A multifactorial trial design to assess combination therapy in hypertension. Treatment with bisoprolol and hydrochlorothiazide.

BACKGROUND: The safety and effectiveness of different dosages and combinations of antihypertensive agents can be efficiently studied using a multifactorial trial design. In consultation with the Cardio-Renal Division of the Food and Drug Administration, we conducted a randomized, double-blind, placebo-controlled, 3 x 4 factorial trial of bisoprolol, a beta 1-selective adrenergic blocking agent, and hydrochlorothiazide. METHODS: A total of 512 patients with mild to moderate essential hypertension were randomized to once-daily treatment with bisoprolol (0, 2.5, 10, or 40 mg), hydrochlorothiazide (0, 6.25, or 25 mg), and all possible combinations. Diastolic and systolic blood pressures were monitored during this 12-week trial. RESULTS: The effects of bisoprolol and hydrochlorothiazide were additive with respect to reductions in diastolic and systolic blood pressures over the dosage ranges studied. The addition of hydrochlorothiazide (or bisoprolol) to therapy with bisoprolol (or hydrochlorothiazide) produced an incremental reduction in blood pressure. Dosages of hydrochlorothiazide as low as 6.25 mg/d contributed a significant antihypertensive effect. A hydrochlorothiazide dosage of 6.25 mg/d produced significantly less hypokalemia and less of an increase in uric acid levels than a dosage of 25 mg/d. The low-dose combination of bisoprolol, 2.5 mg/d, and hydrochlorothiazide, 6.25 mg/d, reduced diastolic blood pressure to lower than 90 mm Hg in 61% of patients and demonstrated a safety profile that compared favorably with that of placebo. CONCLUSIONS: The utility of factorial design trials to characterize dose-response relationships and to test the potential interactions between various antihypertensive agents has been demonstrated. The combination of low dosages of bisoprolol and hydrochlorothiazide may be a rational alternative to conventional stepped-care therapy for the initial treatment of patients with mild to moderate hypertension.

Sympathetic activity and cardiac adrenergic receptors in one-kidney, one clip hypertension in rats.

The activity of the sympathetic nervous system, as measured by levels of plasma and cardiac catecholamines and catecholamine metabolites and the function of cardiac alpha- and beta-adrenergic receptors, was evaluated at 3 days and 4 weeks after induction of one-kidney, one clip hypertension (1K1C) in the rat. At 3 days, the plasma level of norepinephrine (NE) was lower in the 1K1C group than the control group (p less than 0.01), whereas epinephrine (E) and the metabolites dihydroxymandelic acid (DOMA), dihydroxyphenylglycol (DOPEG), and normetanephrine (NMN) were similar in both groups. In addition, cardiac content of catecholamines, their metabolites, and adrenergic receptors were similar in both groups. At 4 weeks, plasma levels of NE and DOPEG were lower (p less than 0.01), whereas levels of DOMA and NMN were higher (p less than 0.02 and p less than 0.001, respectively) in the 1K1C group than the control group. Cardiac content of NE (p less than 0.01), and DOPEG (p less than 0.05) was significantly lower, whereas DOMA and NMN were significantly higher (p less than 0.01) in the 1K1C group as compared to controls. In addition, cardiac density of both alpha- and beta-adrenergic receptors was reduced in the 1K1C group, whereas receptor affinities were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Sympathetic system function and vascular reactivity in hypercalcemic patients.

To elucidate the pathophysiology of elevated blood pressure in hypercalcemic patients, we studied the plasma concentration of catecholamines and their major metabolites (as an index of sympathetic function) and the blood pressure response to norepinephrine infusion (vascular reactivity) in patients with primary hyperparathyroidism, in patients with primary hypertension, and in normal controls. In addition, we evaluated the hemodynamic response to calcium infusion in normotensive and hypertensive subjects. Plasma levels of both norepinephrine and epinephrine and the metabolites normetanephrine and dihydroxyphenyl-glycol were significantly higher in the hypercalcemic group than in the other two groups. Norepinephrine infusion increased blood pressure by 8.5 +/- 1.4 mm Hg in the control group, by 19 +/- 2 mm Hg in the hypercalcemic group and by 29 +/- 3 mm Hg in the primary hypertensive group. Infusion of calcium produced a significant rise in both systolic and diastolic blood pressures and in peripheral resistance in the hypertensives, whereas in the normotensive group only systolic blood pressure increased, associated with a rise in cardiac output. We conclude that the observed increased activity of the sympathetic nervous system in hypercalcemia could account for the elevation in blood pressure and the enhanced vascular reactivity could explain the hypertension in some patients with primary hyperparathyroidism.

