effect of combination therapy with arotinolol and sustained-release nifedipine in patients with...

CURRENT THERAPEUTIC RESEARCH VOL. 55, NO. 7, JULY 1994

EFFECT OF COMBINATION THERAPY WITH AROTINOLOL AND SUSTAINED-RELEASE NIFEDIPINE IN PATIENTS WITH

ESSENTIAL HYPERTENSION RESISTANT TO MONOTHERAPY

KAZUO TAKEDA, TETSUO NAKATA, ATSUSHI UCHIDA, HIROSHI FUJITA, KAZUE NAKAMURA, TOSHIAKI TAKESAKO, HIROSHI ITOH, SUSUMU SASAKI,

AND MASAO NAKAGAWA

Second Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan

A B S T R A C T

Two major classes of antihypertensive drugs enjoy widespread clinical use: calcium antagonists and beta-adrenoceptor blockers. Although both classes have proven efficacy, some patients with hypertension are refractory to treatment with either class alone. To evaluate the efficacy of combined therapy, 30 patients with refractory hypertension who had been treated with either arotinolol (10 mg BID) or sustained- release nifedipine (nifedipine SR; 20 mg BID) alone were given these two drugs in combination. Significant antihypertensive responses to combination therapy were observed in both groups, with a reduction in blood pressure of/>14% in the group initially treated with arotinolol and t>22% in the group initially treated with nifedipine SR. Adverse effects were noted in four patients after addition of nifedipine SR to arotinolol, but all symptoms resolved after discontinuation of nifedipine SR. This study shows that a combination of arotinolol and nifedipine SR is effective in controlling blood pressure in patients with mild-to-moderate hypertension who are resistant to monotherapy with either drug alone.

I N T R O D U C T I O N

Remarkable progress has been made in the therapy of essential hypertension, and various antihypertensive drugs are commonly used in clinical practice. According to the guidelines of the US Joint National Committee,1 calcium antagonists and beta-adrenoceptor blockers (beta-blockers) are the drugs of first choice. Moreover, most recently introduced antihypertensive drugs are highly effective in most hypertensive patients who have exhibited an adequate response to treatment with a combination of two or three drugs.

A secondary preventive effect for myocardial infarction has been seen with beta-blockers2; this effect has not been confirmed for calcium antagonists other than diltiazem. 3 Nevertheless, the potent vasodilative action

Address correspondence to: Kazuo Takeda, MD, Second Department of Medicine, Kyoto Prefectural Uni- versity of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602, Japan. Received for publication on May 4, 1994. Printed in the U.S.A. Reproduction in whole or part is not permitted,

817 0011-393X/94/$3.50

COMBINATION THERAPY IN ESSENTIAL HYPERTENSION

of calcium antagonists is known to be effective against vasospastic angina pectoris, the incidence of which is high in Japan. Hence, these two classes of antihypertensive drugs are generally used for the prophylaxis and treatment of ischemic hear t disease.

Arotinolol, a beta-blocker with alpha-blocking action developed in Ja- pan, is two to three times more potent than propranolol and has a sustained action, a plasma half-life of approximately 7 hours, an absence of membrane-stabil izing activity and intrinsic sympathomimetic activity (ISA), and an alpha-blocking action approximately one tenth that of phentolamine and less potent than that of labetalol. 4 Therefore, arotinolol is a Class 3, Group 4 blocking agent according to Prichard's classification. 5'6

Nifedipine is a calcium antagonist that was developed in 1980. It has been used extensively in Japan as an antihypertensive drug since 1983, and a sustained-release preparation (nifedipine SR), which was launched in 1987, is now also widely used. Both beta-blockers and calcium antagonists are effective when administered alone, but when the desired effect is not achieved at their respective starting doses, it is common to use them in combination rather than continue with monotherapy at a higher dose. A study of start ing dose efficacy showed that arotinolol 20 mg/d was effective in 81.3% of patients, and nifedipine SR 40 mg/d was effective in 73.8% of patients. 7,s This study examined the efficacy of combination therapy with nifedipine SR and arotinolol in patients with refractory essential hypertension in whom no antihypertensive response was observed at the starting dose for monotherapy with either drug.

