first dose response and 24-hour antihypertensive efficacy of the new once-daily angiotensin...

First Dose Response and 241Hour Antihypertensive Efficacy of the New Once-Daily

Angiotensin Converting Enzyme Inhibitor, Ramipril

Mary E. Heber, MRCP, Geoffrey S. Brigden, MRCP, Michael P. Caruana, FRACP, Avijit Lahiri, MB, BS, MSc, and Edward B. Raftery, BSc, MD

The reduction in blood pressure (BP) after the first dose and after 8 weeks of treatment with a new once-daily angiotensin converting enzyme (ACE) inhibitor, ramipril, was examined in 12 untreated hypertensive patients, using ambulatory intraarterial BP monitoring. The first period of monitoring be- gan 24 hours before the first dose was given, and continued for 24 hours afterwards. A second 24- hour period of monitoring was carried out after 8 weeks of treatment, commencing immediately after the morning dose. Angiotensin II levels and serum drug levels were measured at 0,2,6 and 24 hours after the acute dose. BP decreased progressively from the first hour after the first dose, reached a maximum in the fifth hour (p <O.OOl) and then the effect diminished. The maximum reduction of systolic BP in any patient was 64 mm Hg, the mini- mum 4 mm Hg. Blood pressure was significantly (p <0.05) reduced throughout the 24 hours after dosing, with a mean daytime reduction of 13/12 mm Hg, and a mean nighttime reduction of 15/T mm Hg. Angiotensin II levels were significantly (p cO.02) and maximally reduced by 2 hours after administration, but the reduction was no longer significant after 24 hours. Serum drug levels were also maximal 2 hours after administration. The trial population could be clearly divided into groups of good and poor responders on the basis of BP reduction. The angiotensin II levels were higher before treatment, and decreased further, in all patients with a good response than in those with a poor response. Serum drug levels also tended to be higher in good responders. After 8 weeks of treatment with the drug, the decrease in BP was less pronounced (mean daytime reduction 1 l/8 mm Hg, mean nighttime reduction 6/4 mm Hg) but 24-hour duration of action was maintained.

(Am J Cardiol 1988;62:239-245)

From the Department of Cardiology and Division of Clinical Sciences, Northwick Park Hospital and Clinical Research Center, Harrow, Mid- dlesex, England. This study was supported in part by Hoechst UK Ltd. Manuscript received January 7, 1988; revised manuscript received and accepted April 4, 1988.

Address for reprints: E.B. Raftery, MD, Department of Cardiolo- gy, Northwick Park Hospital, Watford Road, Harrow, Middlesex, HA1 3UJ, England.

I nhibition of angiotensin I converting enzyme (ACE) has proved to be effective for the treatment of hypertension.’ Agents that inhibit this enzyme block

the conversion of angiotensin I to the potent hypertensive and salt-retaining octapeptide, angiotensin II. The first ACE inhibitor described, captopril,2*3 proved a highly effective antihypertensive agent,’ but its mer- capto function undergoes slow oxidation, and the drug thus has a relatively short duration of action4 This problem was overcome by the development of N-car- boxymethyl dipeptide inhibitors, in particular enalapril, which has proved to be a potent antihypertensive agent.5 Ramipril also belongs to this class of ACE inhibitors, but in animal experiments has been shown to have a more rapid onset and longer duration of action than enalapril. Studies in healthy volunteers have shown that ACE activity decreases rapidly within the first hour and after a 5 mg dose of ramipril almost complete ACE inhibition is maintained for 8 hours, with some residual effect up to 8 days.7 Preliminary studies in hypertensive patients have shown a significant reduction in blood pressure, persisting up to 24 hours after the dose.8-10 The present study was designed to investigate the rate of onset of the antihypertensive action of ramipril and to test its efficacy over 24 hours, both after the first dose and after long-term administration, in patients with essential hypertension.