Antihypertensive effects of tolamolol.

The antihypertensive and renin-lowering efficacy and side effects of tolamolol, a beta adrenergic blocking drug with cardioselectivity, were examined in 10 patients with mild essential hypertension while on regular diet. Tolamol, at a dose of 300 to 900 mg per day, given over a period of 2 to 4 wk significantly decreased systolic and diastolic blood pressures in both the recumbent and standing positions. Normal blood pressure (140/90 mm Hg or less) was attained in 8 subjects. Mean heart rate and ambulatory midday plasma renin activity (PRA) decreased significantly; however, there was no significant correlation between blood pressure decrease and either the pretreatment PRA or decrease in PRA. Body weight did not change significantly. No adverse side effects were detected and no changes in the liver or renal function or in the blood count were observed. It is concluded that tolamolol is effective in lowering blood pressure and PRA in patients with hypertension.

Acute effect of labetalol on blood pressure in relation to the sympathetic nervous system and plasma renin activity.

A single oral dose of 300 mg labetalol was given to 10 subjects with uncomplicated primary hypertension; its effects on blood pressure, heart rate (HR), plasma renin activity (PRA), and plasma concentration of catecholamines and of their major metabolites, octopamine ( OTP ), and dopamine-beta hydroxylase (DbH) were investigated. Although HR did not change after dosing, both systolic and diastolic blood pressure decreased in 2 hr and remained below control up to 12 hr. There was symptomatic orthostatic hypotension in two subjects in the first 2 hr after dosing. PRA decreased in the first 2 hr and followed a gradual rise that became significant at 24 hr. Although DbH did not change, plasma concentrations of norepinephrine (NE) and its major metabolites and of OTP increased between 2 and 4 hr after dosing and remained elevated up to 12 hr. There was no correlation between change in blood pressure and control levels or changes of PRA or NE concentrations.

Hemodynamic effect of lofexidine with a diuretic in hypertension.

We measured the first dosage effect and the long-term effect of lofexidine on blood pressure, heart rate, plasma catecholamines, and their major metabolites in 16 patients with primary hypertension who were receiving 50 mg hydrochlorothiazide twice a day while they were recumbent and upright and during isometric handgrip contraction. We also measured the first dosage effect of lofexidine on forearm blood flow and its long-term effect on plasma renin activity. Lofexidine, both in a single dose and after long-term therapy, induced a substantial fall in blood pressure of patients in recumbent and upright positions, whereas it decreased heart rate in both positions only during long-term dosing. Lofexidine did not prevent or diminish the pressure and heart rate rise by isometric handgrip contractions. Single and long-term lofexidine dosing induced a fall in plasma levels of catecholamines and their metabolites. There was a positive correlation between the fall in blood pressures and the reduction in plasma norepinephrine during long-term therapy. There was a positive correlation between the decrease in blood pressure induced by single doses and by long-term dosing, which suggests that lofexidine in a single dosage at the start of therapy may facilitate identification of responders.

Oral potassium chloride and amiloride in hydrochlorothiazide-induced potassium loss.

To compare the effect of amiloride with that of oral potassium chloride (KCl) in hypokalemia, metabolic balance studies were carried out in hospitalized subjects with mild hypertension without edema who developed negative potassium balance after 4 days on hydrochlorothiazide (HCTZ). Subjects' diets contained measured amounts of sodium and potassium. While HCTZ treatment continued, oral preparations of either KCl solution or amiloride was added for 5 additional days. Potassium balance in the KCl-treated group further decreased by -44.9 +/- 32.3 mEq K+, while subjects on amiloride went into positive balance that averaged +51.7 +/- 24.1 mEq K+. Hypokalemia after HCTZ did not respond to KCl, while K+ levels rose from 3.32 +/- 0.22 to 3.67 +/- 0.26 mEq/l after amiloride.

Pharmacodynamics of intravenous labetalol and follow-up therapy with oral labetalol.