P A T I E N T S A N D M E T H O D S

After informed consent was obtained, 41 men and women with mild or moderate essential hypertension according to the World Heal th Organiza- tion (WHO) classification (class I or II), who did not respond to monotherapy with either arotinolol or nifedipine SR and who were without serious complications, were selected from the outpatient clinic. They were aged between 40 and 75 years and had a stable mean systolic blood pressure (SBP) i>160 mm Hg and a mean diastolic blood pressure (DBP) >195 mm Hg. Blood pressure (BP) was recorded in the sitting position and expressed as the mean of measurements taken at 2 weeks and immediately before t rea tment during a 4-week baseline period.

Pat ients with the following conditions were excluded from the study: marked bradycardia; atrioventricular block (second- or third-degree) or sinoatrial block; diabetic ketoacidosis or metabolic acidosis; high risk of developing bronchial asthma, bronchospasm, or cardiogenic shock; right heart failure induced by pulmonary hypertension; existing or potential congestive heart failure; severe hepatic or renal disease; pregnancy or

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K. TAKEDA ET AL.

childbearing potential; or other conditions regarded by the attending phy- sician as justifying exclusion from the study.

After a 4-week baseline period during which no t rea tment was administered, patients were randomly divided into two groups. The first group (arotinolol-starting group) received arotinolol* 10 mg twice daily for 4 weeks, and the second group (nifedipine-starting group) received nifedipine SRt 20 mg twice daily for 4 weeks. At the end of 4 weeks and after confirmation of an inadequate BP response, the al ternate drug was added to the t rea tment regimen for 8 weeks (combination therapy).

An adequate antihypertensive response was defined as either (1) a reduction in BP of at least 30/15 mm Hg (reduction in mean BP of 20 mm Hg) between the mean of the two baseline measurements and the final measurement during monotherapy; or (2) an SBP of ~<149 mm Hg and/or a DBP of ~<89 mm Hg at the end of monotherapy.

The concomitant use of other drugs, including beta-blockers, calcium antagonists and other antihypertensive drugs, beta-stimulants, coronary vasodilators, and tricyclic antidepressants, was prohibited during the study.

Pat ients were examined every 2 weeks to investigate specified test items, such as BP and adverse effects. BP and heart rate were measured in the sitting position at each hospital visit. DBP was recorded at Korotkoffs phase V (disappearance of hear t sounds).

The following tests were carried out during the baseline period and at the end of combination therapy: body weight, urinalysis, complete blood counts (hemoglobin, red blood cell count, white blood cell count, differen- tial white blood cell count), and blood biochemistry (aspartate aminotransferase [AST], alanine aminotransferase, alkaline phosphatase, creatine phosphokinase, lactate dehydrogenase [LDH], total cholesterol, fasting blood glucose, serum creatinine, blood urea nitrogen, uric acid, Na + , K + , and C1-). Electrocardiograms were recorded and chest roentgenograms were obtained during the baseline period.

Adverse effects were defined as symptoms that appeared for the first t ime during t rea tment and could not be at tr ibuted to any variable other than the test drug. When adverse effects were observed, time of onset, description, duration and course, management, and association with the test drug were recorded. The treatment response to adverse effects was clas- sified as: "dose unchanged," "dose reduced," "administration discontinued," or "switched to another antihypertensive drug or other drug added."

Results were analyzed using the Student's t test, chi-square test, the Mann-Whitney U-statistic test, and Fisher's exact test. Data are presented as mean -+ SE.

* Trademark: Almarl ® (Sumitomo Pharmaceuticals, Tokyo, Japan). t Trademark: Adalat L ® (Bayer Japan, Tokyo, Japan).

