Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24-hour blood pressure control in patients with hypertension.

OBJECTIVES: This dose-ranging study evaluated the antihypertensive efficacy and tolerability of aliskiren in patients with mild-to-moderate hypertension. BACKGROUND: Low blood pressure (BP) control rates among patients with hypertension indicate a need for improved treatment options. This study investigates aliskiren, the first in a new antihypertensive class called renin inhibitors. METHODS: Patients with mean sitting diastolic BP 95 to 109 mm Hg were randomized to aliskiren 150, 300, or 600 mg or placebo once daily for 8 weeks. Patients completing this treatment phase entered a 2-week treatment-free withdrawal period. Office BP was recorded at baseline, weeks 2, 4, 6, and 8 of treatment, and 4 days and 2 weeks after cessation of treatment. A subgroup of patients underwent ambulatory BP monitoring. RESULTS: In total, 672 patients were randomized to treatment. After 8 weeks, aliskiren 150, 300, and 600 mg significantly reduced mean sitting BP (systolic/diastolic) by 13.0/10.3, 14.7/11.1, and 15.8/12.5 mm Hg, respectively, versus 3.8/4.9 mm Hg with placebo (all p < 0.0001 for systolic and diastolic BP). The BP-lowering effect of aliskiren persisted for up to 2 weeks after treatment withdrawal. Aliskiren significantly reduced mean 24-h ambulatory BP (p < 0.0001 vs. placebo with all doses) exhibiting smooth, sustained effects and high trough-to-peak ratios. Aliskiren was well tolerated; overall adverse event rates were 40.1%, 46.7%, and 52.4% with aliskiren 150, 300, and 600 mg, respectively, and 43.0% with placebo. Few patients discontinued treatment due to adverse events. CONCLUSIONS: Aliskiren provides significant antihypertensive efficacy in patients with hypertension, with no rebound effects on blood pressure after treatment withdrawal.     

Omapatrilat Provides Long-Term Control of Hypertension: A Randomized Trial of Treatment Withdrawal

Omapatrilat simultaneously inhibits neutral endopeptidase and angiotensin-converting enzyme, increasing levels of vasodilatory peptides while decreasing production of angiotensin II. This study evaluated the clinical effects of withdrawal of omapatrilat after a patient's hypertension had been controlled (seated diastolic blood pressure <90 mm Hg) on omapatrilat for at least 6 months, with or without adjunctive antihypertensive medications. This double-blind study randomized 83 patients to receive either their established omapatrilat dose or placebo for 8 weeks; any concomitant antihypertensive medications were kept constant. Patients continuing on omapatrilat had no change in blood pressure. Patients whose chronic omapatrilat treatment was replaced by placebo had clinically important increases in both systolic (+16.5 mm Hg) and diastolic (+9.6 mm Hg) blood pressures (both p<0.001). An increase in blood pressure was also seen in patients who were taking adjunctive antihypertensive medications prior to withdrawal of omapatrilat. This study demonstrates that when compared to withdrawal placebo, omapatrilat maintains clinically and statistically significant blood pressure reductions.     

Omapatrilat provides long-term control of hypertension: a randomized trial of treatment withdrawal

Omapatrilat simultaneously inhibits neutral endopeptidase and angiotensin-converting enzyme, increasing levels of vasodilatory peptides while decreasing production of angiotensin II. This study evaluated the clinical effects of withdrawal of omapatrilat after a patient's hypertension had been controlled (seated diastolic blood pressure <90 mm Hg) on omapatrilat for at least 6 months, with or without adjunctive antihypertensive medications. This double-blind study randomized 83 patients to receive either their established omapatrilat dose or placebo for 8 weeks; any concomitant antihypertensive medications were kept constant. Patients continuing on omapatrilat had no change in blood pressure. Patients whose chronic omapatrilat treatment was replaced by placebo had clinically important increases in both systolic (+16.5 mm Hg) and diastolic ((+9.6 mm Hg) blood pressures (both p<0.001). An increase in blood pressure was also seen in patients who were taking adjunctive antihypertensive medications prior to withdrawal of omapatrilat. This study demonstrates that when compared to withdrawal placebo, omapatrilat maintains clinically and statistically significant blood pressure reductions.     