The effectiveness, safety, and pharmacodynamics of repeated doses of intravenous labetalol for rapid reduction of severe hypertension and of subsequent oral labetalol dosing were studied. Twelve patients with severe hypertension were admitted to the hospital after the withholding of antihypertensive therapy for 2 to 14 days. Thirty minutes after an injection of vehicle only, labetalol, 0.25 mg/kg body weight, was injected and followed by repeat injections of 0.5 mg/kg every 15 minutes until the supine diastolic blood pressure (BP) was reduced to less than 90 mm Hg or a total of 3.25 mg/kg had been administered. Twenty-four hours after the last injection, oral labetalol was started at an initial dosage of 100 or 200 mg b.i.d., then increased every 2 days until the standing diastolic BP was less than 90 mm Hg or a maximum daily dosage of 2400 mg was reached. The initial injection achieved mean falls in supine systolic/diastolic BPs of 11/7 mm Hg. Subsequent injections produced additional falls in a dose-related fashion; the mean falls after the last injection (total cumulative dose 2.7 mg/kg) were 40/20 mm Hg. The effect lasted for 12 hours or more in most patients and tended to be biphasic, with one peak at approximately 5 minutes and another much less pronounced peak at about 4 hours. There was no evidence of precipitous falls in BP. All patients were able to ambulate 6 hours after the last injection without symptoms of postural hypotension. Oral labetalol effectively and safely restored and maintained the BP reductions achieved with intravenous labetalol.

Platelet aggregation in relationship to plasma catecholamines in patients with hypertension.

Plasma catecholamine concentration and platelet aggregation were studied in 22 patients with uncomplicated primary hypertension and 13 age-matched normotensive, healthy subjects at rest and in some during isometric handgrip exercise. The effect of norepinephrine (NE) infusion upon platelet aggregation was also examined. Plasma catecholamine concentration was slightly higher in the hypertensive than the normotensive group, but the difference was not significant. However, platelet aggregation to ADP was significantly greater in the hypertensive than the normotensive subjects. Exercise increased significantly both catecholamines and aggregation in both groups. Platelet aggregation was correlated with age (r = 0.62, P less than 0.01) and plasma NE (r = -0.34, P less than 0.05 for the total group of subjects). The infusion of NE increased significantly plasma NE and platelet aggregation and there was an inverse correlation between NE increase and threshold decrease (r = -0.69, P less than 0.05). Thus, plasma catecholamines and important determinants of platelet aggregation. However, in our study, uncomplicated primary hypertension was not associated with abnormal plasma catecholamine concentration. It is likely that the observed abnormal platelet aggregability to ADP represents a secondary phenomenon, possibly related to more advanced atherosclerotic vascular changes in hypertensive than normotensive subjects.

Diminished baroreceptor sensitivity in elderly hypertensives. Possible role of atherosclerosis.

Baroreceptor sensitivity was studied in twelve young normotensive subjects and forty hypertensive patients, separated into two groups according to their age, severity of hypertension and signs of severe atherosclerotic vascular disease. Under stabilized circulatory conditions, the changes of pulse rate in response to changes of blood pressure, attained by infusion of trimethaphan camphorsulfonate alone or with norepinephrine, was examined. There was gradually diminished change of pulse rate in relationship to blood pressure change as age and hypertension advanced. However, although the blood pressure threshold of stimulation was obviously higher in the middle-aged hypertensive subjects than in the normotensive ones, the slightly reduced baroreceptor sensitivity was not significantly different from that in the normotensive group. Only in the elderly hypertensive patients was significantly diminished baroreceptor sensitivity demonstrated, which was also significantly different from that in the middleaged hypertensive patients. It is speculated that the significantly diminished baroreceptor sensitivity found in the elderly hypertensive patients may be due to atherosclerotic changes in the region of the baroreceptor, although proof of that is not available at the present time.

Study of single and multiple dose pharmacokinetic/pharmacodynamic modeling of the antihypertensive effects of labetalol.

This was an open-label, two-phase crossover study of labetalol in 11 patients with mild to moderate hypertension. A two- to four-week outpatient placebo phase was followed by a three-day inpatient placebo period. Patients were then randomly assigned to receive either labetalol, 200 mg, as a single dose and three times a day for three days and, on the final day, another single dose or a similar sequence with 300 mg as the single dose and multiple twice a day treatment. A two-week placebo outpatient period was followed by the second phase of the study in which the treatment regimen was reversed for the two groups. Blood samples for the determination of free and conjugated labetalol plasma levels were collected, and blood pressures and heart rate were recorded sequentially for 24 hours after the first and last dose of labetalol, and during the multiple dose treatment period before and two hours after each dose as well as four times daily with the patient supine and upright. Of the 11 patients analyzed, five were men and six were women, ranging in age from 33 to 62 years. Labetalol (200 mg and 300 mg) was rapidly absorbed with peak concentrations achieved in approximately one hour. The pharmacokinetic data best fit a two-compartment pharmacokinetic model with first order absorption. At steady state, the absorption, distribution, and elimination kinetics were similar for both dosage regimens with elimination half life of 7.65 and 7.92 hours for the 200 mg three times a day and 300 mg twice a day regimens, respectively. During the multiple dosing period average steady-state plasma drug concentrations were 0.149 mg/ml and 0.145 mg/ml for the 300 mg twice a day and 200 mg three times a day regimens, respectively. Approximately 12 percent of total plasma labetalol was free drug. The balance was conjugated. The first dose of 200 mg or 300 mg of labetalol significantly (p less than 0.01) lowered standing and supine mean blood pressure over a period of eight to 12 hours, respectively, with peak effects occurring at two (standing) and four (supine) hours. A significant reduction (p less than 0.01) in supine mean blood pressure was present 24 hours after the initial dose of 300 mg. At steady state the antihypertensive effects of the 200 mg three times a day and the 300 mg twice a day dosage regimens were similar.(ABSTRACT TRUNCATED AT 400 WORDS)

