Amlodipine versus atenolol in essential hypertension

The efficacy and safety of amlodipine (2.5–10 mg) once daily was compared with atenolol (50–100 mg) once daily in patients with mild-to-moderate essential hypertension in a randomized, doubleblind, parallel, placebo-controlled study. A total of 125 patients were randomly allocated at the end of a 4-week run-in placebo period to 8 weeks of double-blind treatment with amlodipine (n = 41), atenolol (n = 43), or placebo (n = 41). The placebo group had small mean changes in supine and standing blood pressure compared with baseline. The mean blood pressure changes from baseline 24 hours postdose in the amlodipine group (mean daily dose 8.8 mg) were −12.8/−10.1 mm Hg for supine blood pressure and −11.5/−9.8 mm Hg for standing blood pressure (p < 0.001 compared with placebo), and for the atenolol group (mean daily dose 83.7 mg) the changes were −11.3/−11.7 mm Hg for supine blood pressure and −13.3/−12.3 mm Hg for standing blood pressure (p < 0.001 compared with placebo). There were no statistically significant blood pressure differences between active treatments. The responder rates for amlodipine, atenolol, and placebo were 61.1, 64.9, and 11.1%, respectively. The blood pressure values taken over the 24-hour period at final visit revealed that amlodipine and atenolol maintained the supine blood pressure ≤ 140/90 mm Hg throughout the period of observation; the corresponding time-effect curve for the placebo group was clearly in the hypertensive range. Heart rate was significantly lowered by atenolol only. Both amlodipine and atenolol were well tolerated. Only 1 patient was withdrawn due to adverse effects (development of peripheral edema, arthralgia and fatigue) related to amlodipine. This study demonstrates that once-daily therapy with amlodipine or atenolol was well tolerated in patients with mild-to-moderate essential hypertension and provided control of blood pressure throughout the 24-hour dosing interval.     

Combination therapy with amlodipine and captopril for resistant systemic hypertension

This study was conducted to assess the therapeutic utility of combining amlodipine with captopril in patients with moderate-to-severe hypertension. Patients had hypertension of WHO grades I–III, with initial mean sitting and standing diastolic blood pressure of 100–119 mm Hg (phase V) after 2–4 weeks on placebo, and had remained uncontrolled (diastolic blood pressure > 95 mm Hg) despite a further 4 weeks on low-dose captopril. Twenty-nine patients entered the computer-randomized, double-blind, placebocontrolled, 2-way crossover comparison of either amlodipine 10 mg once daily or matching placebo added to continued therapy with captopril 25 mg twice daily for 4 weeks. Patients then acted as their own control and received the alternative amlodipine/placebo treatment plus their continued captopril therapy for another 4 weeks. Once-daily amlodipine was shown to be effective when combined with captopril. Mean baseline supine systolic blood pressure decreased from 167 to 149 mm Hg and standing systolic blood pressure from 167 to 144 mm Hg. Mean supine diastolic blood pressure decreased from 105 to 92 mm Hg, and standing diastolic blood pressure decreased from 110 to 96 mm Hg. The placebo-corrected amlodipine differences in mean changes from captopril baseline were −18/−12.2 mm Hg for supine and −20.1/−11.9 mm Hg for standing systolic and diastolic blood pressures, respectively (p < 0.001 for all 4 measurements). The most common side effects encountered with amlodipine were flushing and pedal edema. The combination of amlodipine and captopril was well tolerated, and no patient discontinued therapy. No significant treatment-related effects on biochemical and hematologic parameters were noted.     

Concomitant administration of terazosin and atenolol for the treatment of essential hypertension