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RESULTS

Forty-one patients were enrolled in the study; 11 were excluded from the analysis because of protocol violations. Thus 17 patients were analyzed in the arotinolol-starting group (4 men and 13 women; mean age, 62.7 +- 7.8 years) and 13 in the nifedipine-starting group (5 men, 7 women, and 1 sex not stated; mean age, 59.7 -+ 8.5 years). No differences were found between groups in sex ratio, age, severity of disease, family history, duration of hypertension, past history, or complications. Complications appeared in 4 patients in the arotinolol-starting group (diabetes mellitus in 1, gout in 1, and chronic pancreatit is in 2) and in 5 patients in the nifedipine-starting group (polycythemia vera, cerebral arteriosclerosis, hyperuricemia, diabetes mellitus, and kidney disease, each in 1 patient). There were no intergroup differences in BP measured during monotherapy (table).

Four of 17 patients who initially received arotinolol were eliminated from the study: 1 due to an excessive antihypertensive response after addition of nifedipine SR, and 3 due to adverse effects of nifedipine SR. Combination therapy was terminated in these patients.

Antihypertensive Efficacy

Arotinolol-Starting Group

In week 4 of t reatment with arotinolol at a dose of 20 mg/d (week 8 of the study), hear t rate decreased significantly relative to baseline (Figure 1). In contrast, almost no antihypertensive response was seen. In the second week after the addition of nifedipine SR (week 10), a significant an- t ihypertensive response of >114% was seen in both SBP and DBP. This effect persisted with little fluctuation until the final assessment (week 16).

Table. Intergroup comparison of blood pressure (mean -+ SE) for each t ime of measurement and drug group.

Baseline Monotherapy Combination

Arotinolol-starting group SBP 176.2 -+ 2.4 178.3 -+ 3.5 DBP 101.2 -+ 1.8 98.8 -+ 1.1

Nifedipine-starting group SBP 188.3 -+ 3.6 174.5 -+ 4.31- DBP 105.0 -+ 3.5 100.5 -+ 3,5

t test values SBP P < 0.01 NS DBP NS NS

142.8 +- 3.4* 85.6 -+ 2.1"

144.0 _+ 3.6* 85.8 _+ 2.7*

SBP = systolic blood pressure; DBP = diastolic blood pressure; NS = not significant. * P < 0.001 versus baseline (paired t test). 1 P < 0.01 versus baseline (paired t test).

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K. TAKEDA ET AL.

200

~ 180 t c- E E 16o

g~ 140 ~ ~ 120

~ ~ 100 13_

~O~_o 8o rn 60

40

Baseline Monotherapy Combination Therapy

(12) (11) (11) (12)

(10) (11) (7) (12) (10) (9) (9) (11)

I I I I t I I I I 0 2 4 6 8 10 12 14 16

Time (weeks)

5 -

CD c 0

- 5 - rn

m -10 - >

m -15 - r-

-20 I I I I I i I B 6 8 10 12 14 16

Time (weeks)

F i g u r e 1. Blood p r e s s u r e (BP) and h e a r t r a t e (top), and c h a n g e s in BP a n d h e a r t r a t e (bottom) in the a ro t ino lo l - s t a r t ing group. N u m b e r s in p a r e n t h e s e s represent the n u m b e r of pat i ent s . • = systol ic blood p ressure ; • = diastol ic blood p ressure ; • h e a r t ra te . *P < 0.01 compared w i t h base l ine ; I"P < 0.001 compared w i t h base l ine ; SP < 0.05 compared w i t h base l ine .

Heart rate increased slightly after addition of nifedipine SR, but with the exception of the value obtained at week 14, did not significantly differ from that recorded in the baseline period.