METHODS Patients: Patients were recruited from the Harrow

Hypertension Clinic, from among those with untreated hypertension either recently diagnosed or after with- drawal of previous therapy that was not adequately con- trolling their blood pressure (BP). Patients of either sex between the ages of 18 and 65 years were considered for inclusion if their diastolic BP at 3 clinic visits was >95 mm Hg without antihypertensive therapy. Women of child-bearing potential were excluded, as were any patients with significant liver disease or renal impairment (serum creatinine > 150 mmol/liter). Recent myoca rdi- al infarction, severe angina and cerebrovascular disease were also reasons for exclusion, All patients gave in- formed written consent and the study was approved by the Harrow Health Authority Ethical Committee.

Study design: The study was of open design; it has been previously demonstrated that no placebo effect is seen on intraarterial BP recordings” and thus, in view

I-HE AMERICAN JOURNAL OF CARDIOLOGY AUGUST 1,1988 239

ANTIHYPERTENSIVE ACTION OF RAMIPRIL

TABLE I Reduction in Systolic Blood Pressure (mm Hg) After the First Dose of Ramipril Compared with Six Hours the Previous Day

Hours After Dosing

Pt 1 2 3 4 5 6

1 -28 2 -8 3 +12 4 * 5 * 6 0 7 * 8 0 9 -8

10 +12 11 f4 12 0

* Mwng data.

-12 -16 -28 -64 -56 0 -4 -20 -4 i-32 * -48 -24 -32 -20

-16 0 -28 * -4 -4 +16 -4 -16 -12 f8 0 -12 -4 -12 -8 i-8 f4 * +4 -8 +4 -4 -24 -20

+12 -4 -32 -32 -12 -36 -60 -36 -64 -40

-4 -36 -30 -24 -28 t4 -12 -4 -24 -16

of the invasive nature of the investigation, a placebo period was considered to be ethically unwarranted. On the first day of the study, patients attended the hospital for commencement of intraarterial ambulatory BP recording. After insertion of the cannula and fitting and cali- bration of the recording equipment, they underwent a standard regimen of physiologic testing before leaving to resume their normal daily activities. The following morning, after completion of 24 hours of recording, the patients returned to the hospital. Patients were given their first 10 mg dose of ramipril, and 2 hours later physiologic testing was repeated. Intraarterial BP monitoring was continued for 24 hours from the first dose after which the patients returned to the hospital for re-

O-

-5 -

-10 -

-15 -

-20 -

-25 -

-30 -

1 2 3 4 5 6

Time (hours)

moval of the intraarterial cannula and recording equipment.

Ramipril was then administered at a starting dose of 10 mg daily. The patients attended the hospital at 2- week intervals for assessment of BP control by sphyg- momanometer. The dose was titrated in 10 mg incre- ments up to 40 mg or until the diastolic BP was <90 mm Hg. Dosage was then maintained for 4 weeks before a further 24-hour period of intraarterial BP monitoring was performed. Physiologic testing and radionu- elide ventriculography were carried out 2 hours after the morning dose of ramipril, as after the first dose.

Blood samples were taken for measurement of angiotensin II and plasma drug concentration levels before administration of the first dose and after 2, 6 and 24 hours. Further samples were taken immediately before and 6 hours after drug administration on the final day of the study.

Intraarterial ambulatory blood pressure recording: This technique has been fully reported and validated previously.12J3 Briefly, a disposable 3Fr gauge cannula (Seldicath) was inserted into the brachial artery of the nondominant arm under local anesthesia, using a sterile Seldinger technique. This was connected via a l-m length of fine tubing to a specially designed transducer/ perfusion unit, which infused heparinized saline in a concentration of 10 IU/ml at a rate of 1.5 to 2 ml/hr. The BP signal from the transducer and the electrocar- diogram from bipolar chest leads were recorded on a miniature tape recorder (Oxford Medilog, Mark l), which also incorporated a time channel with an event marker. The equipment was designed so that patients could be fully ambulant and carry out their normal daily activities.13

Physiologic testing: The standard regimen of physiologic testing comprised 20 minutes of supine rest followed by head-up tilt to 60° maintained for 5 minutes. Isometric exercise was performed using a handgrip dy- nanometer held at 50% of maximal voluntary contrac- tion for 2 minutes. After at least 5 minutes of rest, this was followed by dynamic exercise on an electrically braked cycle ergometer, at workloads increasing by in- crements of 25 watts at 3-minute intervals, stopping at the patients’ request when they felt they had achieved their maximal effort.