The safety and efficacy of once-daily terazosin hydrochloride administered concomitantly with once-daily atenolol for the treatment of essential hypertension were evaluated in this double-blind, multiclinic, placebo-controlled study. After each patient received 50 mg of atenolol daily for eight weeks, patients with a supine diastolic blood pressure (DBP) of 95 to 110 mm Hg and whose supine DBP had decreased at least 5 mm Hg were randomized to receive either terazosin (plus atenolol) or placebo (plus atenolol) for ten weeks. Patients assigned to the terazosin hydrochloride treatment group received increasing dosages (1,2,5, and 10 mg daily) [corrected] of terazosin at two-week intervals until the maximum dose was reached or until the supine DBP was decreased to less than 90 mm Hg. Terazosin-treated patients (n = 43) had significant mean decreases from the baseline in supine BP (systolic/diastolic = -8.8/-8.5 mm Hg) and standing BP (-10.9/-9.5 mm Hg), whereas the decreases in BP in the placebo-treated patients (n = 49; supine, -2.3/-2.6 mm Hg; standing, -1.4/-1.3 mm Hg) were not significant. When terazosin and placebo were compared, the differences in BP were significant. Terazosin-treated patients had significantly greater decreases in mean percent change of total cholesterol (-4.8%) and low-density lipoprotein plus very-low-density lipoprotein cholesterol (-6.3%) levels, compared with the placebo-treated patients (+0.6% and +1.1%, respectively). Concomitant administration of terazosin and atenolol to patients with essential hypertension was found to be safe and efficacious.     

A double-blind parallel trial to assess the efficacy of doxazosin, atenolol and placebo in patients with mild to moderate systemic hypertension

The antihypertensive and lipid effects of doxazosin and atenolol were compared in a 10-week, double-blind, parallel, placebo-controlled study. The 129 adults enrolled had mild to moderate hypertension (average supine diastolic blood pressures for doxazosin, atenolol and placebo were 100.6, 101.0 and 99.7 mm Hg, respectively). Patients were randomly assigned to treatment with doxazosin, 1 to 16 mg daily, atenolol, 50 to 100 mg daily or placebo. Among 114 patients included in the efficacy analysis, standing blood pressure (systolic/diastolic) changed by -13/-11 mm Hg with doxazosin (n = 37), -12/-12 mm Hg with atenolol (n = 39) and +1/-1 mm Hg with placebo (n = 38). Mean reductions in blood pressure for doxazosin and atenolol were significantly greater than those for placebo (p less than 0.01), although no statistically significant differences between the active agents were noted. Serum lipid measurements were evaluable for 116 patients, and the 38 doxazosin-treated patients in this group experienced reductions in total cholesterol, total triglyceride and very low density lipoprotein cholesterol levels. Both doxazosin and atenolol demonstrated comparable acceptance profiles. Doxazosin is an effective hypotensive agent with beneficial effects on serum lipid levels.     

The effect of amlodipine on ambulatory blood pressure in hypertensive patients

Certain high-risk populations, such as diabetics and blacks, have sustained elevation in blood pressure and heart rate throughout the day and night, with blunting of the usual diurnal variability pattern. This may contribute to their higher incidence of left ventricular hypertrophy (blacks) and cardiovascular complications (diabetics). Hypertensives who maintain a diurnal pattern of blood pressure variation still exhibit higher daytime and nocturnal blood pressure levels than normotensives. Thus, to achieve maximum effectiveness in treating hypertension, 24-hour control of blood pressure is necessary. Antihypertensive agents should effectively reduce blood pressure consistently throughout a 24-hour period. The objective of this study was to assess the effects of amlodipine, 5 mg once daily, on blood pressure measured by 24-hour ambulatory monitoring in a randomized, double-blind, placebo-controlled single-site study. Patients with mild-to-moderate essential hypertension were randomized to receive amlodipine (n = 11) or placebo (n = 5) in a 2:1 ratio. A 4-week single-blind placebo run-in period was followed by a 4-week double-blind phase. Ambulatory monitoring of blood pressure was carried out for 24 hours at the end of each 4-week phase. Patients receiving amlodipine had significantly lower blood pressure compared with placebo 24 hours after the last dose (supine blood pressure −25.1/−10.1 mm Hg; standing blood pressure −21.2/−9.7 mm Hg) after 4 weeks of treatment. This effect was clearly demonstrated by the 24-hour postdose measurement and the mean blood pressure over the 24-hour interval as measured by ambulatory recordings. The mean hourly ambulatory recordings showed that amlodipine maintained both diastolic and systolic pressures below the baseline levels at every hour during the 24-hour observation period. Nine of 10 evaluable patients (90%) on amlodipine responded vs only 1 of 5 patients (20%) on placebo. The decrease in blood pressure for the amlodipine patients was not accompanied by a significant increase in pulse rate. Amlodipine was well tolerated; possibly drug-related side effects of intermittent headache and nocturia were experienced by 1 patient each; the latter had been present during the placebo run-in phase. Amlodipine is effective, well tolerated, and may be administered once daily for effective 24-hour blood pressure control.     

