Influence of beta2 agonism and beta1 and beta2 antagonism on adverse effects and plasma lipoproteins: Results of a multicenter comparison of dilevalol and metoprolol

Influence of Beta2 Agonism and Beta1 and Beta2 Antagonism on Adverse Effects and Plasma Lipoproteins: Results of a Multicenter Comparison of Dilevalol and Metoprolol Barry J. Materson, MD, Nicholas D. Vlachakis, MD, Stephen P. Glasser, MD, Charles Lucas, MD, K.B. Ramanathan, MD, Suhail Ahmad, MD, John H. Morledge, MD, Elijah Saunders, MD, Lawrence J. Lutz, MD, Harold W. Schnaper, MD, Morton Maxwell, MD, and Marcia P. Poland, MA Dilevalol combines vasodilation due to selective & agonism and nonselective B antagonism. We studied 311 patients randomized to dilevalol and 138 to metoprolol in a multicenter trial. After a 4-week placebo washout, dilevalol was titrated from 200 to 1,600 mg once daily and metoprolol from 100 to 400 mg to a goal supine diastolic blood pressure
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THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63

ilevalol is a selective &agonist and a nonselective P-adrenergic antagonist.1-7 The &agonist property causes peripheral vasodilation and decreased systemic vascular resistance, in contrast to conventional /I blockers, which are associated with peripheral vasoconstriction and increased systemic vascular resistance. The purpose of this study was to compare dilevalol to metoprolol, a Pi-selective antagonist, examining the therapeutic efficacy on blood pressure (BP) reduction, adverse effects, and effects on serum cholesterol fractions and triglycerides.

D

SUBJECTS AND METHODS This double-blind, randomized, unbalanced group design involved 674 patients in 11 investigational sites. Nonhospitalized patients of either gender and any race who were 18 years or older and had mild to moderate hypertension (defined as an average untreated supine diastolic BP of 95 to 115 mm Hg) comprised the study population. Patients with the following conditions were excluded from the study: myocardial infarction within 3 months, cerebrovascular accident within 1 year, congestive heart failure requiring treatment, insulin-dependent diabetes mellitus, liver enzymes greater than twice normal, serum creatinine >2.5 mg/dl, clinically significant hematologic disease, secondary hypertension, grade III or IV retinopathy, and pregnancy or lactation. In addition, patients with a documented or clinically suspected previous drug reaction or idiosyncrasy to P-adrenergic blocking drugs were also excluded. Each patient gave written informed consent, and the study protocol and informed consent were approved by the human research committee at each investigational site. After a 4-week single-blind placebo period free of antihypertensive therapy (phase I), 449 patients whose supine diastolic BP was 95 to 115 mm Hg at each of the last 2 visits (and the variability between these visits 15 mm Hg) were randomized to 1 of 2 double-blind regimens. Three hundred and eleven patients were randomized to dilevalol and 138 to metoprolol. Phase II of the study was a 2- to 8-week titration period during which doses of the study drug were titrated weekly to achieve a supine diastolic BP of <90 mm Hg and a reduction from baseline of 210 mm Hg on 2 consecutive visits on the

same dose level. The doses of dilevalol were 200,400,800 and 1,600 mg once daily. However, the 1,600-mg dose could only be prescribed if the supine diastolic BP was reduced from baseline by 5 mm Hg when the dose was increased from 400 to 800 mg. The doses of metoprolol were 100, 200 and 400 mg. Placebo was labeled dose A, and the first 3 levels of study drug dose B. An additional dose level of 400 mg was used to blind the 1,600-mg dose of dilevalol and was labeled dose C. All drugs, including placebo, were provided in identical maroon opaque capsules. Visits were scheduled at the end of the dosing interval (i.e.; 20 to 24 hours after the last dose). Trained observers, experienced in the use of a mercury sphygmomanometer, made all BP determinations. The fifth phase, or disappearance of the Korotkoff sounds in the supine position, was used to determine the diastolic pressure. History, physical examination, chest roentgenogram and electrocardiogram were recorded and basic laboratory tests performed during the placebo baseline. In addition, after 3 weeks of placebo administration, plasma high-density lipoprotein (HDL) cholesterol was measured by the manganese heparin precipitation method and low-density lipoprotein (LDL) cholesterol was calculated by the Friedewald formula.8 Patients who attained goal BP on 2 consecutive visits before titration to the maximal dose of study drug were entered into a l-year maintenance phase. Patients who received the maximal dose of study drug for 2 weeks and had a reduction in supine diastolic BP of 25 mm Hg from baseline to a level of <90 mm Hg also entered a l-year maintenance phase. If the supine diastolic BP with the maximal dose was decreased by <5 mm Hg, the patient was terminated as a treatment failure. If the supine diastolic BP was >90 mm Hg but reduced by >5 mm Hg, then the patient received hydrochlorothiazide (HCTZ) at an initial dose of 25 mg once daily that could be increased to a maximum of 50 mg once daily. If the supine diastolic BP was 195 mm Hg with maximal doses of study drug and HCTZ, patients then entered a l-year maintenance phase. STATISTICAL