Plasma angiotensin and drug quantitation: Angio- tensin levels were measured by radioimmunoassay after rapid extraction on bonded-phase silica (SEPPAK pro- cedure) and subsequent separation by high performance liquid chromatography. 14,15 S82 6971, the active diacid metabolite of ramipril, was also measured by radioimmunoassay. l6

Analysis of data: The BP tape recordings were re- played and written out on a linear direct-writing recorder to allow assessment of signal quality and elimination of artifact. Hourly sections were then analyzed on a hy brid computer to give mean levels of systolic and diastolic BP and heart rate. Hourly mean values for all

FIGURE 1. Pooled blood pressure and heart rate trends In the patients were pooled and the pooled data used to con- 6 hours after the first dose of ramipril. bpm = beats/min. struct curves to show the 24-hour profiles of BP and

240 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 62

heart rate before and after the first dose of ramipril and after long-term treatment with the drug. Mean 24-hour, mean daytime (12 to 6 P.M.) and mean nighttime (12 to 6 A.M.) BP before and after treatment were calculated for each patient and the values for all patients pooled. These periods were selected as they represented the most stable plateau and trough periods of the 24-hour diurnal curve.” The significance of differences in mean values of BP and heart rate was assessed using Stu- dent’s paired t test (2-tailed).

Mean BP and heart rate during the last 5 minutes of supine rest, the first 90 seconds after tilting and during isometric and dynamic exercise were computed using a standard digitizing program previously described.18 The differences in values before and after treatment were also assessed using Student’s paired t test (2-tailed).

Plasma levels of the active diacid of the drug were compared with inhibition of ACE activity and with reduction in BP using regression analysis; reduction in angiotensin II levels was compared with BP reduction using a similar analysis.

RESULTS Clinical course: Twelve patients (8 men, 4 women)

were studied; their mean age was 53 years (range 41 to 68). None complained of any symptoms of hypotension, or any change in their state of well-being, after the first dose of the drug. One (patient 5) complained of dizzi- ness when the dose was increased to 20 mg, but tolerat- ed the drug well when the dose was reduced again to 10 mg. Another (patient 6) developed a rash 2 weeks after commencing medication. Unfortunately, although he stopped taking the medication, he did not report this until his next planned visit, at which time no rash could be seen, but he was withdrawn from the study. Another (patient 10) developed a hematoma after her first intraarterial study, and a second study was not performed.

Blood pressure: Technically adequate BP recordings were obtained throughout the first 48 hours of monitoring in all patients.

The reduction in systolic BP in each patient for the 6 hours after the first dose is listed in Table I. Assessment of the pooled data showed BP was reduced progressively from the first hour after the first dose, and reached a maximum in the fifth hour (p <O.OOl); the effect then diminished. The maximum reduction in systolic BP after the first dose in any patient was 64 mm Hg. The mean change in BP and heart rate from the pooled data during the first 6 hours after administration is shown in Figure 1.

Heart rate was slower in the first hour after administration compared with the previous day, gradually re- turning to normal by 5 hours, at the time of peak drug effect. This is difficult to explain, but may be because patients were actually tachycardic over this period on the first day of the study, due to a residual altering response induced by the arterial cannulation.

