Comparative effects of candesartan cilexetil and amlodipine in patients with mild systemic hypertension. Comparison of Candesartan and Amlodipine for Safety, Tolerability and Efficacy (CASTLE) Study Investigators.

The comparative antihypertensive efficacy and tolerability of the angiotensin II receptor blocker candesartan cilexetil and the calcium channel blocker amlodipine were evaluated in an 8-week, multicenter, double-blind, randomized, parallel-group, forced-titration study in 251 adult patients (45% women, 16% black) with mild hypertension (stage 1). Following a 4- to 5-week placebo run-in period, patients with sitting diastolic blood pressure (BP) of 90 to 99 mm Hg received candesartan cilexetil 16 mg (n = 123) or amlodipine 5 mg (n = 128) once daily. After 4 weeks of double-blind treatment, patients were uptitrated to candesartan cilexetil 32 mg or amlodipine 10 mg once daily. There were no significant differences between the candesartan cilexetil and amlodipine regimens for reducing BP; mean systolic BP/diastolic BP reductions were -15.2/-10.2 mm Hg versus -15.4/-11.3 mm Hg, respectively (p = 0.88/0.25). Overall, 79% of patients on candesartan cilexetil and 87% of those on amlodipine were controlled (diastolic BP <90 mm Hg). A total of 3.3% of patients on candesartan cilexetil discontinued treatment, compared with 9.4% of patients on amlodipine, including 2.4% versus 4.7% for adverse events and 0% versus 1.6% for peripheral edema, respectively. Peripheral edema, the prespecified primary tolerability end point, occurred with significantly greater frequency in patients on amlodipine (22.1%; mild 8.7%, moderate 11.8%, severe 1.6%) versus patients on candesartan cilexetil (8.9%; mild 8.1%, moderate 0.8%) (p = 0.005). Candesartan cilexetil and amlodipine are both highly effective in controlling BP in patients with mild hypertension. Candesartan cilexetil offers a significant tolerability advantage with respect to less risk of developing peripheral edema.

Clinical significance of alpha1-adrenoceptor selectivity in the management of benign prostatic hyperplasia.

Alpha1-adrenoceptor antagonists have been shown to provide effective relief from symptoms of benign prostatic hyperplasia (BPH) with attendant improvements in quality of life. Although the alpha1A-adrenoceptor subtype predominates over other subtypes of alpha1 adrenoceptors in the prostate gland, there is no evidence that a subselective alpha-adrenoceptor antagonist provides a clinical advantage over a selective alpha1-adrenoceptor antagonist in the treatment of patients with BPH. The pharmacokinetic profiles of alpha1A-adrenoceptor antagonists and their documented penetration of the blood-brain barrier (CNS adverse effects) preclude a clinical benefit of subselective alpha-adrenoceptor blockers over selective alpha1 blockers.

Neurosurgical notes: World War II.

This concerns my activities as a neurosurgeon in the European Theater of Operations and the North African, Tunisian campaign, during World War II. Action during the Battle of the Bulge came later. Our mobile tent hospital, the 9th Evacuation Hospital, was similar to that depicted in the television show M*A*S*H. To lend flavor to these comments, I have referred to medical and surgical matters in other units as well as our own, mentioned global aspects of the war, and included vignettes of life off-duty. The story begins after induction into the Army Medical Corps as a volunteer in July 1942 and ends with honorable discharge in April 1946.

Interpretation of the ALLHAT interim analysis and implications for the treatment of patients with BPH.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was designed to see if the effects of doxazosin, amlodipine and lisinopril were superior to those of chlorthalidone on the incidence of cardiovascular disease in high-risk patients with hypertension. Earlier this year, following an interim analysis of 24,335 patients, the doxazosin treatment arm was stopped amid reports of an increased incidence of secondary cardiovascular endpoints relative to chlorthalidone. This paper will offer some insight into the interpretation of the ALLHAT interim data, and clarify any issues around the use of alpha-1 adrenoceptor antagonists, such as doxazosin, in the management of patients with benign prostatic hyperplasia. Prostate Cancer and Prostatic Diseases (2000) 3, 152-156

The role of angiotensin II in hypertension and end-organ damage.