ANALYSIS

The sample sizes for this protocol were selected for both statistical and practical reasons. Statistically, the study was designed to achieve an 80% power ((Y level of 0.05,2-tailed) to detect a >3-mm Hg difference in supine diastolic BP between treatments. To meet this criterion, at least 120 patients per treatment group were required. Another objective was to ensure that >lOO dilevaloltreated patients completed 248 weeks of treatment. Both of these criteria were satisfied by choosing at least 120 patients for the metoprolol group and more than 280 patients for the dilevalol group. The continuous variables (age, body weight, duration of hypertension and baseline supine diastolic BP) were compared using an analysis of variance (ANOVA) model-extracting investigator, treatment and investigator-bytreatment effect. Categorical data (gender and race) were compared using a categorical linear model extracting the same effects as mentioned.

ANOVA was performed to test the null hypothesis that the BPS, heart rates and body weight in the 2 treatment groups were the same. Both the actual values and changes from baseline were analyzed at the first titration visit, at the end of titration, and at the monotherapy end point (i.e., the last on study drug alone). Two-tailed t tests were used to compare the results within individual centers. The proportion of patients discontinuing for all reasons, treatment failures and adverse experiences were compared for the 2 treatment groups using the 2-tailed Fisher exact 2 X 2 test. This test was also used to compare the proportion of patients reporting adverse experiences and reporting specific adverse experiences. Assuming an incidence of 10% for any individual side effect with the sample sizes in each treatment group, with an cylevel of 0.05 (Ztailed) there was an 80% power to detect differences of 12% (e.g., 10 vs 22%). The Mann-Whitney statistic was used to compare the effects of the 2 treatments on plasma lipid levels, and the paired t test was used for changes from baseline. All results are presented as mean f standard error of the mean. RESULTS Comparability

of groups: Of the 674 patients entering the study, 449 (67%) met the requirements for randomization. ANOVA with treatment, investigator and investigator-by-treatment interaction effects revealed no significant interaction effects at baseline or during treatment. The most common reason for prerandomization withdrawal was supine diastolic BP above or below the randomization criteria (169 of 225; 75%). The 449 patients were randomized using a 2: 1 ratio: 3 11 to dilevalol and 138 to metoprolol. One patient in each treatment group was lost to follow-up after randomization and an additional patient in each group discontinued treatment more than 2 days before the first titration visit. These patients were excluded from the efficacy, but not the safety, analyses. The groups were statistically alike in regard to age, gender, race, body weight, duration of hypertension and previous antihypertensive treatment (Table I). The median duration of monotherapy treatment was 11.9 months in the dilevalol group and 10.7 months in the metoprolol group. Blood pressure and heart rate changes: Table II lists the effects of dilevalol and metoprolol on BP, by race and combined. Both drugs effectively reduced both systolic and diastolic BP for the groups as a whole. However, black patients had a significantly higher baseline pressure and their diastolic response to both dilevalol and metopro101was significantly less (p
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TABLE I Baseline Demographic

TABLE Ill Effects on Supine Blood Pressure (mm Hg) of

Data and Prior Treatment

Dilevalol and Metoprolol Hydrochlorothiazide

Status of the Efficacy Population*

No. of patients Age (yr) 265 Weight (Ibs) Gender Men

Dilevalol

Metoprolol

309 51.3+0.6 9% 193 f 2.2

136 50.7 f 0.9 8% 194 f 3.2

71%

74%

39% 9.5 f 0.4

44% 9.3 f 0.7

32% 23% 26% 19%

32% 33% 16% 19%

Alone and When Combined with

Placebo baseline End monotherapy Reduction from baseline After hydrochlorothiazide Reduction from baseline

Dilevalol

Metoprolol

160/103 153/96.5 7.5/6.7 139/89 20.8/14.7

158/103 155/96.2 3.2/6.7 139/89 19.4/13.6

Race Black Duration of hypertension Prior treatment status No prior treatment Diuretic alone Diuretic + nondiuretic Other monotherapy * Age, weight. and duration error of the mean.