N ifedipine-Starting Group

In patients initially treated with nifedipine SR, only SBP showed a significant decrease during monotherapy relative to the baseline period (Figure 2). As this value was still high (170 -+ 3 mm Hg), the antihypertensive effect of nifedipine SR was not adequate. Almost no difference in DBP was seen between the baseline and monotherapy periods. Two weeks after addition of arotinolol to the therapeutic regimen (week 10), an antihypertensive effect of/>22% was seen in both SBP and DBP. This reduction persisted until the final assessment (week 16). Monotherapy with nifed-

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Baseline Monotherapy Combination Therapy

200 7 ---(~ l,, 180 1

7" ,_ 1601 E E (11) ( 1 3 ) ~ E ~ v ~ 1404 (12) (10) (12) (1-1) 12o ~-- 100 1 1

rn 60 (5) (9) (12) (9) (1 (10) (9) (9) (11)

4 0 I I I I I ; I I I 0 2 4 6 8 10 12 14 16

Time (weeks)

e-

f ~

>

e-

5

- 5 -

-10

-15

-20

-25 I t t l I t t B 6 8 10 12 14 16

Time (weeks)

F i g u r e 2. Blood pressure (BP) and heart rate (top), and changes in BP and heart rate (bottom) in the nifedipine-starting group. N u m b e r s in parentheses represent the number of patients. • = systolic blood pressure; • = diastolic blood pressure; • = heart rate. *P < 0.01 compared with baseline; t P < 0.001 compared with baseline; SP < 0.05 compared with baseline.

ipine SR did not cause any significant change in heart rate compared with baseline. However, combination therapy led to a 14% decrease in heart rate.

Adverse Effects and Laboratory Data

Adverse effects were noted in 4 of 17 patients in the arotinolol-starting group (23.5%). In 1 of these patients, there was an abnormal laboratory finding (increased total cholesterol level), but it was not sufficient to discontinue treatment. However, combination therapy was withdrawn in the other 3 patients, as 2 developed rash and 1 reported headache after the addition of nifedipine SR. Because these symptoms resolved after discon- t inuation of treatment, they were assumed to have been caused by the addition of nifedipine SR to the therapeutic regimen.

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K. TAKEDA ET AL.

In the nifedipine-starting group, significant changes were seen in AST levels (19.9 -+ 1.5 IU during baseline compared with 16.1 -+ 1.0 IU at the end of the study; P < 0.05), LDH levels (353.1 -+ 29.3 IU compared with 327.1 +-- 23.5 IU; P < 0.05), and K + levels (4.08 --+- 0.2 mmol/L compared with 4.43 -+ 0.1 mmol/L; P < 0.05), but values remained within the normal range. There were no significant differences between baseline and treatment periods for any other laboratory parameters in either group.

D I S C U S S I O N

The drugs recommended as first choice for the t rea tment of hypertension at present are calcium antagonists, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and diuretics. 9 These agents are selected on an individual basis by matching specific drugs and patient characteristics. The beta-blocking activity of arotinolol is two to three t imes greater than that of propranolol, while its alpha-blocking activity is one tenth that of phentolamine. Compared with labetalol, which has an alpha:beta blocking ratio of about 1:3, arotinolol, with an alpha:beta ratio of 1:8, acts predom- inantly through beta-blockade.

It has been shown that arotinolol reduces heart rate, cardiac output, and plasma renin activity (PRA).10 However, unlike other beta-blockers, its alpha-blocking action reduces peripheral vessel resistance to a level below that of propranolol.

Nondihydropyridine calcium antagonists, such as verapamil and diltiazem, act by inducing delayed atrioventricular conduction and by reduc- ing myocardial contractility. 11 The combination of these calcium antagonists with a beta-blocker should be avoided, as it can increase the risk of cardiac failure. In contrast, dihydropyridine calcium antagonists exhibit little suppression of cardiac conduction, 12 but their vasodilative action induces reflex tachycardia 13 and immediate elevation of PRA. 14 These characteristics suggest that combined use with a beta-blocker can enhance the antihypertensive response.