Both high blood pressure and the local effects from Ang II contribute to cardiovascular morbidity and mortality. From all these effects, it is clear that antihypertensive treatment by interfering with the Ang II regulatory system has two benefits: It leads to a reduction of blood pressure per se, with the positive effects of reducing stress, turbulence and stretch of the vascular wall. It decreases Ang II-mediated responses involved in cardiovascular remodelling. The recent emergence of several specific Ang II-receptor antagonists such as losartan or valsartan has considerably widened the therapeutic options available for the treatment of hypertension-related diseases.

Prolonged fenoldopam infusions in patients with mild to moderate hypertension: pharmacodynamic and pharmacokinetic effects.

Thirty-three patients with mild-to-moderate essential hypertension received either placebo or fenoldopam, a selective dopamine-1 agonist, by intravenous infusion at a fixed infusion rate ranging from 0.1 to 0.8 microg/kg/min for 48 h during a double-blind, placebo-controlled, randomized inpatient clinical trial. Blood pressure and heart rate were measured every 15 min for 24 h before, during, and 24 h after the 48-h drug infusion. Plasma concentrations of racemic fenoldopam were measured at frequent intervals during and for 24 h after fenoldopam infusion. In the 26 patients who received fenoldopam, there were dose-dependent reductions in systolic and diastolic blood pressure, which usually reached a nadir within 2 h of beginning infusion and were significant even at the lowest dose studied (-9 and -9 mm Hg for systolic and diastolic blood pressure, respectively, at 24 h for the dose of 0.04 microg/kg/min, P < .05). There were associated increases in heart rate that were greater in the first than in the last 24 h of drug infusion. Compared to the average 24-h control blood pressure, maximum mean reductions in systolic and diastolic blood pressures of 33 and 21 mm Hg, respectively, were noted in patients receiving fenoldopam at 0.8 microg/kg/min and occurred 4 and 1 h, respectively, after beginning infusion. Tolerance to the blood pressure lowering effects of the drug developed slowly during the 48 h of drug infusion; the half-life for this effect was 60 h. No serious adverse clinical effects were noted in any patient. These results demonstrate that fenoldopam is effective in reducing blood pressure of patients with mild-to-moderate hypertension at doses as low as 0.04 microg/kg/min, is well tolerated at doses up to 0.8 microg/kg/min, maintains most of its antihypertensive efficacy throughout 48 h of continuous, constant rate infusion, and produces neither prolonged pharmacodynamic effects nor rebound hypertension when discontinued. The pharmacodynamic effects of the drug are best predicted by pharmacokinetics of racemic and R-fenoldopam.

Dose-response efficacy of valsartan, a new angiotensin II receptor blocker.

OBJECTIVE: To study the efficacy and tolerability of a range of valsartan doses in patients with mild-to-moderate hypertension. DESIGN: 122 adult out-patients were randomised in equal numbers to receive valsartan 10 mg, 40 mg, 80 mg, 160 mg or placebo once daily (OD) for 4 weeks in this multicentre, double-blind, fixed-dose, parallel trial. Patients were assessed at 0, 2 and 4 weeks. MAIN OUTCOME MEASURES: The primary efficacy variable was change from baseline in trough mean supine diastolic blood pressure (MSuDBP). Other variables included change from baseline in trough mean supine systolic blood pressure (MSuSBP), responder rates and trough/peak ratio. RESULTS: All treatments significantly reduced MSuDBP and MSuSBP at 4-week end-point compared to baseline (P < 0.001). The magnitude of blood pressure lowering was greater with increasing doses of valsartan (least square mean change from baseline for placebo, valsartan 10 mg, 40 mg, 80 mg, 160 mg respectively: MSuDBP -4.4 mm Hg, -4.9 mm Hg, -6.5 mm Hg, -8.2 mm Hg, -9.1 mm Hg; MSuSBP -1.3 mm Hg, -3.6 mm Hg, -7.0 mm Hg, -11.1 mm Hg, -11.9 mm Hg). A fitted quadratic curve, to predict relationship between dose and change from baseline in trough MSuDBP, indicated a positive dose response. Responder rates were 16%, 24%, 33%, 46%, 54% for placebo, valsartan 10 mg, 40 mg, 80 mg, 160 mg respectively, which also indicated a positive dose response in the dose range of 10 mg to 160 mg. Greater than 50% of the antihypertensive effect measured at peak persisted at trough for each of the four active treatment groups, confirming efficacy over a 24-h period. No dose-related adverse experiences were observed, with overall incidence (regardless of relationship to trial medication) of 44% with placebo and 44%, 36%, 22%, 21% for valsartan 10 mg, 40 mg, 80 mg, 160 mg respectively. The most common adverse experience reported was headache which occurred most frequently with placebo (12%). No trial drug-related cough was observed. Treatment with valsartan did not produce clinically significant orthostatic changes in diastolic or systolic blood pressure. One case of symptomatic orthostatic hypotension was observed on placebo. CONCLUSIONS: The results of this trial show valsartan to effectively lower blood pressure in patients with mild-to-moderate hypertension, and demonstrate that the reduction in blood pressure increases with increasing dose levels.