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.     

Amlodipine with enalapril therapy in moderate-severe essential hypertension

The efficacy and toleration of amlodipine (10 mg once daily) was compared with placebo in a four-week double-blind parallel group two-centre study in 38 patients who were receiving enalapril. Patients were moderate to severe hypertensives whose blood pressure was not adequately controlled by enalapril (5-10 mg once daily) (diastolic blood pressure greater than 95 mmHg after four weeks). Results are expressed as the mean difference, in baseline to final changes, between the two treatment groups. At the end of the double-blind period amlodipine patients had significantly greater decreases in supine (-19.4/-10.2 mmHg, P less than 0.001/P less than 0.001) and standing (-16.2/-10.2 mmHg, P less than 0.005/P less than 0.001) blood pressures than the placebo group. There was a greater fall (P = 0.005) in standing diastolic blood pressure at the UK centre (-17.1 mmHg) than in Denmark (-11.2 mmHg). However, pooling the standing diastolic blood pressure data from the two centres gave an overall significant mean treatment difference (-10.2 +/- 2.4 mmHg/P less than 0.001). There were no clinically or statistically significant changes in mean heart rate. Nineteen out of 20 patients in the amlodipine group compared to seven out of 18 patients on placebo, were assessed as improved by the investigator. Similarly 14 out of 19 patients receiving amlodipine were classified as responding to treatment (supine diastolic blood pressure less than 90 mmHg or reduction from baseline of greater than 10 mmHg after four weeks of double-blind therapy) in contrast to four out of 17 receiving placebo.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of diltiazem and atenolol in young, physically active men with essential hypertension

The antihypertensive efficacy and effect on maximal exercise performance of diltiazem was evaluated and compared with atenolol in patients specifically selected on the basis of their being young and physically active. Diltiazem (sustained-release preparation, 90 mg twice daily) was administered to 14 patients (aged 33 +/- 2 years) and atenolol (50 mg once daily) to 13 patients (aged 30 +/- 2 years) with essential hypertension in a 16-week randomized, double-blind, parallel study. The 2 drugs had comparable antihypertensive effects at rest, with mean decreases of 18 and 17 mm Hg (p less than 0.001) for supine and standing diastolic blood pressure (BP), respectively, during diltiazem treatment, and mean decreases of 21 and 18 mm Hg (p less than 0.001) during atenolol treatment. During maximal graded exercise testing, systolic BP, diastolic BP, heart rate and heart rate-BP product were significantly reduced by both drugs. However, the reductions in systolic BP, heart rate and heart rate-BP product during exercise were considerably greater (p less than 0.001) with atenolol than with diltiazem. Maximal exercise performance was essentially unchanged with diltiazem and slightly (3%, p less than 0.05) reduced with atenolol. Thus, diltiazem is effective and well-tolerated single therapy for young patients with mild to moderate essential hypertension who lead a physically active life style and compares favorably with atenolol.     

Effect of indapamide SR in the treatment of hypertensive patients with type 2 diabetes