The results of this study demonstrate the efficacy of combining nifedipine SR with arotinolol in patients who did not respond to monotherapy with one of these agents. As our study protocol did not allow for crossover of the two drugs, but involved a change from monotherapy to combination therapy, we were not able to compare the independent efficacies of the two drugs. However, our findings indicate that combination therapy augments the antihypertensive response.

It has been reported that combination therapy with atenolol and nifedipine was more effective than monotherapy with either drug. 15 Other reports have documented improvement 16 or no change 17 in beta-blockade- induced b radycard ia when monotherapy with the be ta-b locker was

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switched to combination therapy with a calcium antagonist. In this study, nifedipine SR reduced the tendency to develop bradycardia when added to the regimen of patients initially treated with arotinolol. An interesting finding in this study was that bradycardia occurred in patients treated with nifedipine SR after the addition of arotinolol.

It has been reported that administration of a beta-blocker increases the sensitivity of the cardiac beta-receptors and that subsequent combination therapy with nifedipine SR leads to a slight elevation of blood catecholamine levels. 13 This result might be expected to increase the heart rate, but the opposite outcome is thought to arise from the efficacy of beta-blockade. Moreover, the tendency for an appreciable antihypertensive response in patients initially treated with arotinolol after addition of nifedipine SR might have been due to enhancement of the baroreceptor reflex.

An important factor in achieving an antihypertensive response through combination therapy in this study was the opposite effect of each drug on PRA, although we were not able to confirm this finding. Other investigators have demonstrated that arotinolol suppresses PRA through beta-blockade 1° and that nifedipine SR elevates it.14 Another recent report describes findings similar to this study. It documents an antihypertensive response in patients given combination therapy with an alpha/beta- blocker who did not respond to monotherapy with a calcium antagonist, is There have also been several reports of patients who did not respond to monotherapy with a beta-blocker but who responded to the addition of a calcium antagonist to their therapeutic regimen. 19-23

In this study, many patients initially treated with arotinolol showed a marked antihypertensive response to combination therapy, suggesting the existence of some factor that enhances the antihypertensive action of calcium antagonists in patients with a poor response to arotinolol. A possible explanation may be that alpha-blockade action alone is not sufficient to lower the peripheral resistance in patients with a poor response to arotinolol, and that the potent vasodilative action of the calcium antagonist reduces peripheral resistance, thereby inducing an antihypertensive response. An alternative explanation is that the initial administration of arotinolol may create a special set of in vivo conditions that amplify the pharmacologic action of the calcium antagonist to the point where adverse effects may occur. This hypothesis would explain the appearance of adverse effects and the need to discontinue treatment in three patients initially receiving arotinolol after they were switched to combination treatment with nifedipine SR. These results suggest that when nifedipine SR is added to the therapeutic regimen of a patient receiving arotinolol, it may be advisable to administer a lower dose of nifedipine than that used in this study.

Other investigators have also reported an appreciably larger antihy-

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K. TAKEDA ET AL.

pertensive response after combination therapy in a group started on a beta-blocker than a group started on a calcium antagonist. 24 This finding should be considered when selecting drugs for combination therapy in the future.

The t reatment of hypertension sometimes causes problems related to concomitant conditions, particularly diabetes and hyperlipidemia, which are frequently associated with hypertension. The a lpha/beta-blocker labetalol was reported to cause hyperglycemia and suppress insulin secre- tion in pat ients with diabetes mellitus. 25 In contrast , another s tudy showed that arotinolol had no effect on glucose metabolism in diabetic patients. 26

Regarding the effects of beta-blockers on lipids, nonselective agents without ISA appear to raise triglyceride (TG) levels and reduce high- density lipoprotein (HDL) levels, and beta-selective agents without ISA also raise TG and reduce HDL levels to some extent. In contrast, it has been reported that beta-blockers with ISA did not affect TG levels and caused a slight increase in HDL levels. 27 Other investigators have reported that arotinolol had no effect on blood lipids, including TG and HDL. 2s There have not been any reports of adverse effects of calcium antagonists on lipids, indicating that combination therapy with arotinolol and a calcium antagonist can be used in hypertensive patients with the above complications. Moreover, this combination therapy appears to be ideal for hypertensive patients with ischemic heart disease.

