 102 (n.s.), and after 20 mg. to 149 (p < 0.05). In three subjects, however, the occurrence of marked SAR after the various doses of C 50,005/A-Ba was no more frequent than after placebo, and in some instances even less so. In general, not only the frequency of SARs increased but also their intensity, since there was a dose-related acceleration of the basic heart rate, and such abrupt bradycardic phases resulted in extreme fluctuations of sinus rhythm by up to almost 50 beats/minute. Between the second and fourth hours after the administration of C 50,005/A-Ba, but also after placebo, SARs tended to be slightly more frequent; otherwise they were fairly regularly distributed throughout the observation period. In particular, their occurrence did not specifically coincide with the maximum effect of the drug.

In four subjects, transient sinus arrest lasting for 1.1 to 1.4 seconds was observed on one or two occasions, with subsequent slowing of rhythm and unchanged QRS complexes. In one case, this phenomenon only occurred after placebo; in the other three, it was noted once after 5 mg. C 50,005/A-Ba, twice after 10 mg., and once after 20 w.

Changes in the ST segment were visible in the E.C.G. of one 55-year-old subject whose tracings both at rest and during effort had been normal before treatment. Twenty-five minutes after a dose of 20 mg. C 50,005/A-Ba, depressions of the ST segments by more than 1 mm. appeared, unaccompanied by any corresponding clinical symptomatology. As can be seen in Fig. 5, there was .a correlation between the extent of the ST depression and that of the rise in heart rate and systolic blood pressure.

Effects of repeated administration.

Continuous E.C.G. recordings (Table II). The changes in cardiac rhythm observed in four healthy young volunteers after 15 mg. three times a day of C 50,005/A-Ba and placebo on two consecutive days are indicated in Table II. The E.C.G. tracings recorded continuously for an average of nine hours daily showed isolated SVES in all four subjects after the placebo. On the first day of treatment with C 50,005/A-Ba SVES were only seen in two subjects, but on the second day

A PEP, in msec

6 3b Bo Go do 2iO 30bmin

Fig. 3. Changes in rate-corrected pre-ejection period (PEP,) after single oral doses of C 50,005/A-Ba (n = 8).

they were again present in all four. No alterations due to treatment could be established. VES did not occur after placebo medication, and altogether only four were seen on the two consecutive days of treatment with C 50,005/A-Ba.

The frequency of marked SAR increased on the first day of treatment with C 50,005/A-Ba and diminished again on the second. They tended to occur more often during the first hour after the first dose on the first day. None of the above- mentioned changes was statistically significant.

Subjective tolerability. Single doses of C 50,005/A-Ba were subjectively well tolerated. Fifteen to 20 minutes after doses of 10 mg. and 20 mg. six of the eight subjects experienced palpitations, which usually disappeared within an hour. One of the younger subjects also had a feeling of tightness in the chest and slight headaches at all dose levels.

On the first day of repeated administration, two of the four subjects felt slight palpitations 15 minutes after taking C 50,005/A-Ba. No other undesirable effects were reported.

American Heart Journal 605

Knaus et al.

after Placebo

aftur C 50 005/A-L 5q

aftrC50 005/A-88 10~14

aftc C 50 005/A-Ba 20119

Fig. 4. Accentuation of sinus arrhythmia by single oral doses of C 50,005/A-Ba in one healthy volunteer.

Fig. 5. Depression of ST segment in a 55-year-old subject after a single oral dose of 20 mg. C 50,005/A-Ba.

606 May, 1978, Vol. 95, No. 5


Table I. Occurrence of arrhythmias during an observation period of 5% hours after single oral doses of C 50,005/A-Ba and placebo (n = 8)

Subj, No. Activity

Placebo 5 mg. 10 mg. 20 nlg.

SVES VES SAR SA SVES VES SAR SA SVES VES SAR SA SVES VES SAR SA

197

200

222

226

162

192

195

224

Everyday activity during ergometry







Everyday activity

3 5 2 10

30 16 32 1 27 2 1

18 3 20 1 1 20 1 1 25

14 1 2 12 1 1 8 14

7 2 1 8 1 1 10

2 3 9 4 1 10 1 21 1 1 1 1

1 10 7 1

7 11 15 32 I during ergometry 1

Total -i Tlr .-F 5 YiT-7 TGG-3 3 147* r

‘p < 0.05. Abbreviations: SVES = supraventricular extrasystolee; VES = ventricular extrasystoles; SAR = sinus arrhythmias; SA = sinus arrest.