Sustained hemodynamic effects of the selective dopamine-1 agonist, fenoldopam, during 48-hour infusions in hypertensive patients: a dose-tolerability study.

Eight patients with stage I-II hypertension received a continuous IV infusion of the selective dopamine-1 agonist, fenoldopam, for up to 48 hours at rates from 0.4 to 1.9 micrograms/kg/min. Hemodynamics and clinical symptoms during infusion were compared to the same parameters in the 24-hour periods before and after infusion. Fenoldopam lowered blood pressure and increased heart rate. Greatest changes occurred during the first 12 hours of infusion and gradually returned toward preinfusion values throughout the remaining 36 hours in the six patients who completed 48 hours of infusion. Fenoldopam was discontinued within 2 hours of starting the infusion in two patients who received drug rates of 0.9 microgram/kg/min and 1.9 micrograms/kg/min because of precipitous bradycardia. Clinical symptoms noted at fenoldopam doses higher than 0.8 microgram/kg/min were headache, dizziness, diaphoresis, nausea and vomiting, and restlessness. In this pilot study, fenoldopam effectively reduced blood pressure in patients with stage I-II hypertension for up to 48 hours, but fixed-dose infusion rates above 0.8 microgram/kg/min were associated with a high frequency of clinically significant and often intolerable adverse effects.

A randomized, double-blind, placebo-controlled, parallel-group, multicenter trial of four doses of tasosartan in patients with essential hypertension. Tasosartan Investigator's Group.

Tasosartan, a new, long-acting, nonpeptide angiotensin II receptor antagonist was evaluated in a randomized, double-blind, placebo-controlled, multicenter trial at 21 sites in the United States and Canada. After a 2-week, placebo washout qualification period, 278 patients (187 men/91 women) with a mean age of 53.4+/-9.5 years (range, 30 to 70 years) and a baseline sitting diastolic blood pressure (DBP) of 95 to 114 mm Hg were randomly assigned to receive placebo (n = 56), or 10 mg (n = 57), 30 mg (n = 55), 100 mg (n = 55), or 300 mg (n = 55) tasosartan for 4 weeks. The treatment period was followed by a 2-week washout period. Ambulatory blood pressure (BP) monitoring was performed at the end of the placebo washout period and after at least 4 weeks of double-blind treatment. Clinically significant placebo-adjusted differences in baseline sitting systolic blood pressure (SBP)/DBP were observed in the 10 mg (5/3 mm Hg), 30 mg (5/4 mm Hg), 100 mg (10/7 mm Hg) and 300 mg (10/7 mm Hg) dose groups (P < .05). A dose-response relationship (P < .001) was observed within 1 to 2 weeks of treatment initiation and was maintained throughout the double-blind period. Discontinuation of tasosartan therapy was not associated with rebound hypertension. Moreover, significant (P < .05) placebo-adjusted differences in ambulatory SBP/DBP and a significant dose-response relationship (P < .001) were observed with all tasosartan dosages during the 24-h, daytime, and nighttime periods. Placebo-adjusted trough-to-peak ratios ranged from 87% to 100% for ambulatory SBP and 64% to 81% for DBP. In general, no significant differences were observed between the tasosartan treatment groups and the placebo group in the incidence of adverse events. Headache incidence was significantly lower in the 300 mg dose group than the placebo group. In conclusion, tasosartan at dosages of 10, 30, 100, or 300 mg given once daily produced a significant and dose-related reduction in both clinic and ambulatory BP that was maintained over the 24-h period. Tasosartan was generally well tolerated.