BACKGROUND: To evaluate the effect of the sustained-release formulation of indapamide (indapamide SR) in type 2 diabetic patients with mild-to-moderate hypertension and its possible side effects, particularly on glucose metabolism and lipid profiles. METHODS: A total of 64 patients randomly received 1.5 mg of indapamide SR or placebo once daily for 3 months. The effects were evaluated by 24-h ambulatory blood pressure monitor, fasting blood sampling for biochemistry, lipid profiles, and frequently sampled intravenous glucose tolerance test. RESULTS: The changes in standing and supine blood pressure (BP) were significant (154.7 +/- 9.4/94 +/- 2.9 mm Hg v 134.4 +/- 5.1/82.4 +/- 5 mm Hg and 155 +/- 9.8/94.6 +/- 3.6 mm Hg v 135.1 +/- 4.9/82.1 +/- 4.7 mm Hg) in the indapamide group, but not in the placebo group. According to the 24-h ambulatory blood pressure monitor reading, a significant reduction was observed in not only in the whole-day mean BP (mean systolic BP/mean diastolic BP, 149 +/- 19.3/87.6 +/- 11.3 mm Hg v 135.7 +/- 12.6/79.6 +/- 9 mm Hg) but also the whole-day mean median arterial pressure (109 +/- 12.7 mm Hg v 98.7 +/- 8.2 mm Hg) for the indapamide group, but not the placebo group. There were no changes in biochemical data including serum sodium, potassium, chloride, uric acid, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, creatinine, lipid profiles, fasting blood glucose, insulin, hemoglobin Alc, and glucose metabolism parameters (insulin sensitivity, glucose effectiveness, and acute insulin response) from frequently sampled intravenous glucose tolerance test after indapamide or placebo therapy. CONCLUSIONS: Indapamide SR can significantly lower the whole-day BP in hypertensive patients with type 2 diabetes. Also, it did not alter or aggravate patients' lipid profiles, glucose metabolism, and did not exert possible side effects of hypokalemia and hyperuricemia. Therefore, monotherapy with indapamide SR should be suggested in type 2 diabetic patients with mild-to-moderate hypertension.     

Atenolol plus nifedipine for mild to moderate systemic hypertension after fixed doses of either agent alone

Three therapies were used to treat 35 patients with mild to moderate systemic hypertension: (1) the cardioselective beta-adrenoceptor blocker atenolol, (2) the calcium antagonist nifedipine and (3) combination therapy for those who failed to reach the target diastolic blood pressure (BP) of less than 90 mm Hg with monotherapy. After an initial run-in placebo period, when the mean supine diastolic BP was 102 +/- 1 mm Hg (mean +/- standard error of the mean), patients were randomized (double-blind) to atenolol, 100 mg as a single daily dose or nifedipine (slow-release form), 20 mg twice daily, then to a washout dummy placebo period before crossover. Each period lasted 4 weeks. Supine, erect and exercise BP were recorded. Atenolol and nifedipine, in the same fixed doses but in combination, were given to 20 patients in whom either supine or erect diastolic BP exceeded 90 mm Hg after the period of monotherapy. Atenolol monotherapy reduced the erect diastolic BP to less than 90 mm Hg in 14 patients (40%); of the remainder, 1 patient responded only to fixed-dose nifedipine and 11 to combination therapy, yielding a total success rate of 74%. The combination gave enhanced control, as shown by a further decrease in supine and erect BP and by better control of exercise BP; these effects were achieved without an increased incidence of adverse effects. The mean reductions in supine diastolic BP were: atenolol, 9 +/- 2 mm Hg; nifedipine, 6 +/- 2 mm Hg; and combination therapy, 16 +/- 2 mm Hg (p less than 0.05 vs atenolol or nifedipine).(ABSTRACT TRUNCATED AT 250 WORDS)     

Antihypertensive effects of fasidotril, a dual inhibitor of neprilysin and angiotensin-converting enzyme, in rats and humans

The aim of this study was to assess the antihypertensive activity of fasidotril, a dual inhibitor of neprilysin (NEP) and angiotensin I-converting enzyme (ACE), in various models of hypertension in rats (spontaneously hypertensive rats [SHR]; renovascular Goldblatt 2-kidney, 1-clip rats; and deoxycorticosterone acetate [DOCA]-salt hypertensive rats) and in patients with mild-to-moderate essential hypertension. Fasidotril treatment (100 mg/kg PO twice daily for 3 weeks) resulted in a progressive and sustained decrease in systolic blood pressure (-20 to -30 mm Hg) in SHR and Goldblatt rats compared with vehicle-treated rats and prevented the progressive rise in blood pressure in DOCA-salt hypertensive rats. After a 4-week placebo run-in period, 57 patients with essential hypertension were included in a randomized double-blind, placebo-controlled, parallel-group study and received orally either fasidotril (100 mg twice daily) or placebo for 6 weeks. Blood pressure was measured during the 6 hours after the first intake and then at trough (12 hours after the last intake) on days 7, 28, and 42. The first dose of fasidotril had no significant effect on blood pressure. After 42 days, compared with placebo, fasidotril lowered supine systolic and diastolic blood pressures by 7.4/5.4 mm Hg and standing blood pressure by 7.6/6.8 mm Hg. Fasidotril, a dual NEP/ACE inhibitor, was an effective oral antihypertensive agent during chronic treatment in high-renin renovascular rats, normal-renin SHR, and low-renin DOCA-salt hypertensive rats and in patients with essential hypertension.     