Twenty-four hour profiles, plotted from consecutive mean hourly BP and heart rate during the 24 hours before and after first administration of the drug and

after long-term administration, are shown in Figure 2. The BP was reduced throughout the 24 hours after the first dose, with a mean daytime reduction of 13/12 mm Hg (p <0.02) and a mean nighttime reduction of 16/9 mm Hg (p <0.02). There was no significant change in heart rate.

The trial population could be divided into a group of good responders (patients 1, 3, 8, 9, 10, 11 and 12) and a group of poor responders (patients 2,4, 5, 6 and 7) on the basis of a daytime systolic BP reduction >lO mm Hg over the first 24 hours of monitoring (Table II). The mean reduction in daytime BP for the group of “good responders” was 24/19 mm Hg, for the “poor responders” the mean change was +l/-3 mm Hg. The mean reduction in nighttime BP was 19/l 1 and 9/3 mm Hg, respectively.

BP was also reduced throughout the 24-hour period during the second period of monitoring after long-term administration of the drug (Figure 2). However, it was less compared with pretreatment levels, and neither mean daytime reduction in BP (1 l/8 mm Hg) nor mean nighttime reduction (6/4 mm Hg) reached statistical significance when the pooled data for all 10 patients were considered. One patient (3), who had responded well to the first dose of ramipril, went into an accelerated phase of hypertension before the second study. His mean daytime BP increased by 42/15 mm Hg from the untreated to long-term treatment measurement, which heavily weighted the pooled results, especially with the small sample size. Two other patients, who had responded poorly to the first dose, had a better BP reduction at the time of the second study. Excluding

E 160 = 5

140 120

2 100 ,” : 60 80

o Untreated *Acute 9Chronic

L-20

1012 14 16 18 20 22 24 2 4 6 832

Time of day (hours)

Systolic

Diastolic

FIGURE 2. Twenty-four hour plots of blood pressure and heart rate. bpm = beats/min.

THEAMERICANJOURNALOFCARDIOLOGY AUGUSTl, 1988 241


TABLE II Reduction in Blood Pressure (mm Hg) After the First Dose and After Long-Term Treatment with Ramipril In Good and Poor Responders

Acute Study Long-Term Study

Pt. Mean Daytlme Mean NIghttime Mean Daytlme Mean NIghttIme No. S D HR S D HR S D HR S D HR

Good 1 -34 -28 -7 -26 -14 -4 -41 -26 -4 -24 -10 +3 Responders 3 -23 -25 -14 -28 -16 -6 +42 -15 +6 +56 +23 +3

8 -16 -16 +14 -16 -15 -2 -10 -11 +5 -13 -9 +1 9 -15 -4 -3 -36 -17 +3 -15 -4 -3 -36 -17 +3

10 -40 -30 -16 0 +4 -4 - - -

11 -20 -13 -14 -3 -1 -11 -6 0 -7 +5 +5 -2 12 -18 -14 -8 -27 -17 -6 -23 -20 +9 -15 -15 fl Mean -24 -19 -7 -19 -11 -4 -19* -12 0 -17” -9 +1

Poor 2 +25 +8 0 0 +1 +2 -25 -15 -5 -8 +1 +9 Responders 4 -7 -13 -5 -7 -11 -1 +2 -6 -2

5 -8 -5 -6 -22 -12 -3 -26 -8 -5 -14 -4 -5 6 -6 -3 -6 - - - - -

7 +1 +1 -15 -4 +1 -2 +6 +5 -13 -13 -2 +11 Mean +1 -2 -6 -9 -3 -1 -13 -7 -6 -8 -3 f2

* Excludmg patlent 3 (see text), - mss~ng data D = dmtok BP, HR = heart rate, S = systolic BP

the patient who developed accelerated hypertension, the mean reduction in daytime BP for the good responder group was 19/ 12 mm Hg; for the poor responders the mean reduction was 13/7 mm Hg. The mean reduction in nighttime BP was 17/9 and 8/3 mm Hg, respectively.