Intravenous labetalol in the treatment of severe hypertension and hypertensive emergencies.

The antihypertensive effects of intravenous labetalol were evaluated in 59 patients with hypertensive crises or severe hypertension in need of rapid lowering of blood pressure in a multicenter study. Patients appearing with a supine diastolic blood pressure 125 mm Hg or greater, or a supine systolic blood pressure of more than 200 mm Hg received an initial mini-bolus injection (20 mg) of labetalol. This was followed by repeated incremental doses of 20 to 80 mg given at 10 minute intervals to achieve a supine diastolic blood pressure of less than 95 mm Hg or decrease 30 mm Hg or greater, or a satisfactory decrease in systolic blood pressure. Patients were stratified into those who had taken antihypertensive medication within 24 hours and those who had not. The initial mini-bolus injection caused rapid but not abrupt reduction in blood pressure; the baseline mean blood pressure decreased 23/14 mm Hg. Further injections were needed in the majority of patients (mean: 197 mg). The blood pressure reduction after the last dose of labetalol was 55/33 mm Hg. In pretreated patients and in those who had no medication for 24 hours prior to the intravenous labetalol, the response was similar. Heart rate decreased 10 beats per minute in the total population. In patients pretreated with beta-adrenergic blockers, blood pressure response was similar to that in the total group (59/35 versus 55/33 mm Hg), but heart rate remained essentially unchanged. The dose required to achieve the therapeutic effect was less in pretreated patients than in untreated patients, but the duration of action was shorter. No serious adverse effects were encountered even in patients with concomitant diagnoses of acute left ventricular failure, myocardial infarction, stable congestive heart failure, atrial fibrillation, angina pectoris, acute stroke, transient ischemic attack or encephalopathy. Labetalol is a safe and effective treatment for a rapid blood pressure reduction in hypertensive emergencies.

Hypertension and propranolol therapy: effect on blood pressure, plasma catecholamines and platelet aggregation.

The effects of propranolol on blood pressure, plasma catecholamine concentration and platelet aggregation were examined in 16 patients with uncomplicated primary hypertension. The patients were studied at rest, during isometric handrip stress and 48 hours after sudden discontinuation of propranolol therapy. Plasma catecholamine concentration and platelet aggregation studies were also carried out in 11 age-matched normotensive and healthy subjects at rest. Plasma catecholamine concentration and platelet aggregation were greater in the hypertensive than in the normotensive subjects, but the difference reached statistical significance for aggregation only. Exercise significantly increased catecholamines and platelet aggregability. The administration of propranolol (240 mg/day) produced a significant decrease in systolic and diastolic blood pressue and in aggregation (the percent of light transmission at 1 microM adenosine diphosphate, at rest) and a significant increase in catecholamine concentration. However, propranolol did not prevent the changes in all these variables with exercise. The abrupt discontinuation of propranolol was not associated with any subjective or objective untoward cardiovascular effect or abnormal changes in plasma catecholamines. However, in some patients the platelet aggregation studies demonstrated a hyperaggregable state, which may be due to a state of supersensitivity of platelets to circulating catecholamines.

Similar efficacy of nitrendipine in young and elderly hypertensive patients.