Dose-related antihypertensive effects of irbesartan in patients with mild-to-moderate hypertension.

Two multicenter, double-blind, placebo-controlled, parallel group studies were conducted to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of the angiotensin II receptor (AT1 subtype) antagonist irbesartan. The effect of irbesartan withdrawal and the effect of adding hydrochlorothiazide (HCTZ) to irbesartan were also assessed. After a placebo lead-in phase, all patients were randomized to 8 weeks of double-blind therapy with either placebo (n = 158) or irbesartan at doses of 1, 5, 10, 25, 50, 100, 200, or 300 mg (n = 731 total) orally once daily. Irbesartan reduced blood pressure in a dose-related manner. Reductions from baseline in trough seated diastolic blood pressure ranged from 7.5 mm Hg for 50 mg irbesartan to 11.6 mm Hg for 300 mg irbesartan. At week 8, statistically significant reductions over placebo were observed in trough seated blood pressure with all irbesartan doses > or = 50 mg. These reductions reached statistical significance versus placebo within 2 weeks with 100, 200, and 300 mg irbesartan. Plasma irbesartan concentrations correlated with dose. Angiotensin II and aldosterone levels generally showed dose-related changes, consistent with AT1 receptor blockade. In patients not controlled at 8 weeks, the addition of 12.5 mg HCTZ resulted in further dose-related reductions in blood pressure. Irbesartan demonstrated a placebo-like safety profile and no dose-related toxicity. Irbesartan, administered alone or in combination with HCTZ, was well tolerated. Withdrawal of irbesartan did not result in rebound hypertension or adverse events. Thus, once-daily irbesartan is both an effective and safe antihypertensive agent for the treatment of mild-to-moderate hypertension.

A 3-dimensional analysis of modes of cardiovascular adaptation: concepts, methods and preliminary findings.

OBJECTIVE: To present a 3-dimensional approach to displaying and interpreting processes of cardiovascular adaptation. DESIGN: Laboratory study of blood pressure changes in response to a protocol set in advance. The authors plotted the coordinates of 3711 cardiovascular change events (CVCEs) in 3-dimensional space defined by changes in systolic blood pressure, diastolic blood pressure and heart rate. This was followed by cluster analyses and preliminary estimates of reliability and construct validity. SETTING: The teaching hospitals of a large southwestern US medical centre. PARTICIPANTS: Approximately 100 female nursing personnel aged 25 to 50 years. INTERVENTIONS: Medical history, self-administered questionnaires, laboratory protocol of pressor challenges, rest periods. RESULTS: Nine distinct clusters ("species of response") were identified and replicated in randomly chosen halves of the sample. Postural, isomorphic and psychologic challenges generated several distinctive profiles of "rising" responses, and were also followed by distinctive "declining" responses. The frequencies of various cardiovascular reactions ("clusters") to the same protocol were correlated with psychosocial characteristics and hypertension risk indicators. CONCLUSIONS: The 3-dimensional approach reveals many features of cardiovascular adaptation not discernible from traditional univariate displays and analyses. This paradigm might prove useful for matching patients with hypertension by their cluster patterns to their most suitable medication, but it requires further validation by direct hemodynamic measurements.

Alpha adrenoceptor blockade in the treatment of benign prostatic hyperplasia: past, present and future.

The treatment of BPH by alpha blockade is built upon a sound anatomical, physiological and pharmacological rationale. The theory is borne out in clinical practice; alpha adrenoceptor antagonists have been shown in placebo-controlled studies to improve symptoms of BPH and increase urinary flow rate. In hypertensive patients, there is a clinically significant reduction in blood pressure, with little or no effect on the blood pressure of normotensive patients with BPH. The development of selective alpha-1 adrenoceptor antagonists with a gradual onset and long duration of action has improved the tolerability and makes this class of drug a valuable alternative to surgery in many cases. Further refinements in the selectivity of alpha-1 adrenoceptor antagonists may enable even better targeted alpha blockade for BPH in the future by specific antagonism of the alpha-1 A adrenoceptor, although this hypothesis has yet to be confirmed clinically.

Use of the factorial design and quadratic response surface models to evaluate the fosinopril and hydrochlorothiazide combination therapy in hypertension.