Mean BP during the last 5 minutes of supine rest and in the first 90 seconds after tilting, before medication and after acute and long-term treatment, are shown in Figure 3. Blood pressure was significantly reduced by acute therapy in the supine and 60” head-up tilt posi- tions, and there was no significant increase in postural dron on tilting after the first dose.

z = s 90 al P 80 r

3 :v s 70 I 0 Untreated

’ Acute 200

1 . Chronic

180-i 0

- diastolic .

OJ , I I I I I I 0 15 30 45 60 75 90

Time (seconds)

The BP at peak of isometric handgrip exercise was significantly reduced after the first dose (30 mm Hg, p <O.OOS) although less after long-term administration (14 mm Hg, p <0.05).

Dynamic exercise data were only available for 9 patients after the first dose. A significant reduction in BP was demonstrated up to the sixth minute of exercise (p <0.05), when all 9 patients were exercising. A similar trend was observed in patients who exercised for longer but because of the small sample the reduction did not reach statistical significance. Data were available for only 7 patients after long-term treatment, when a significant reduction in BP was observed up to the ninth minute of exercise. Heart rate and BP trends during exercise before treatment and after acute and long-term administration are shown in Figure 4. (Data from the remaining patients were lost due to unacceptable signal artifact.)

Angiotension II levels: Angiotensin II levels at 0, 2, 6 and 24 hours after the first dose are shown in Table III. Angiotensin levels were significantly (p <0.02) and maximally reduced by 2 hours after dosing. The reduction was no longer significant after 24 hours, but 8 of 10 patients for whom data were available still showed some reduction at this time. Angiotensin levels were higher in those patients with a good response to the drug than those with a poor response (Figure 5) but this difference did not reach statistical significance. Reduction in angiotensin II levels did not correlate with reduction in BP at 2 hours, but a significant correlation (r = 0.8, p

~ <0.05) was demonstrated at 6 hours after drug administration.

Plasma concentration of ramipril diacid: The dosage requirements of individual patients at the end of the ti- tration period are listed in Table IV, with the plasma levels of the active diacid metabolite of ramipril before

FIGURE 3. Pooled values of blood pressure and heart rate dosing, at 2, 6 and 24 hours after the acute dose and

during the last 5 minutes of supine rest and in the first 90 sec- before and 6 hours after long-term administration. In onds after tilting. bpm = beats/min. most patients the highest plasma levels were recorded 2


TABLE III Angiotensin Levels Before and After Treatment with Ramlpril in Good and Poor Responders (pg/ml)

Long-Term

First Dose (Hours After (Hours After Dose) Dose)

Pt 0 2 6 24 6 24

I+ 5 2 2 3 3 L

2 * 7 8 * 3 10 3+ 14 6 3 32 5 7 4 * 9 3 3 * 6 5 8 3 4 7 3 17 6 7 5 3 4 WIthdrawn

7 8 3 5 4 3 3 8+ 23 6 * 10 124 57 9+ 16 11 * 5 Withdrawn

lo+ 27 16 * 22 13 72 11+ 141 187 87 * * 157 12+ 65 12 1% 14 0 5

*La . , - A^&. +--..-I _ ^ ^ _I _

hours after administration, although in patient 11, who had the highest levels, these were reached at 6 hours. The plasma concentration of the drug correlated significantly (r = 0.8, p <0.002) with the reduction in BP 2 hours after dosing, but not after 6 hours. No correlation was demonstrated between plasma angiotensin II levels and coincident plasma drug concentration, but drug levels were higher at 2, 6 and 24 hours after the first 10 mg dose in good responders than in poor responders (Figure 5).