Discussion

Stimulation of the cardiac adrenergic /3-receptors leads to an increase in heart rate and myocardial contractility. If the cardiostimulation is not accompanied with peripheral vasodilatation, there is an increase in systolic blood pressure, which through the intervention of the barorecep- tom checks the acceleration of heart rate. This is certainly one reason why the increase in heart rate following the administration of dobutamine,9 and also C 50$05/A-Ba, is generally fairly moder- ate. A further explanation could be that there are-as various authors have postulated**, 25-two different types of cardiac &receptor, of which one predominantly mediates chronotropic and the other inotropic effects. There would accordingly be &stimulants and &blockers that preferen- tially act on the one or the other type of receptor. Evidence has, in fact, been adduced suggesting that this is true of certain P-blockers3

One, as it were, unexpected by-product of this study was the finding that the susceptibility of the cardiac adrenergic P-receptors to stimulation diminishes with age, as manifested by the smaller increase in systolic blood pressure noted in the older subjects. No such difference due to aging was, however, detectable in the increase in heart rate, which in the case of preparations like C

Table II. Occurrence of arrhythmias during an observation period of 9 hours daily on two consecutive days after 15 mg. t.i.d. C 50,005/A-Ba and placebo (n = 4)

Placebo Day 1 Day 2 Subj. . No. SVES VES SAR SVES VES SAR SVES

197 1 4 1 14 3 1 200 1 10 58 2 33 220 1 2 2 28 2 1 5

226 7 11 195 14 - A -

Total 10 25 3 -i-10912 -i-iii

Abbreviations: SVES = supraventricular extrasystoles; VES = ventricular extrasystoles; SAR = sinus arrhythmias.

50,005/A-Ba is, of course, also mediated by the /3-receptors. This can be attributed to the loss of sensitivity of the baroreceptors with advancing age,2o as a result of which the restraint on the increase in heart rate following the rise in systolic pressure was less marked in the older subjects than in the younger subjects; hence no difference in the increase in heart rate in the two groups was seen for reasons not directly connected with cardiac function. Whether the diminished susceptibility to &stimulation is caused by a loss of sensitivity or a decrease in the density of


Knaus et al.

P-receptors due to aging is a matter for specula- tion. This finding is concordant with the observations by Btihler and colleagues,4 who reported that the extent to which the P-receptors could be blocked in hypertensive patients diminished with age.

Another object of the present study was to ascertain whether the cardioselective P-adrenergic receptor stimulant effect of C 50,005/A-Ba is inevitably associated with an arrhythmogenic effect, such as the catecholamines are known to produce. Several authors’. ?. IQ. 23 maintain that dobutamine has no such effect, but their cdnclu- sions are based on observations made in patients confined to bed. There have also been reports to the contrary: Loeb and associates19 and Gunnar and co-workers,‘3 for instance, noted an increase in the frequency of ventricular extrasystoles during the infusion of dobutamine in patients with heart failure. The fact that ventricular and supraventricular extrasystoles can also occur in persons free of any cardiac disorders makes it extremely difficult to assess the arrhythmogenic potential of a drug. The published incidences of extrasystoles in healthy persons vary widely; in one study Engel and Burckhardt’” recorded an incidence of 31 per cent, whereas Dietz and KirchholF and Clarke and collaborators’ quote figures up to 70 per cent and 72 per cent. McHenry and co-worker9 found a clear correlation between age and the occurrence of extrasystoles during maximum effort on a treadmill. In a later study, the same authors” also observed that the individual reproducibility of effort-induced ventricular extrasystoles in two consecutive tests was not more than 55 to 62 per cent, depending on age; according to Jelinek and Lown15 it was even below 50 per cent. Moreover, studies carried out by various investigators have shown that both the frequency and the type of arrhythmias occurring in clinically sound-hearted persons differ greatly.‘. *. lo Conclusions as to the possible arrhythmogenic potential of a drug can only be reached if the E.C.G. is recorded continuously over many hours. This was done in our study, and in addition to pursuing their normal everyday activities after being treated with the substance, the subjects were also repeatedly subjected to a submaximum workload on the bicycle ergometer, to increase the likelihood of arrhythmias becom- ing manifest by raising sympathetic tone. It was found that C 50,005/A-Ba caused a slight, statis-