The combination of angiotensin converting enzyme (ACE) inhibitor and thiazide diuretic has advantages over monotherapy for the treatment of hypertension. Previous study designs have often been inadequate to demonstrate the details of interactions between these antihypertensive agents. This study used a modified 4 x 4 factorial randomized, double-blind, placebo-controlled, parallel group design to study the efficacy of 17 different doses of fosinopril (Fos), a phosphinic acid derived ACE inhibitor, and hydrochlorothiazide (HCTZ) in 550 patients with mild to moderate hypertension. Data from these variables were fit to quadratic response surface models (QRSM) using polynomial functions in the doses of the two components. Using QRSM, seated systolic (SeSBP) and diastolic blood pressure (SeDBP) responses at 8 weeks were predicted for actual doses and interpolated for intermediate doses not studied. Fos and HCTZ alone and in combination produced a dose-related reduction in SeSBP and SeDBP. Using 10 mg Fos + 12.5 mg HCTZ reduced the adjusted mean SeDBP 6.3 mm Hg and 20 mg Fos + 12.5 mg HCTZ lowered the same measure 9.1 mm Hg. Coadministration of Fos and HCTZ produced an additive antihypertensive effect. This study of combination agents for hypertension using a factorial design with QRSM accurately predicts dose responses and is a valuable clinical trial methodology.

A history of the Neurological Institute of New York and its Department of Neurological Surgery.

The neurological institute of New York was founded in 1909 as the first hospital in North America devoted exclusively to the care of patients afflicted with neurological diseases. The Institute amalgamated with Columbia University's College of Physicians and Surgeons and The Presbyterian Hospital in New York City in 1928. The Department of Neurological Surgery developed under the successive leadership of Charles Elsberg, Byron Stookey, J. Lawrence Pool, Lester Mount, Edward Schlesinger, and Bennett Stein, each of whom brought unique qualities to the role of Department Chairman. This article traces the history of the Institute and its affiliates, present activities, and future plans.

Doxazosin: a new approach to hypertension and benign prostatic hyperplasia.

Doxazosin, a selective alpha 1-adrenoceptor antagonist, is an established first-line antihypertensive agent that is being introduced for the management of benign prostatic hyperplasia. Hypertension and benign prostatic hyperplasia are linked by the sympathetic nervous system, which has an aetiologic role in both conditions. The alpha 1-adrenoceptor is a mediator of increased tension, both in vascular and prostatic smooth muscle. Studies have shown that doxazosin, through its balanced action on alpha 1-adrenoceptor subtypes, reduces blood pressure and improves other risk factors for coronary heart disease, such as lipid profile, insulin sensitivity, left ventricular hypertrophy, platelet aggregation and fibrinolysis. Data are now accumulating to show that doxazosin improves urinary flow rates and symptoms in patients with benign prostatic hyperplasia. These effects have been demonstrated in controlled clinical studies, within weeks, and long term. Since hypertension and benign prostatic hyperplasia are widespread and often undiagnosed in the community, particularly with increasing age, doxazosin may be a particularly appropriate therapy for the considerable number of older men with both conditions.

Combined terazosin and verapamil therapy in essential hypertension. Hemodynamic and pharmacokinetic interactions.

alpha-Blockers and calcium antagonists are commonly used in the treatment of hypertension, but few data are available concerning first dose or steady state (SS) hemodynamic and pharmacokinetic effects of these drugs when they are used in combination therapy. To examine these interactions, we measured supine and standing blood pressure (BP), heart rate (HR), and cardiac index (CI) for 6 h in 24 hypertensive patients after 2 weeks of placebo, again after the first dose or 3 weeks of therapy (SS) with either 120 mg verapamil (V) twice a day, or 1 mg terazosin (T) titrated weekly to 5 mg daily, and finally when T was added to V (group VT) or V added to T (group TV), acutely and at SS. Changes in supine hemodynamics when T was added to V or when V was added to T were similar and included a further reduction in BP, a transient increase in HR, and little or no change in CI. Both groups experienced significant decreases in standing blood pressure, especially 0.5 to 2 h following initiation of combination therapy despite significant increases in standing HR and CI. Standing BP tended to be lower in group TV after the first dose, but minimum standing systolic BP was not significantly different between groups (group TV 97 mm Hg at 1 h; group VT 109 mm Hg at 1.5 h, P > .05). Four patients in group TV and two in group VT experienced symptomatic orthostatic hypotension with the first dose of double-agent treatment. Pharmacokinetic interactions, including an increase in the bioavailability of T when V was added, did not correlate with the degree of orthostasis. After 3 weeks of combined therapy, the orthostatic change in BP had attenuated and symptoms had improved in all patients. We conclude that T and V represent an effective combination for the treatment of essential hypertension, but that orthostasis may result when initiating combination therapy. The orthostasis seen in some patients appears to be due to the combined vasodilatory effects rather than negative ionotropic or chronotropic effects.