DISCUSSION The aim of this study was to observe the response to

the first dose of ramipril and to measure the efficacy of the drug over 24 hours. The results demonstrate that the first dose of the drug may produce a marked decrease in BP, usually maximal at the fourth or fifth hour after dosing. None of our patients complained of symptoms of postural hypotension, although the lowest systolic BPS recorded were 98 and 126 mm Hg. How- ever, cerebrovascular disease was an exclusion criterion for this study, and such patients may well be at risk from such profound decreases in BP. Other published work suggests this problem might be aggravated in patients taking concurrent diuretic medication.19

The 24-hour BP trends confirmed that ramipril has an effective 24-hour duration of action after the first dose, and as demonstrated in a previous study,20 the drug had no effect on the normal diurnal variation. As with other ACE inhibitors, the BP decrease was not ac- companied by a reflex tachycardia.*l Measured serum angiotensin levels were no longer significantly depressed after 24 hours. Prolongation of BP reduction beyond effective ACE inhibition in the plasma has been reported previously22 and suggests that inhibition of the plasma renin angiotensin system is not the sole mechanism for the drug’s antihypertensive effect. ACE activity is also reduced in the lung, kidney, vascular wall and brain, and this inhibition has been shown to persist in the kidney and vascular wall for long periods.23 Angiotensin II

may affect vascular tone by modulation of sympathetic activity within the vascular wa11,24 and a recent study suggests that decrease in sympathetic tone may contrib- ute to the BP-lowering effect of ramipril.25 Also, angiotensin II generated within the kidney may have a local action in regulating salt and water excretion and renal hemodynamics.26

It was clear from simple observation that some patients responded very well to the drug, others hardly at all. In those patients who responded well the BP decrease was greater than the mean group values suggested. This division into “responders” and “nonresponders” must be related to the mechanism of action of the drug. Previous reports have suggested that the response of ACE inhibitors is not related to the degree of inhibition in individual patients.27 In this study, the drug proved

150

140 rl 130

120

110

100

90 80

70

60 i l Untreated 0 Chronic a Acute

260

240 Systolic

80

60 I!! lFz-z-L!3

Pre Ex Ex

Time (minutes)

lR?

Recovery

FIGURE 4. Blood pressure and heart rate response to dynamic exercise. bpm = beats/min.

THE AMERICAN JOURNAL OF CARDIOLOGY AUGUST 1,1988 243


TABLE IV Ramipril Dosage and Plasma Concentrations of

S82 6971, the Active Diacid Metabollte of Ramlpril

Long-Term

Ramlpnl First Dose Diacld

(rig/liter) Ramipril Diacld (ng/llter) (Hours (Hours After Dose) After Dose)

Ramipril Ramipril ~ Pt 0-w) 0 2 6 24 (mg) 6 24

1+ 10 * * * * 30 153 13 2 10 0 78 26 * 20 144 3 3+ 10 2 160 96 11 40 357 15 4 10 0 22 10 2 40 * 5 5 10 0 41 19 3 10 44 4 6 10 0 54 38 5 WIthdrawn 7 10 0 47 14 2 40 la5 lo a+ 10 0 42 15 2 10 45 2 9+ 10 4 ii5 * a WIthdrawn

lo+ 10 0 73 * 75 20 274 53 11+ 10 1 98 124 9 10 * 5 12+ 10 0 22 10 2 20 65 5

* Missing data, + good responder

more effective in those with higher pretreatment angiotensin levels, and BP decreased further in this group. Unfortunately, the number of patients studied was small; a larger group should be studied before we could be confident of this finding. Clearly it is important ther- apeutically: if such a distinction between responders and nonresponders can be proven, then there is a clinical indication for measuring angiotensin levels before treatment with an ACE inhibitor, to ensure that it is rational antihypertensive therapy for the patient concerned.

The results from the long-term phase of this study are difficult to interpret, especially since 1 patient developed accelerated hypertension. They suggest, however,

y .P- 160 I L 140

z 120 P f 100 zz 80 2F 60 "g gg 4. 20 II 0 -

0 2 6 24 6 < *. *

Acute dosage Chronic dosage

FIGURE 5. Angiotensin II and plasma ramiprli d&id levels in good and poor responders. (The apparent Increase In angio- tensln levels at 6 hours is artifactual, due to missing data for 3 patients).

that the drug continues to have an effective 24-hour duration of action after long-term administration, but that the BP reduction is less after long-term administration than after the first dose. It is probable that its effective- ness would be enhanced by concomitant administration of a diuretic.19

Acknowledgment: We wish to thank Dr. H. Pelling and P. Smart for their technical assistance and Julie Barth for her clerical assistance with this study.