A noninferiority comparison of valsartan/hydrochlorothiazide combination versus amlodipine in black hypertensives

The objective of the study was to demonstrate that reduction in mean 24-hour diastolic blood pressure with 160 mg valsartan and 12.5 mg hydrochlorothiazide was not inferior to 10 mg amlodipine in hypertensive blacks. A total of 482 blacks with stage 1 and stage 2 hypertension (mean seated blood pressure 140 to 180/90 to 110 mm Hg) were enrolled in a double-blind, randomized, prospective study. After a placebo run-in period, patients were randomized to 160 mg valsartan or 5 mg amlodipine for 2 weeks, then force-titrated to 160 mg valsartan and 12.5 mg hydrochlorothiazide or 10 mg amlodipine for an additional 10 weeks. Blood pressure was assessed by 24-hour ambulatory blood pressure monitoring. Other assessments included quality of life, peripheral edema, and safety. Noninferiority of valsartan/hydrochlorothiazide to amlodipine was demonstrated by comparable reductions in mean 24-hour diastolic blood pressure with both treatments (-10.2+/-8.6 mm Hg versus -9.1+/-8.3 mm Hg, respectively; P<0.001 for noninferiority), as well as in mean 24-hour systolic blood pressure (-15.9+/-12.1 mm Hg versus -14.5+/-12.2 mm Hg; P<0.001 for noninferiority). The proportion of patients reporting adverse events and the incidence of most events were similar in both treatment groups, although more patients treated with amlodipine reported peripheral edema (5.8% versus 1.7%; P=0.03) and joint swelling (2.9% versus 0%; P=0.008) compared with valsartan/hydrochlorothiazide. We conclude that a starting dose of valsartan/hydrochlorothiazide (160/12.5 mg) is as effective as high-dose amlodipine (10 mg) in reducing blood pressure in blacks with stage 1 and stage 2 hypertension, and valsartan/hydrochlorothiazide is better tolerated.     

Direct Renin inhibition with aliskiren in obese patients with arterial hypertension

Current guidelines from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommend first-line treatment with a thiazide diuretic but do not provide specific guidance for obese patients. The renin system is activated in obesity-associated arterial hypertension. Therefore, we tested the hypothesis that the oral direct renin inhibitor aliskiren could provide additive blood pressure lowering in obese patients with hypertension (body mass index >or=30 kg/m(2); mean sitting diastolic blood pressure: 95 to 109 mm Hg) who had not responded to 4 weeks of treatment with hydrochlorothiazide (HCTZ) 25 mg. After a 2- to 4-week washout, 560 patients received single-blind HCTZ (25 mg) for 4 weeks; 489 nonresponders were randomly assigned to double-blind aliskiren (150 mg), irbesartan (150 mg), amlodipine (5 mg), or placebo for 4 weeks added to HCTZ (25 mg), followed by 8 weeks on double the initial doses of aliskiren, irbesartan, or amlodipine. After 8 weeks of double-blind treatment (4 weeks on the higher dose), aliskiren/HCTZ lowered blood pressure by 15.8/11.9 mm Hg, significantly more (P<0.0001) than placebo/HCTZ (8.6/7.9 mm Hg). Aliskiren/HCTZ provided blood pressure reductions similar to those with irbesartan/HCTZ and amlodipine/HCTZ (15.4/11.3 and 13.6/10.3 mm Hg, respectively), with similar tolerability to placebo/HCTZ. Adverse event rates were highest with amlodipine/HCTZ because of a higher incidence of peripheral edema (11.1% versus 0.8% to 1.6% in other groups). In conclusion, combination treatment with aliskiren is a highly effective and well-tolerated therapeutic option for obese patients with hypertension who fail to achieve blood pressure control with first-line thiazide diuretic treatment.     