An earlier report on atenolol and nifedipine documented a heightened antihypertensive response following combination therapy, relative to the efficacy of monotherapy with each drug. 15 Another study showed that nifedipine therapy with either a beta-blocker or an ACE inhibitor was effective, and the addition of a diuretic provided an additional antihypertensive benefit. 29 This supports the empirical findings of many Japanese studies, which have shown that combining a calcium antagonist with a diuretic can augment the antihypertensive response.

CONCLUSION

The results of the present s tudy have shown that combination therapy using arotinolol, an alpha/beta-blocker , with a sustained-release nifedipine preparation, a calcium antagonist, was effective in patients who did not exhibit an antihypertensive response to either of these drugs when administered as monotherapy.

References:

1. The Fif th Report of the Jo in t Nat ional Committee on Detection, Evaluat ion, and Treat- ment of High Blood Pressure (JNC V). Arch Intern Med. 1993;153:154-183.

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2. Yusuf S, Peto R, Lewis J, et al. Beta blockade during and after myocardial infarction: An overview of the randomized trials. Prog Cardiovasc Dis. 1985;27:335-371.

3. The Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. NEJM. 1988;315:385-392.

4. Takekoshi N, Murakami E, Matsui S, et al. Studies on concurrent alpha- and beta- adrenoceptor blocking action of S-596 (arotinolol). Jpn Heart J. 1983;24:925-933. In Japanese.

5. Prichard BNC. ~-adrenergic receptor blockade in hypertension: Past, present, and future. Brit J Clin Pharmacol. 1978;5:379-399.

6. Miyagishi A, Nakahara H, Hara Y, Nakatani H. Effects of the new ~-adrenoceptor blocking agent, S-596, on the peripheral autonomic nervous system and smooth muscles. Arch Int Pharmacodyn Ther. 1983;261:222-237.

7. Ikeda M, Tsuchiya M, Inagaki Y, et al. Antihypertensive efficacy of S-596 (arotinolol) in essential hypertension--pilot study in 13 centers. Kiso To Rinsho. (The Clinical Report). 1984;18:639-653. In Japanese.

8. Kokufu T, Masuyama Y, Ikeda M, et al. Clinical efficacy of KB-1712 (sustained-release nifedipine) alone and in combination with a thiazide diuretic in essential hypertension-- open multicenter study. Sinryo To Shinyaku (Medical Consultation & New Remedies). 1984;21:2287-2304. In Japanese.

9. Guideline Sub-Committee. 1993 Guidelines for the Management of Mild Hypertension: Memorandum from a WHO/ISH Meeting. Bulletin of the World Health Organization. 1993;71:503-513.

10. Kuramoto K, Matsushita T, Kato Y, et al. Hemodynamics, plasma renin activity and catecholamine fluctuation after single administration of the new alpha/beta-blocker, arotinolol. Kiso To Rinsho (The Clinical Report). 1983;17:2599-2604. In Japanese.

11. Nayler WG. Calcium antagonists and arrhythmias. In: Calcium Antagonists. San Diego: Academic Press; 1993:193-198.

12. Talano JV, Tommaso C. Slow channel calcium antagonists in the treatment of supra- ventricular tachycardia. Prog Cardiovasc Dis. 1982;25:141-156.

13. Kiowski W, Bertel O, Erne P, et al. Hemodynamic and reflex responses to acute and chronic antihypertensive therapy with calcium entry blocker nifedipine. Hypertension. 1983;5(Suppl I):I-70-I-74.

14. Singer DRJ, Markandu ND, Shore AC, MacGregor CA. Captopril and nifedipine in combination for moderate to severe essential hypertension. Hypertension. 1987;9:629-633.