REFERENCES 1. Ferguson RK, Vlasses PH. Clinical pharmacology and the therapeutic applications of the new oral angiotensin converting enzyme inhibitor captopril. Am Heart J 198 I;1 01650-656. 2. Ferguson RK, Turini GA, Brunner HR, Gavras H. A specific orally active inhibitor of angiotensm-converting enzyme inhibitor in man. Lancet 1977:1.775- 778. 3. Cushman DW, Cheung HS, Subo EF, Ondetti MA. Design ofpotent competi- tive inhibitors of angiotensin-conuerting enzyme. Carboxyalkattoyl and mercap- toalkanoyl amino acids. Biochemistry 1977;16:5484-5491. 4. Bunning P. Inhibition of angiotensin converting enzyme by 2-[N-[(S)]-l- carboxy-3-phenylpiopyl]-L-alany]-(lS,3S,5S-2-azabicyclo-[3.3.0]octane-3 carboxylic acid (HOE 498 diacid) comparison with captopril and enalaprilat. Arzneimitte[foschung 1984;34:1406-1410, 5. Patchett AA, Harris E, Tristan+ EW, Wyvratt MJ, Wu MT, Taub D, Peterson ER, Ikeler TJ, ten Broeke J, Payne LG, Ondeyka DL, Thorsett ED, Greenlee WJ, Lohr NS, Hoffsommer RD, Joshua H, Ruyle WV, Rothrock JW, Aster SD, Maycock AL, Robinson FM, Hirschmann R, Sweet CS, Ulm EH, Gross DM, Vassil TC, Stone CA. A new class of angiotensrn-converting enzyme inhibitors. Nature 1980:288:280-283. 6. Becker RHA, Scholkens BA, Metzger M, Schulze KJ. Pharmacologicalprop- erties of the new orally active angiotensin converting enzyme inhibitor 2-[N- [(S)- l-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(ls,3s,5s)-2-azabicyclo [3.3.0]octane-3-carboxylic acid (HOE 498) Arzneimitte[forschung 1984:34: 1411-1416. 7. Wilte PU, Metzger H, Eckert HG, Irmisch R. Tolerance and pharmacodynamics of the angiotensin converting enzyme inhibitor 2-[N-[(S)-1-Ethoxycar- bonyl-3-phenylpropyl]-L-alanyl]-(ls,3s,5s)-2-azabicyclo[3.3.0]octnne-3- carboxylic acid (HOE 498) in healthy volunteers. Arzneimittelforschung 1984; 34:1448-1451. 8. Felder K, Witte PV. Effects of the new oral angiotensin converting enzyme inhibitor 2-[N-[(S)-1 -ethoxycarbonyl-3-phenylpropyl]-L-alany~-(ls,3s,5s)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (HOE 498) in essential hypertension. Arzneimittelforschung 1984,34:1452-1454. 9. Tochikubo 0, Asahina S, Kaneko Y. Effect of ramipril on 24 hour uariability of blood pressure and heart rate in essential hypertension. Am J Cardiol 1987;59:83D-850. 10. Kariberg BE, Lindstrom T, Rosenquist U, Ohman KP. Efficacy, tolerance and hormonal effects of a new oral angiotensin converting enzyme inhibitor ramipril (HOE 498), in mild to moderate primary hypertension. Am J Cardiol 1987:59:1040-1090, 11. Gould BA, Mann S, Davies AB, Altman DG, Raftery EB. Can placebo therapy influence arterial blood pressure? Clin Sci 1981,61:478-490. 12. Goldberg AD, Green HL, Raftery EB. The Oxford continuous bloodpres- sure recorder-technical and clinical evaluation. Postgrad Med J 1976:52(suppl 7):104-109. 13. Millar-Craig MW, Hawes D, Whittington J. A new system for recording ambulatory blood pressure in man. Med Biol Eng Comput 1978:16:133-142. 14. Dusterdieck G, McElwee G. Estimation of AZZ concentrations in human