ABPM comparison of the antihypertensive profiles of the selective angiotensin II receptor antagonists telmisartan and losartan in patients with mild-to-moderate hypertension.

The antihypertensive efficacy and tolerability profiles of the selective AT1 receptor antagonists telmisartan and losartan were compared with placebo in a 6-week, multinational, multicentre, randomised, double-blind, double-dummy, parallel-group study of 223 patients with mild-to-moderate hypertension, defined as clinic diastolic blood pressure (DBP) >/=95 and /=140 and /=85 mm Hg. After a 4-week single-blind placebo run-in, eligible patients were randomised to receive telmisartan 40 mg, telmisartan 80 mg, losartan 50 mg, or placebo. Ambulatory blood pressure monitoring (ABPM) after 6 weeks of double-blind therapy showed that all active treatments produced significant (P < 0.01) reductions from baseline in 24-h mean SBP and DBP compared with placebo. During the 18-to-24 h period after dosing, the reductions in SBP/DBP with telmisartan 40 mg (10.7/6.8 mm Hg) and 80 mg (12.2/7. 1 mm Hg) were each significantly (P <0.05) greater than those observed for losartan 50 mg (6.0/3.7 mm Hg), and losartan was no better than placebo. Also for the 24-h mean blood pressure, telmisartan 40 mg and 80 mg were significantly (P< 0.05) better than losartan 50 mg. Compared with losartan, telmisartan 80 mg produced significantly (P < 0.05) greater reductions in both SBP and DBP during all monitored periods of the 24-h period, while telmisartan 40 mg produced significantly greater reductions in SBP and DBP in the night-time period (10.01 pm to 5.59 am) (P < 0.05) and in DBP in the morning period (6.00 am to 11.59 am) (P < 0.05). All treatments were comparably well tolerated. Telmisartan 40 mg and 80 mg once daily were effective and well tolerated in the treatment of mild-to-moderate hypertension, producing sustained 24-h blood pressure control which compared favourably with losartan.     

A randomized, double-blind, placebo-controlled, parallel-group study to assess the efficacy and safety of dual ACE/NEP inhibitor GW660511X in mild-to-moderate hypertensive patients

This multicentre, double-blind, placebo-controlled, parallel-group study determined the efficacy and safety of GW660511 200 mg, a dual inhibitor of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), in mild-to-moderate hypertensive patients (diastolic blood pressure (DBP), > or =90 and < or =109 mm Hg; systolic blood pressure (SBP), > or =150 and < or =180 mm Hg). After a single-blind 2- to 4-week placebo run-in period, 123 patients (aged 18-65 years) were randomized to either placebo (n=62) or to active treatment (n=61) consisting of two consecutive 3-day dose titration periods of GW660511X 50 mg once daily and 100 mg once daily followed by GW660511X 200 mg once daily for 14 days. GW660511X 200 mg significantly lowered (baseline and placebo-corrected) both trough mean cuff SBP (-8.00 mm Hg, P=0.002) and DBP (-5.38 mm Hg, P=0.003). GW660511X 200 mg significantly reduced placebo-corrected mean 24-h and daytime but not night-time ambulatory SBP and DBP. Over the 0-24 h time period following GW660511X 200 mg, there were significant (P<0.001) reductions in serum ACE activity and significant (P<0.001) increases in plasma ANP concentration compared with placebo in terms of both peak and trough effects. In addition, treatment with GW660511X 200 mg significantly (P=0.003) increased (placebo-corrected, 1.52-fold) urinary excretion of cGMP over the 0-24 h interval. Treatment-related adverse events were experienced by 43% of the patients administered GW660511X 200 mg and 44% of those dosed with placebo with headache the most commonly reported. In conclusion, GW660511X 200 mg is an effective antihypertensive in mild-to-moderate hypertensive patients with potent effects on biological markers of ACE and NEP inhibition.     