(yr)

of hypertension

are expressed

as mean f standard

One-third of the patients in the dilevalol group and 29% in the metoprolol group required the addition of HCTZ. Most (i.e., >50%) of those needingHCTZ had a baseline diastolic BP of >105 mm Hg (i.e., moderate hypertension). Most patients required 50 mg of HCTZ in combination with the study drug. There were no age or racial differences. However, approximately 50% of the white patients in both combination treatment groups neededonly 25 mg, whereas only 25% of the black patients in the dilevalol group and 39% in the metoprolol group had hypertension controlled with this dose. This latter finding may reflect the higher baseline BPS observedin the black patients. The supine BP effectsat the end of monotherapy and at the end of combination therapy are shown in Table III. Dilevalol treatment alone resulted in a larger reduction in systolic BP than metopro101monotherapy. However, the drugs were equally efficacious when combined with HCTZ. Terminations: A total of 49 (11%) patients werewithdrawn from the study becauseof adverseeffectsjudged by the investigator to be related to either metoprolol or dilevalol: 22( 16%) from the metoprolol group and 27 (9%) from the dilevalol group. This difference was statistically significant (p = 0.03). The difference betweenthe 2 treatments only becameevident after 36 weeksof treatment (Fig. 1). The late adverseeffects with metoprolol

were predominantly fatigue or lethargy (4 patients) and impotence (4 patients). Only 1 dilevalol-treated patient was a late withdrawal becauseof fatigue and headaches. The highest proportion of those with adverseeffects resulting in termination were white men, although the proportion in the metoprolol group discontinuing was always higher regardlessof gender or race (Fig. 2). Most patients who withdrew from the study in both treatment groups were receiving the first 2 doselevelsat the time of discontinuation (12 of the 22 were receiving 100 to 200 mg of metoprolol and 16 of the 27 were receiving 200 to 400 mg of dilevalol). The incidence of fatigue and somnolenceas a reasonfor withdrawing was the samefor both treatments (i.e., 2%). However, significantly more patients treated with metoprolol than dileva101discontinued becauseof impotence(5 vs 1%;p = 0.03) and depression (3 vs
TABLE II Supine Blood Pressure at Baseline and Changes at End of Titration and End of Monotherapy

Metoprolol

Dilevalol White (n = 187) Baseline (mm Hg) A End titration p value+ A End monotherapy p value+ Normotensive %

,

Black (n = 127)

Combined (n = 309)

White (n = 76)

157/103* -7.5/-7.4 p <0.001/<0.001 -9.4/-9.7 -6.1/-5.4 p = 0.08/<0.006 74 37

154/101 -11.7/-11.1

151/100 -11.4/-13.6

153/100 -14.5/-13.5

* Black patients had significantly higher (p 50.03) systolic and diastolic t Differences within treatment, by race (analysis of variance).

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by Race and Combined

-8.1/-8.0 60 blood pressures

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Black (n = 60)

156/102* -6.9/-9.2 p = 0.09/<0.01 -9.1/-11.0 -4.O/-6.8 p <0.07/<0.006 68 43

at baseline than did whites.

Combined (n = 136) WI/101 -9.4/-l -6.8/-9.1 57

1.7

20-

FIGURE 1. Cmmdative percemt of pathts dlscentimledfrumstudybecauseefslde effects.

Dilevalol

z 15w 2 .r_ E g lo; Y .-5 i;j 0.

5-

0 ’

I


Table IV. The incidence of fatigue, bradycardia, pruritus, depression and nervousness were significantly more frequent (p 10.04) in patients treated with metoprolol than with dilevalol. There were more patients treated with dilevalol who reported diarrhea than those treated with metoprolol (8 vs 3%), and this difference approached statistical significance (p = 0.06). However, diarrhea was dose-related in the dilevalol group (3% with 200 mg, 4% with 400 mg, 6% with 800 mg and 10% with 1,600 mg). Two other adverse effects appeared to be dose-related with both study drugs. The incidence of dizziness was 4% with the lowest dose of dilevalol and metoprolol and 15% with the highest dose of each drug. Similarly, the incidence of nausea was 8% with dilevalol (200 mg) and 7% with metoprolol (100 mg); with dilevalol(l,600 mg), the incidence was 25% compared with 19% with metoprolol (400 mg). Plasma lipoprotein effects: Fasting plasma lipoproteins were measured before and after treatment with dilevalol alone in 99 patients and with metoprolol alone in