Calcium channel blockers have been postulated to be more effective as monotherapeutic antihypertensive agents in the elderly than in younger patients. To determine if a new dihydropyridine derivative, nitrendipine, is more effective in the elderly (older than 60 years) than in younger hypertensive subjects (younger than 60 years), nitrendipine was administered in a multicentered study to 21 elderly and 33 younger subjects with essential hypertension. After gradual discontinuation of previous antihypertensive therapy and 2 weeks of placebo, the daily dose of nitrendipine (10 to 40 mg) was titrated over 3 weeks to achieve a 10 mm Hg decrease in supine diastolic blood pressure (BP) for patients entering with 90 to 99 mm Hg. For patients entering with at least 100 mm Hg, the dose was titrated to diastolic BP no greater than 90 mm Hg. Titrated dose of nitrendipine was maintained for 4 additional weeks. Propranolol was added for "symptomatic" tachycardia. Nitrendipine reduced BP in 90% of patients completing all phases of the study (n = 49). The proportion of responders was 47% among the elderly and 44% among young subjects. Change in heart rate was similar in both groups (-0.1 +/- 9.9 and +2.9 +/- 8.8 beats/min, mean +/- standard deviation). Two elderly and 1 younger subject required addition of propranolol (difference not significant). There was no correlation between the age of patients and changes in supine systolic and diastolic BP or heart rate (r = 0.21, -0.15 and -0.21, respectively). Adverse effects occurred with equal frequency in older and younger subjects (19 of 21 vs 23 of 33 patients, difference not significant).(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of beta 2 agonism and beta 1 and beta 2 antagonism on adverse effects and plasma lipoproteins: results of a multicenter comparison of dilevalol and metoprolol.

Dilevalol combines vasodilation due to selective beta 2 agonism and nonselective beta 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 less than 90 and greater than or equal to 10 mm Hg decrease from baseline. Responders were followed for 1 year. The average age of patients was 51 years; 72% were men and 54% were white. Both drugs reduced blood pressure effectively to a similar level. Fewer patients discontinued dilevalol than did those taking metoprolol (9 vs 16%; p less than 0.03). More metoprolol-treated patients withdrew because of depression (6 vs less than 1%; p = 0.03) and impotence (5 vs less than 1%; p = 0.03). Lipoprotein levels before and after treatment were measured in 99 patients treated for 53.5 weeks with dilevalol (mean dose 438 mg). Dilevalol increased high-density lipoprotein (HDL) cholesterol by 2.5 mg/dl to 47.2 (p = 0.05), reduced low-density lipoprotein (LDL) cholesterol by 2.5 mg/dl, increased HDL/LDL by 0.03, and decreased total cholesterol/HDL cholesterol by 0.18. Triglycerides increased by 21 mg/dl (p = 0.06). In patients with an initial HDL cholesterol less than 35 mg/dl, dilevalol increased it by 9 mg/dl. In patients treated with metoprolol, the only significant change (p = 0.02) was a 41.9-mg/dl increase in triglyceride levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Conjugated normetanephrine in human and rat plasma and erythrocytes.

Enzymatic hydrolysis was applied to the deconjugation of normetanephrine (NMN) in plasma and red blood cell lysate. By this procedure, in human plasma 77% of total NMN circulated in sulfate-conjugated form, while in rat plasma 63% was in glucuronidated form. Total NMN in human lysate was significantly higher than in plasma (P less than 0.001) and was mostly in the free form, indicating that red blood cells may play an important role in metabolism of norepinephrine. Enzymatic hydrolysis is superior to the standard method by acid hydrolysis plus heat since: (1) more conjugated NMN is hydrolyzed in human plasma and (2) a smaller sample is needed for hydrolysis.

Blood pressure responses to catecholamines during beta-adrenergic blockade with propranolol in hypertensive subjects.

In 14 patients with essential hypertension, the response of the heart rate and blood pressure to infusion of norepinephrine and epinephrine separately while off (control period) or on therapy with beta-adrenergic receptor blockade was examined. By titrating dosage against the response of blood pressure and pulse rate, propranolol hydrochloride was administered orally at 160 mg/day in four divided doses. There was a significant decrease in systolic blood pressure and in pulse rate during propranolol therapy, whereas diastolic blood pressure decreased but not significantly so. Normal blood pressure (140/90 mm /g or less) was attained only in five patients. The infusion of epinephrine and then norepinephrine produced a significant increase in both systolic and diastolic blood pressure during propranolol therapy, but the magnitude of the rise was significantly greater than that attained in the control period only during epinephrine infusion. We conclude that the transient hypertensive episodes which have been observed during offive visits in some hypertensive patients treated with propranolol are due mainly to release of epinephrine.

Alpha- and beta-adrenergic receptor blocking agents combined with a diuretic in the treatment of essential hypertension.