Comparison of hydrochlorothiazide and sustained-release diltiazem for mild-to-moderate systemic hypertension

The safety and efficacy of sustained-release diltiazem, 120 to 180 mg twice daily, was compared with those of hydrochlorothiazide, 25 to 50 mg twice daily, in 207 patients with mild-to-moderate hypertension (supine diastolic blood pressure [BP] 95 to 114 mm Hg) using a baseline, placebo, parallel-design study protocol. All patients received placebo for 2 to 4 weeks, followed by either study drug during the double-blind phase, titrated over 8 weeks to achieve a goal of supine diastolic BP reduction of at least 10 mm Hg and/or a diastolic BP of less than 90 mm Hg. Patients not achieving the treatment goal with either drug alone received the other drug in combination. Both drugs produced significant decreases in supine and upright BP throughout the 26-week study. The magnitude of decrease in mean supine diastolic BP was similar for both drugs as monotherapy at week 14 (-11.4 and -12.1 mm Hg, respectively). Hydrochlorothiazide produced significantly greater reductions at week 14 in mean supine systolic BP than sustained-release diltiazem (-19.5 and -12.7 mm Hg, respectively). The difference in mean supine diastolic BP reduction with the 2 drugs diminished when hydrochlorothiazide (50 mg/day) was compared with sustained-release diltiazem. The BP effects were sustained for 6 months with both drugs. The 2 drugs appeared to lower BP more in patients older than 60 years and more in black than in white patients. The combination of the 2 drugs decreased supine diastolic BP to goal levels in about 56% of the patients not achieving goal with either drug alone. Adverse effects were minimal with either drug alone and in combination, except for hypokalemia, which increased with thiazide alone and in combination.     

Crossover comparison of atenolol, enalapril, hydrochlorothiazide and isradipine for isolated systolic systemic hypertension.

The benefit of antihypertensive therapy in reducing cardiovascular morbidity and mortality associated with isolated systolic hypertension has now been established by the Systolic Hypertension in the Elderly Program. However, there is little information about the relative effectiveness of different drug regimens in this condition. This study compared the efficacy and tolerability of 50 mg of atenolol, 10 mg of enalapril, 25 mg of hydrochlorothiazide and 2.5 mg of isradipine in the treatment of isolated systolic hypertension. After a 3-week placebo run-in phase, 24 subjects were randomized into a 4-period double-blind crossover study by use of an orthogonal latin square design. Treatment periods were of 6 weeks' duration with titration to a higher dose after 4 weeks in those not reaching goal blood pressure (BP). Each active treatment was followed by a 3-week placebo washout. Casual clinic and 24-hour ambulatory BP (Accutracker II) were measured at the end of each treatment phase. Routine biochemistry was also performed after the placebo run-in, at the end of each active treatment phase, and after the placebo run-out. Of the 24 subjects entered (mean age 72.3 years, 38% men) 20 completed the whole study. Mean +/- standard deviation of supine clinic and daytime ambulatory BP on entry were 181/79 +/- 21/9 mm Hg and 165/82 +/- 23/15 mm Hg, respectively. All drugs reduced mean casual and ambulatory BP significantly relative to placebo but only hydrochlorothiazide and enalapril produced a consistent hypotensive effect throughout the entire 24-hour period. Isradipine and enalapril exhibited a relatively greater effect on reducing systolic BP than either hydrochlorothiazide or atenolol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Randomized, double-blind, placebo-controlled, multicenter study of sibutramine in obese hypertensive patients

OBJECTIVES: To compare weight loss efficacy, safety and tolerability of sibutramine and placebo in mildly to moderately obese hypertensive subjects; to assess the effect of weight loss on blood pressure. DESIGN: Randomized, double-blind, parallel-group; 3-week placebo run-in and 12-week treatment phase. SETTING: Nine hospital outpatient clinics and general practices in the Netherlands. PARTICIPANTS: 127 men and women, 18-65 years old, with body mass indices (BMI) ranging from 27 to 40 kg/m(2) and stabilized hypertension - mean resting diastolic blood pressure of 90-120 mm Hg - with or without antihypertensive medication. INTERVENTIONS: Sibutramine 10 mg once daily; placebo. MAIN OUTCOME MEASURES: Body weight, blood pressure, routine laboratory and clinical safety monitoring. RESULTS: Of 113 evaluable patients, 54 received sibutramine and 59 placebo. Weight reduction was significantly greater with sibutramine from week 2 onwards (last observation carried forward): mean, 4.4 kg with sibutramine and 2.2 kg with placebo (p = 0.002); mean percentage weight reduction, 4.7 and 2.3%, respectively (p < 0.001); mean BMI reduction, 1.6 and 0.8 kg/m(2), respectively (p < 0.01). Reduction in excessive body weight was associated with a reduction in blood pressure in both groups, although the mean reduction in supine diastolic blood pressure was numerically, but not statistically significantly, greater in the placebo group (5.7 mm Hg) compared with the sibutramine group (4.0 mm Hg; p = 0.21). Similar reductions were seen in supine systolic blood pressure. Both treatments were well tolerated. CONCLUSIONS: Sibutramine 10 mg once daily is a useful, effective therapy for obesity in the presence of stable hypertension.     