tically nonsignificant and non-dose-related increase in the frequency of supraventricular and ventricular extrasystoles and an increase in the frequency and degree of marked sinus arrhythmias, which at the highest tested dose level of 20 mg. was just barely significant in relation to the placebo values. Marked sinus arrhythmias such as we observed in seven of our eight subjects were seen by Engel and Burckhardt’” in 34 per cent of their group of young subjects. Dietz and KirchhofF noted changes in the P wave with an abrupt, distinct slowing of heart rate in 55 per cent of their series of 30- to 40-year-old subjects. These changes seem to arise in predominantly vagotonic phases, above all in relatively young asthenic individuals. The possibility that they may be due to depression of the sinus node pacemaker has been discussed.“, iii The increase in sinus arrhythmias of this type after the administration of C 50,005/A-Ba likewise seems to result from transient elevations of vagal tone caused by a baroreceptor response to the increase in stroke volume or blood pressure, or both.ls Like all other inotropic catecholamines, the substance would thus appear to have a certain, though slight, arrhythmogenic potential. The clinical significance of this effect can only be assessed by further careful investigation, preferably in patients with heart disease.

The occurrence of a marked depression of the ST segment in one of the elder subjects after the administration of C 50,005/A-Ba can be interpreted as a manifestation of latent coronary disease. It is not surprising that the substance should provoke this effect, since it augments stroke volume and heart rate, and in the absence of vasodilatation also leads to a relative increase in afterload with a corresponding rise in the myocardial oxygen requirement. It is conceivable that a preparation of this type could be employed diagnostically in a simple test of cardiac function similar to that suggested by Rivier and colleagues2” based on the infusion of isoprenaline. At all events this finding underlines the need for the utmost caution in the further evaluation of the compound, if it is administered to patients with coronary disease.

Conclusions

On the basis of the available data, preparation C 50,005/A-Ba would appear to merit clinical trial in all acute and chronic disorders associated

606 May, 1978, Vol. 95, No. 5


with diminished pumping efficiency of the heart due to reduced myocardial contractility (power failure). In patients with coronary disease, however, it is possible that it might increase myocardial oxygen requirement to a potentially dangerous degree. The compound could presum- ably also afford a means of counteracting the cardiac effects of P-receptor blockade in the event of undesired reactions such as acute heart failure during therapy with P-blockers. It could likewise prove beneficial in cases of delayed atrioventric- ular conduction. The elaboration of a simple test of coronary function with the aid of this preparation lies entirely within the bounds of possibility.

tricular premature contractions, and also in the incidence and intensity of sinus arrhythmias not due to respiration. Essentially the same changes in cardiac rhythm were observed in four young volunteers during continuous E.C.G. recordings over a period of 9 hours in response to the repeated administration of C 50,005/A-Ba in a dosage of 15 mg. three times a day on two consecutive days. The differences from the corresponding placebo values were, however, not statistically significant.

Summary

The effects of single oral doses of 5, 10, and 20 mg. of a new cardioselective p-stimulant, preparation C 50,005/A-Ba, were tested and compared with the response to placebo in eight healthy volunteers (four aged 23 to 26 years and four aged 49 to 55 years). The compound induced a dose- related increase in myocardial contractility (reduction of 17 to 24 msec. in PEP,) and in heart rate, which was accelerated by 8 to 20 beats/ minute by comparison with the placebo values. The rise in systolic pressure observed in response to C 50,005/A-Ba was both dose-related and dependent on the age of the subjects; in the younger group there was an increase of 16 to 31 mm. Hg and in the older group an increase of 7 to 21 mm. Hg. A slight decrease in diastolic pressure was noted, which was likewise more prominent in the younger subjects. These changes were ascribed to a decrease due to aging in the respon- siveness of the adrenergic P-receptors to stimulation. The effects of the compound set in quickly, reached their maximum within 30 to 60 minutes, and persisted for about 4 hours. The only side effects observed were slight palpitations. Depres- sion of the ST segment was noted in one 55-year- old subject and was interpreted as a manifestation of latent coronary disease. In view of this finding, it seems possible that the preparation could be used as a diagnostic agent for a simple test of coronary function. Continuous E.C.G. recordings over a period of 5% hours, including three ergometer tests at submaximum effort, showed that by comparison with placebo, C 50,005/A-Ba caused a slight increase in the frequency of isolated ventricular and supraven-

C 50,005/A-Ba is thus an orally active cardio- stimulant agent with a high degree of /?,-receptor selectivity and with only a very slight arrhythmogenic potential. It is well tolerated and could afford beneficial effects in the treatment of heart failure or as a countermeasure in therapy with fi- blockers.

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Documents

Human pharmacology studies with a new, orally active stimulant of cardiac adrenergic beta-receptors