The antihypertensive efficacy and side effects of the combined therapy with propranolol, phenoxybenzamine, and hydrochlorothiazide were examined in 17 patients with moderate and moderately severe hypertension. Following a control period two to three weeks' duration, propranolol was started in nine patients as the sole antihypertensive agent and together with phenoxybenzamine, in eight. By titrating the dosage against pulse rate and blood pressure response, propranolol was given, in divided doses, from 80 to 160 mg and phenoxybenzamine, from 20 to 50 mg per day. When propranolol was given alone in nine patients, for four to 12 weeks, normal blood pressure was not attained in any patients. During three to ten weeks of combined propranolol and phenoxybenzamine therapy in 17 patients, normal blood pressure (150/90 mm Hg or less) or near-normal pressure (150/100 or less) was attained in 12 patients in the recumbent position and in 15 patients in the upright position, while orthostatic hypotension was not observed. Except for a reduction of ejaculation in three out of six male patients, no other side effects were encountered. The addition of hydrochlorothiazide diuretic in all of the above 17 patients, at a dose of 50-100 mg per day with a concomitant decrease in the dose of phenoxybenzamine, produced a further reduction in blood pressure, and normal or near-normal blood pressure was attained in all subjects. Symptomatic orthostatic hypotension, observed in two patients, was treated by a further readjustment of the dose of phenoxybenzamine, while inhibition of ejaculation was persistent in only one patient. It is concluded that the combined administration of propranolol, phenoxybenzamine, and hydrochlorothiazide in individualized doses is very effective in lowering the blood pressure with minimal side effects.

Medroxalol combined with hydrochlorothiazide in the treatment of hypertension.

The antihypertensive effect and safety of hydrochlorothiazide administration as a single drug and together with medroxalol were determined in 20 patients with primary hypertension. Following two biweekly intervals on placebo and hydrochlorothiazide, medroxalol was started at 100 mg three times a day and titrated against blood pressure response up to a maximum of 300 mg three times a day. In nine patients the effect of the single and the combined drug therapy on blood pressure during isometric handgrip exercise, on plasma renin activity, and on plasma catecholamines and their deaminated metabolites was investigated. The administration of hydrochlorothiazide was associated with a significant decrease in blood pressure, but heart rate did not change. The addition of medroxalol produced a substantial decrease in blood pressure and heart rate in both the recumbent and upright positions (P less than 0.001). Due to careful titration of medroxalol, orthostatic hypotension was observed only in one patient. Neither hydrochlorothiazide alone nor the combined drug regimen prevented or diminished the rise in blood pressure with exercise. Although plasma renin activity decreased during the combined drug therapy, there was no correlation between the initial levels or the change in plasma renin activity and the extent of decrease in blood pressure. The concentration of plasma epinephrine increased during the combined drug period, whereas catecholamine metabolites increased significantly during both periods of the study. It is concluded that medroxalol combined with hydrochlorothiazide constituted a potent and safe antihypertensive therapy for the duration of the present study.

Antihypertensive and metabolic effects of concomitant administration of terazosin and methyclothiazide for the treatment of essential hypertension.

The efficacy and safety of once-daily 2.5- or 5.0-mg methyclothiazide (MCTZ) added to once-daily 5.0-mg terazosin (TRZ) versus 5.0-mg TRZ alone was evaluated in this double-blind, multicenter study. All patients received TRZ during a 6-week titration period. Hypertensive patients (222) (mean blood pressure of 159/104 mm Hg) were randomized to one of three treatment groups: TRZ alone (N = 76); TRZ+MCTZ-2.5 mg (N = 74); and TRZ+MCTZ-5.0 mg (N = 72) for the 8-week double-blind period. Changes in the supine and standing SBP/DBP from preTRZ period were: TRZ alone (-4.8/-8.1 and -2.6/-6.1 mm Hg); TRZ+MCTZ-2.5 mg (-17.3/-12.4 and -16.0/-11.2 mm Hg); and TRZ+MCTZ-5.0 mg (-20.6/-14.4 and -23.3/-14.6 mm Hg). Blood pressure changes in the combination groups were significantly greater than those in the TRZ alone group. However, there were no statistically significant differences between the TRZ+MCTZ-2.5-mg and TRZ+MCTZ-5.0-mg groups. The combination of TRZ and MCTZ tends to mitigate the adverse effects on serum glucose, uric, potassium and lipids usually associated with thiazide diuretics. Thus, combination treatment that begins with TRZ and adds MCTZ is effective in lowering blood pressure without any significant adverse metabolic effects.