plasma by radioimmunoassay. Some applications to physiological and clinical states. Ear J Clin Invest 1971:2:32-38. 15. Morton JJ, Webb DJ. Measurement of plasma AZZ. Clin Sci 1985,68:483- 484. 16. Eckert HG, Munscher G, Oekonomopulos R, Strecker H, Urbach H, Wiss- man H. A radioimmunoassay for the angiotensin converting enzyme inhibitor ramipril and its metabolite. Arzneimittelforschung 1985;35:1251-1256. 17. Mann S, Millar-Craig MW, Bala-Subramanian V, Raftery EB. The effects of beta blockade on ambulatory blood pressure. Itx Birdwood GFB, Wink CAS, eds. Modern Aspects of Beta-Blocker Therapy. Geigy Pharmaceuticals, Mac- clesfield;l78:33-40. 18. Hornung RS, Gould BA, Jones RI, Sonecha TN, Raftery EB. Nz>dipine tablets for systemic hypertension a study using continuous ambulatory intraarterial recording. Am J Cardiol 1983;51:1323-1327. 19. Koch-Weser J, Vidt DG, Bravo EL, Fouad FM. Drug therapy. Captopril. N


Engl J Med 1982:306.214-219 20. Kaneko Y, Omiae T, Yoshinaga K, Iimura 0, Inagala Y, Ishii M, Saruta T, Yamada K, Kumanara Y, Ito K, Kokubu T, Arakawa K, Fukiyama K, Ebihara A. Effeci of ramipril, a new angiotemin converting enzyme inhibitor, on diurnal oariatrons of blood pressure in essential hypertension. Am J Cardiol 1987; 59:86D-910. 21. Millar JA, Derkx FHM, McLean K, Reid JL. Pharmacodynamics of converting enzyme inhibition: the cardiovascular, endocrine and autonomic effects of MK 421 (enalapril) and MK 521 Br .I Clin Pharmacol 1982;14:347-355. 22. Waeber B, Brunner HR, Brunner DB, Curtet A, Turini GA, Gavras H. Dtscrepancy between antihypertensive effect and angiotensin convertrng enzyme Inhibition by captopril. Hypertension 1980;2.236-242. 23. Unger T, Ganten D, Lang RE, Scholkens BA. Persistent tissue converting

enzyme inhibitron following chronic treatment with HOE 498 and MK 421 in spontaneously hypertensiue rats. J Cardiooasc Pharmacol 1985;7:36-41. 24. Zimmerman BG. Adrenergic facilitation by angiotettsitr does it serve a physiological function? Clan Sci 1981.60.343-348. 25. Phillip T, Sharma AM, Thiede HM, Krlbben A. Sympathetrc nervous actiui- ty and noradrenaline reactivity during angiotensin converting enzyme mhibition. Am J Cardiol 1987;59:55D-59D. 26. Rowall L, Navar LG. Effects on renal haemodynamics of intra-arterial infusions of angiotensins I and II. Am J Physiol 1983;245:Fl81-187. 27. Unger TH, Ganten D, Lang RE, Scholkens BA. Is tissue conuertingenzynze inhibition a determinant of the antihypertensive efficacy of converting enzyme rnhibitors? Studies wrth two different compounds, HOE 498 and MK 421, in spontaneously hypertensive rats. J Cardtovasc Pharmacol 1984,6:872-880.

THE AMERICAN JOURNAL OF CARDIOLOGY AUGUST 1,1988 245

first dose response and 24-hour antihypertensive efficacy of the new once-daily angiotensin...

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