I

I

<36 <24 Weeks in Study

t48

I

I

End Tltratlon

I 248

34 patients. This subgroup of patients had baseline characteristics similar to the total study group. Most were white (71% dilevalol, 65% metoprolol), men (73% dileva101,82% metoprolol) and middle-aged (mean of 53 years for dilevalol and 55 for metoprolol). Most of the patients were treated for 1 year, with a minority of patients treated for 6 months. The lipid effects are listed in Table V. There was no change in total cholesterol with either treatment, but dilevalol treatment resulted in a significant 2.5mg/dl increase (p = 0.05) in HDL cholesterol, with a nonsignificant decrease in LDL cholesterol of 2.5 mg/dl. Triglycerides increased 21 mg/dl with dilevalol (p = 0.06), but increased twice as much with metoprolol(41.9 mg/dl; p = 0.02). The dilevalol group was stratified retrospectively into traditional coronary heart disease risk factor groups: The high-risk group was defined as an HDL cholesterol 135 mg/dl; average risk, 35 to 49 mg/dl; and the below average risk group was defined as 150 mg/dl. The changes in HDL cholesterol by risk factor group are shown in Figure

Blacks

Whites Males p = 0047

Males

Females

Females

1

24%

FIGURE 2. Percent of patknts uadfremstudybecalwefsldeeRects, stratiiied by race and sex.

diswntin-

0

Dilevalol

m

Metoprolol

P 2 15 ‘= s .-:: ", loE .P iii 0. 5-

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TABLE IV Incidence (percent) of the Most Frequent* Adverse Effects Judged by Investigator to be at Least Possibly Related to Treatment with Dilevalol or Metoprolol

Any side effect Autonomic nervous system Impotence Dry mouth Increased sweating Cardiovascular Chest pain Heart rate <50 beats/min Palpitations Central nervous system Depression Insomnia Nervousness Dreams (vivid, bad) Somnolence Gastrointestinal Abdominal pain Diarrhea (loose stools) Dyspepsia Flatulence Nausea Vomiting Other systems Arthralgia Asthenia Dizziness Dyspnea Edema Fatigue Headache Leg cramps Myalgia Pruritus Rash l

Dilevalol (n = 310)

Metoprolol (n = 137)

51

61


TABLE V Effects of Dilevalol and Metoprolol on Plasma Lipoproteins (mg/dl) After at Least 6 Months of Treatment* Dilevalol

BetweenTreatment Significance, When Present+

4 3 1 7 16 3 4 2 7* 2 7

2 8 5 2 9 3

4 3 5 3 6

3 3 15 7 4 14 10 1 2 2 1

p = 0.005

p = 0.03

p = 0.002

p =

p = 0.04

p = 0.03

2%.

3. The largest increasein HDL cholesterol was observed in those patients at the highest risk for coronary heart diseasein whom HDL cholesterol increasedfrom an averageof 31.3 to 40 mg/dl (p = 0.001). The meanincrease in HDL cholesterol in patients at averagerisk for coronary heart diseasewas 1.7mg/dl, and a meandecreaseof 2.5 mg/dl was found in patients at below averagerisk for coronary heart disease. DISCUSSION

Labetalol derives its P-antagonist, &agonist, and CYantagonist properties from an approximately equal mixture of its 4 stereoisomers.Gold et al3 could synthesize each of the stereoisomersand assay their adrenergic properties in rats. They demonstratedthat the R,R, isomer 2a (SCH 19927) effected P-adrenergic agonismmediated vasodilation and P-adrenergicantagonism and had no ol-blocking effect. Further studies in dogs by Baum and SybertzSdemonstratedthat both labetalol and its isomer SCH 19927 differed from /3 blockers with 1

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Metoprolol

222f4 223f4 +O.l (NS)+

223f7 227f6 +3.6 (NS)

44.7fl 47.2 f 2 +2.5 (p = 0.05)

47.8 zt 3 48.2f3 +0.4 (NS)

146.4 f 4 143.9 f 4 -2.5 (NS) 0.33 0.36 +0.03 (NS) 165.6 f 10 186.6f 11 +21 (NS)

144.9 f 4 144.8 f 6 -0.1 (NS) 0.35 0.36 +O.Ol (NS) 170.9 f 16 212.8 f 26 +41.9 f 17 (p = 0.02)

’ Data are reported as mean f standard error of the mea”. + Not si@ificant (p BO.05). HDLC = hi&r&y lipoprotein cholesterol; LDL-C = low-density lipoprotein ksterol; HDL/LDL = ratio of highdensity to low-density lipoprotein cholesterol.