Expanded Clinical Evaluation of Lovastatin (EXCEL) study results: two-year efficacy and safety follow-up.

The Expanded Clinical Evaluation of Lovastatin study, a randomized, double-blind, placebo- and diet-controlled multicenter trial, evaluated the efficacy and tolerability of lovastatin over 48 weeks in 8,245 patients with moderately severe hypercholesterolemia. During year 1 of follow-up of the full cohort, lovastatin at 20 or 40 mg/day, or 20 or 40 mg twice daily, produced dose-dependent decreases in low-density lipoprotein (LDL) cholesterol (24% to 40%) and triglyceride levels (10% to 19%), and increases in high-density lipoprotein (HDL) cholesterol (6.6% to 9.5%). In all, 977 patients continued their original blinded treatment for an additional year. In year 2, the LDL cholesterol response to lovastatin was maintained, the triglyceride reductions were somewhat less, and the increases in HDL cholesterol were moderately greater than in year 1. Successive transaminase elevations > 3 times the upper limit of normal were observed in only 1 patient in year 2, yielding a cumulative 2-year incidence of from 0.1% (placebo or lovastatin 20 mg/day) to 1.9% (lovastatin 80 mg/day). Myopathy occurred in only 1 patient during year 2, and over the 2-year study was observed rarely and only at lovastatin dosages of 40 and 80 mg/day. This study indicates that lovastatin maintains its efficacy over long-term follow-up, particularly in effectively lowering LDL cholesterol, is generally well tolerated, and has a favorable safety profile.

Effects of doxazosin on coronary heart disease risk factors in the hypertensive patient.

Hypertension often exists as part of a syndrome of cardiovascular, neuroendocrine and metabolic abnormalities. While antihypertensive pharmacotherapy has reduced the rates of stroke, congestive heart failure and renal failure, a disappointing benefit in terms of the reduction in coronary heart disease (CHD) mortality has been seen as a result of the adverse effects of some of the traditional antihypertensive agents on serum lipids and other factors. Doxazosin, a selective alpha 1-adrenoceptor inhibitor, is an effective antihypertensive agent with beneficial effects on an array of atherogenic risk factors. Treatment with doxazosin can lower blood pressure, reduce the levels of atherogenic lipids, increase the levels of cardioprotective lipids, reduce hyperinsulinaemia, insulin resistance and glucose intolerance, increase fibrinolysis, inhibit platelet aggregation, attenuate the adverse haemodynamic and haemostatic effects of smoking, and regress cardiac and smooth muscle hypertrophy. This unique combination of risk factor modifications should produce a reduction in CHD events.

Role of the sympathetic nervous system in hypertension and benign prostatic hyperplasia.

Hypertension and benign prostatic hyperplasia (BPH) have a number of features in common. For example, both occur with increasing frequency in the elderly, and both are a major source of health expenditure worldwide. However, the most striking feature linking hypertension and BPH is the aetiological role of the sympathetic nervous system. Sympathetic tone mediated by the alpha-receptor is vital in the control of blood pressure. By selectively inhibiting the alpha 1-adrenoceptors in the vasculature, thereby inhibiting the response to epinephrine and norepinephrine and thus reducing peripheral resistance, selective alpha 1-inhibitors such as doxazosin produce a physiological reduction in blood pressure. Receptors of the alpha 1 subtype are also found in the prostate, the urethra and bladder neck. Doxazosin, by reducing the tone of the prostatic smooth muscle, has the potential to improve urinary flow rate, as well as the obstructive and irritative symptoms characteristic of BPH.

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.