15. Smith DHG, Neutel JM, Jankelow D, et al. A comparative study of atenolol, nifedipine and their combination in the treatment of hypertension. S African Med J. 1991;79:12-15.

16. Yokota M. Efficacy of monotherapy with the preferential cardiac beta-blocking agent metoprolol and combination therapy with metoprolol and the calcium antagonist nifedipine (Sepamit ®) in patients with essential hypertension. Shinyaku To Rinsho (Journal of New Remedies & Clinics). 1983;32:1901-1908. In Japanese.

17. Arakawa M, Gejo F, Ito G, et al. Study on the antihypertensive efficacy of acebutolol (Sectral®) and combination therapy with nifedipine (Sepamit ®) at other institutions. Shinyaku To Rinsho (Journal of New Remedies & Clinics). 1986;35:1224-1233. In Japanese.

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18. Yamamoto T, Yashima H, Nakamura Y, Imamura Y. Monotherapy with perdipine LA and Lowgan ® and combination therapy with both in essential hypertension. Shinyaku To Rinsho (Journal of New Remedies & Clinics). 1990;39:2625-2632. In Japanese.

19. Hiejima K, Hayakawa H, Ota M, et al. Study on the antihypertensive efficacy and utility of combination therapy with the Ca antagonist nitrendipine and the beta-blocking agent propranolol in essential hypertension. Rinsho To Kenkyu (The Japanese Journal of Clin- ical and Experimental Medicine). 1989;66:254-263. In Japanese.

20. Arakawa K, Kaneko Y, Iimura O, et al. Efficacy and safety of manidipine hydrochloride in patients with essential hypertension--A dose-finding study in monotherapy and combined therapy with thiazide diuretics or g-blocking agents. Yakuri To Chiryo (Japanese Pharmacology & Therapeutics). 1989;17:2681-2712. In Japanese.

21. Yoshinaga K, Iimura O, Abe K, et al. A study of benidipine hydrochloride (KW-3049) on the antihypertensive effect and safety in essential hypertensive patients in long-term treatment. Yakuri To Chiryo (Jpn Pharmacol Ther). 1990;18(Suppl 90):$763-$784. In Japanese.

22. Tagami M. Age-related antihypertensive efficacy of sustained-release nifedipine tablet (Adalat-L) by age in essential hypertensive cases resistant to beta-blocking agents. Prog Med. 1990;10:63t-638.

23. Wilkinson R, Mansy S. A dose finding study of the combination of atenolol and nifedipine in hypertension. Curr Med Res Opin. 1990;12:108-113.

24. Kawamura H, Saito J, Takahashi S, Hatano M. Utility of combined therapy with labetalol and nicardipine in essential hypertension. Junkanki. 1986;20:257-264. In Japa- nese.

25. Pagnan A, Pessina AC, Hlede M, et al. Effects of labetalol on lipid and carbohydrate metabolism. Pharmacol Res Communications. 1979;11:227-236.

26. Akazawa Y, Koide S, Kazutani H, Hattori M. Clinical efficacy of a new alpha/beta- blocking agent arotinolol in cases with essential hypertension complicated with diabetes mellitus. Shinryo To Shinyaku (Medical Consultation & New Remedies). 1986;23:131- 138. In Japanese.

27. Leren P. Comparison of effects on lipid metabolism of antihypertensive drugs with alpha- and beta-adrenergic antagonist properties. Am J Med. 1987;82(Suppl 1A):31-35.

28. Nakamura H, Kondo K, Hirata F, et al. Effect of antihypertensives on serum lipids-- comparison of propranolol and arotinolol in a single case. Prog Med. 1986;6:2649-2652.

29. Ferrara LA, Pasanisi F, Marotta T, et al. Calcium antagonists and thiazide diuretics in the treatment of hypertension. J Cardiovasc Pharmacol. 1987;10(Suppl 10):5136-5137.

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effect of combination therapy with arotinolol and sustained-release nifedipine in patients with...

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