0.06

+ Fisher P-takd exact test. *Two percent occurred during tapering period at end of study: 2% was associated with depression, and 3% was associated with anxiety or tenseness and irritability.

62

Total cholesterol Placebo baseline End monotherapy Change (significance) HDL-C Placebo baseline End monotherapy Change (significance) LDL-C Placebo baseline End monotherapy Change (significance) HDL/LDL Placebo baseline End monotherapy Change (significance) Triglycerides Placebo baseline End monotherapy Change (significance)

63

cho-

strong partial agonismactivity in that labetalol and SCH 19927direct their p-agonist activity at blood vessels(vasodilation) and not at the heart. This isomer was subsequently developedfor testing in humans as dilevalol. Electrophysiologic studies of dilevalol in dogs show that, unlike conventional /3 blockers, dilevalol does not depresssinoatrial nodal or atrioventricular nodal function in P-antagonistic and hypotensive doses.9This suggests that dilevalol could be combined safely with negative chronotropes and dromotropes such as verapamil. Studiesin humans showthat dilevalol had no negative effectson renal function, in contrast to someconventional p blockers.lOJ1It is rapidly absorbed after oral dosing, but is extensively metabolized in the liver. The time to peak serum concentration is only 1.4 hours, and its halflife is 8 to 12 hours.i2 Other studiesin humans documenteddilevalol’s antihypertensive efficacy against placebo13and against propranolol.14 The efficacy of a 200-mg dose of dilevalol administeredoncedaily wasdemonstratedto be in accord with its long half-life. Furthermore, the hypotensive effect of dilevalol was due to reduced systemic vascular resistancewithout decrement in cardiac output.15 The presentstudy sought to comparedilevalol against metoprolol, a pi-selective blocker in worldwide use. We demonstrated that at dosesequipotent in BP-lowering effect, there were substantive differences in patient discontinuations, adversepatient experiencesand changesin the lipoprotein profile. Indeed, after 36 weeksin the trial, terminations from the trial for patients receiving metopro101becamesignificantly higher than for patients taking dilevalol. This appearedto be due to a preponderance of adversepatient experiencesin the metoprolol group. Another important difference between dilevalol and metoprolol in this trial was the effect on the lipoprotein

profile. Although the changes are small, they are in the direction of less potential atherogenicity for dilevalol and more for metoprolol. As demonstrated by Castelli and Andersoni the ratio of total cholesterol to HDL cholesterol is an important predictor of coronary artery disease. Lehtonen” has reviewed published reports on the effect of /3blockers on the serum lipid profile. It is clear that such studies are quite disparate in their duration, methods and results. Our data reflect an average of 53.5 weeks of drug treatment, much longer than most of the studies reported. The mechanism by which p blockers alter the lipoprotein profile have been discussed by Wolinskyi8 and by Lardinois and Neuman.i9 In brief, the mechanisms for hyperlipidemia associated with p blockers are thought to be related to impairment of lipoprotein lipase activity. This could be due to flz-receptor antagonism or unopposed (Y effect, or both. Increased serum catecholamine levels would also increase hepatic cholesterol production. It is possible that the observed effect of dilevalol on increasing HDL cholesterol and reducing LDL cholesterol is a function of its &-agonist effect. This hypothesis is supported by the observation that terbutaline, a ,&-agonist, effects the same qualitative changes in the lipoprotein profile as does dilevalol.20 Although the data in this study indicate a possible directional difference in the effect of dilevalol and metopro101 on lipoprotein fractions, these results should be regarded as preliminary. A definitive prospective trial is currently in progress. In that study, patients are being stratified by baseline HDL cholesterol and then randomized prospectively to treatment with dilevalol or atenolol. In summary, this multicenter trial demonstrated that dilevalol had a lower patient termination rate, fewer adverse patient events, and possibly better lipoprotein profile than did metoprolol in equihypotensive doses.

Average Risk

High Risk

Below-Average Risk NS

1 -60

i-7 42

44

2 % :

25

i

II

n = 27

n = 45

FIGURE 3. Effect of long-term treatment with dilevalol on high-density lipoprotein cholesterol (HDL-C) stratii by baseline risk factor for coronary artery disease.