Effects of Indomethacin,Sulindac, Naproxen,Aspirin, and Paracetamol in Treated Hypertensive Patients

Four placebo controlled, randomised crossover studies were carried out to investigate the effects of non-steroidal antiinflammatory drugs and analgesics on blood pressure control in treated hypertensive patients. Twelve patients completed one study comparing indomethacin, 25 mg tds, with placebo in 2 six week phases; there were increases in mean blood pressure (p < 0.01) of 9 mm Hg (casual), 8 mm Hg (supine) and 10 mm Hg (standing) in the indomethacin phase accompanied by a 50% reduction in plasma renin activity (p < 0.05) and a 47% decrease in plasma aldosterone concentration (p < 0.05). Similar studies on aspirin-SR, 650 mg daily (19 patients), and paracetamol, 1 g 8th hourly (20 patients), revealed only small changes in blood pressure, with a 2 mm Hg increase in supine diastolic blood pressure during aspirin therapy and a 4 mm Hg increase in supine and standing systolic blood pressure during paracetamol therapy (p < 0.05 for both)

Nineteen patients completed a study with 4 three week phases, taking placebo, naproxen 250 mg mane and 500 mg nocte, sulndac 200 mg bd, and aspiring-SR 1950 mg bd. All threee active agents depressed plasma renin activity and plasma aldosterone concentration. Neither sulindac nor aspiring cuased any significant increases in blood pressure, and naproxen had little effect, though it did cause a 4 mm Hg increase in standing systolic pressure (p < 0.05). We conclude that the effects of indomethacin on control of blood pressure in treated hypertensive patients are not exhibited to the same extent by o ther durgs investigated, and that they are not dependent on the concomitant decreases in plasma renin activity or plasma aldosterone concentration. The importance of inhibition of prostaglandin sysnthesis remains unclear     

Multicenter, double-blind comparison of doxazosin and atenolol in patients with mild to moderate hypertension

In a double-blind multicenter study, the new alpha 1-adrenoceptor inhibitor doxazosin was compared with atenolol for efficacy, safety and effect on serum lipids. One hundred and twenty-six patients with mild to moderate hypertension were randomly assigned to receive either doxazosin (n = 63) or atenolol (n = 63). The mean final dosages, administered once daily, to obtain 24-hour blood pressure (BP) control were doxazosin 12 mg (range 1 to 16) and atenolol 91.8 mg (range 50 to 100). Of 12 doxazosin and 7 atenolol patient withdrawals from the study, 7 doxazosin and 4 atenolol patients withdrew for treatment-related reasons. No statistically significant differences between treatment groups were found after 20 weeks in changes from baseline in standing and sitting BPs measured 24 hours after administration. Sitting BP (systolic/diastolic) was reduced by 10.5/9.8 mm Hg after doxazosin treatment and by 10.9/10.7 mm Hg after atenolol therapy. Standing BP was reduced by 8.8/7.7 mm Hg after doxazosin administration and 9.7/9.3 mm Hg after treatment with atenolol. Supine BP was measured in a small cohort of the study population, and doxazosin had a smaller effect than atenolol. After 20 weeks of treatment, both drugs reduced heart rate with atenolol producing a statistically significantly greater decrease than doxazosin (standing, doxazosin 5 beats/min, atenolol 16.2 beats/min, p less than 0.001; sitting, doxazosin 5 beats/min, atenolol 13.1 beats/min, p less than 0.001). Side effects were reported by 37 patients receiving doxazosin therapy and 34 patients receiving atenolol therapy.(ABSTRACT TRUNCATED AT 250 WORDS)