6. Monopoli R,R-isomer hypertensive

A, Bamonte of labetalol, rats during

F, Forlani A, Ongini E. Parravicini L. Effects of the SCH 19927, in isolated tissues and in spontaneously a repeated treatment. Arch lnt Pharmacodyn Thrr

1984:272:256&263. 7. Watkins RW, Sybertz antihypertensive dilevalol

EJ. Antonellis A, Pula KK, Rivelli M. Effects of the on aortic compliance in anesthetized dogs. J Cardiooasc

Pharmacol I988;12:42-50. 8. Friedewald WT, Levy RI, Frederickson DS Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. C/in Chem 1972:18:499-502. 9. Lynch JJ, Montgomery DC, Lucchesi BR. Cardiac electraphysiologic actions of SCH 19927 (dilevalol), the R,R-isomer of labetalol. J Pharmacol Exp Thrr

1986:239:719-723.

1. Sybertz EJ, Sabin CS, Pula KK, Vander Vliet G, Glennon J. Gold EH, Baum T. Alpha and beta adrenoceptor blocking properties of labetalol and its R,Risomer. SCH 19927. J Pharmacol Exp Ther 198/:218:43S-443. 2. Baum T, Watkins RW, Sybertz EJ, Vemulapalli S, Pula KK, Eynon E, Nelson S, Vander Vliet G, Glennon J, Moran RM. Antihypertensive and hemodynamic actions of SCH 19927, the R,R-isomer of labetalol. J Pharmacol Exp Ther

10. Cook ME, Clifton GG, Poland MP, Flamenbaum W, Wallin JD. Effects of dilevalol and atenolol on renal function and haemodynamics of patients with mild to moderate hypertension. J Hyperfens 1986:4:mppl 5S504LY506. 11. Cook ME, Wallin JD, Clifton GG, Poland MP. Renal function effects of dilevalol, a nonselective beta-adrenergic blocking drug with beta-2 agonist activity. Clin Pharmacol Ther 1988;43:393-399. 12. Kramer WG, Nagabhushan N, Affrime MB, Perentesis GP, Symchowicz S, Patrick JE. Pharmacokinetics and bioavailability of dilevalol in normotensive volunteers. J Clin Pharmacol 1988:28:644-64X 13. Frishman WH, Schoenberger JA, Gorwit JI, Bedsole GD, Cubbon J, Poland MP. Multicenter comparison of dilevalol to placebo in patients with mild hyp-ertension. Am J Hypertem 1988:l:295Sm299S. 14. Schoenberger JA, Frishman WH, Wallin JD, Gorwit J. Davidov ME, Michelson E, Bedsole G, Cubbon J, Poland MP. Dilevalol compared with propranolol and placebo for systemic hypertension. Am J Cardiol 1989:63:4-f l-49 1. 15. Strom JA, Vidt D, Bugni W, Atkins J, Fouad-Tarazi F. Cubbon J, Poland MP. Mechanism of antihypertensive action of dilevalol compared with that of “cardioselective” beta-blocking agents. Am J Cordiol /989,63.25 I- 33 I. 16. Castelli WP, Anderson K. A population at risk: prevalence of high cholesterol levels in hypertensive patients in the Framingham study. Am J Mrd 1986:80:

198/:218:444-452.

suppl tA:23-32.

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3. Gold EH, Chang W, Cohen M, Baum T, Ehrreich S, Johnson G, Prioli N, Sybertz EJ. Synthesis and comparison of some cardiovascular properties of the stereoisomers of labetalol. J Med Chem 1982;25:1363-1370. 4. Sybertz EJ, Baum T, Pula KK, Nelson S, Eynon E, Sabin C. Studies on the mechanism of the acute antihypertensive and vasodilator actions of several betaadrenoceptor antagonists. J Cardiouasc Pharmacol 1982;4:749-7S8. 5. Baum T, Sybertz EJ. Antihypertensive actions of an isomer of labetalol and other vasodilator-B-adrenoceptor blockers. Fed Proc /983;42:/76~18/.

17.

Lehtonen

A.

Effect

of beta

blockers

on blood

lipid

profile.

Ant Heart J

I985;109:1192-1196. 16. Wolinsky H. The effects of beta-adrenergic blocking agents on blood lipid levels. Clin Cardiol I987;10:561~566. 19. Lardinois CK, Neuman SL. The effects of antihypertensive agents on serum lipids and lipoproteins. Arch Intern Med 1988;148:1280-1288. 20. Hooper PL, Woo W, Visconti L, Pathak DR. Terbutaline raises high-densitylipoprotein-cholesterol levels. N Engl J Med 1981;305:1455%1457.

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