Intravenous nicardipine for the treatment of severe hypertension. A double-blind, placebo-controlled multicenter trial

A placebo-controlled, double-blind multicenter trial was conducted in 123 patients with severe hypertension to examine the efficacy and safety of intravenously administered nicardipine hydrochloride in controlling blood pressure. Seventy-three patients were initially randomized to receive nicardipine treatment. This group had an initial blood pressure of 213 +/- 3/126 +/- 2 mm Hg. Sixty-seven patients achieved the therapeutic goal (diastolic blood pressure less than or equal to 95 mm Hg; systolic blood pressure less than or equal to 160 mm Hg). Fifty patients were randomized to receive placebo solution. Blood pressure in these patients was 216 +/- 3/125 +/- 2 mm Hg. No patient in this group achieved the therapeutic goal during the "blinded" portion of the study. Forty-four of 49 patients who did not respond to placebo administration responded to subsequent treatment with nicardipine. Patients with end-organ damage were included in the study. These included patients with left ventricular hypertrophy, retinopathy, and renal insufficiency. Patients with and without end-organ damage responded equally well to nicardipine treatment. Serious adverse experiences were infrequent, the most common adverse reaction being headache in 24% of the patients studied.     

Low dose bendrofluazide (1.25 mg) effectively lowers blood pressure over 24 h: results of a randomized, double-blind, placebo-controlled crossover study.

Previous studies indicate that low dose bendrofluazide (1.25 mg/day) has no deleterious effect on insulin sensitivity in contrast to conventional doses. To evaluate the antihypertensive effect of 1.25 mg bendrofluazide across 24 h, we studied 12 subjects in a randomized, double blind, cross-over trial, comprising 8 weeks of either 1.25 mg/day bendrofluazide or placebo. Twenty-four-hour blood pressure averages were significantly lower after bendrofluazide compared with placebo (systolic 125 +/- 4 v 136 +/- 3 mm Hg, P < .005; diastolic: 78 +/- 2 v 85 +/- 2 mm Hg, P < .01). Trough:peak ratios were 0.67 +/- 0.07 for systolic and 0.72 +/- 0.15 for diastolic blood pressure reduction. In conclusion, 1.25 mg bendrofluazide daily produced a useful antihypertensive effect across the full 24-h period.     

The addition of doxazosin to the therapeutic regimen of hypertensive patients inadequately controlled with other antihypertensive medications: a randomized,placebo-controlled study

This randomized, double-blind, placebo-controlled study evaluated the use of doxazosin as an add-on therapy for inadequately controlled hypertension. Patients with a sitting diastolic blood pressure (BP) of 95 to 115 mm Hg received either doxazosin (n = 38) or placebo (n = 32) in addition to one or two baseline antihypertensive medications. After an upward titration period, patients were maintained on a fixed dosage of doxazosin (1 to 16 mg/day) or matching placebo for 4 weeks. Doxazosin add-on therapy led to improvements, compared with placebo, in sitting systolic BP (adjusted mean change = −20.9 v −8.5 mm Hg, P = .001), sitting diastolic BP (−13.0 v −8.1 mm Hg, P = .026), and standing systolic BP (−22.0 v −11.5 mm Hg, P = .011). Baseline antihypertensive therapy was gradually tapered or discontinued in patients who achieved a target reduction in BP (sitting diastolic BP of < 90 mm Hg in addition to a minimum improvement of 10 mm Hg in sitting diastolic BP over baseline) with add-on therapy (55% [n = 21] with doxazosin, 31% [n = 10] with placebo). Twelve patients in the doxazosin group maintained the target reduction in BP after complete withdrawal of their baseline antihypertensive therapy, compared with none in the placebo group. A small but statistically significant positive effect on the lipid profile was seen in the doxazosin group during add-on therapy. Doxazosin treatment was well tolerated, with an adverse event profile similar to that of placebo. These findings demonstrate that doxazosin add-on therapy is an effective, well-tolerated treatment strategy for patients with inadequately controlled hypertension.     

Efficacy and safety of an oral fixed low-dose perindopril 2 MG/indapamide 0.625 MG combination: a randomized, double-blind, placebo-controlled study in elderly patients with mild to moderate hypertension.

The efficacy and safety of 12 weeks treatment with an oral fixed low-dose perindopril 2 mg + indapamide 0.625 mg (Per/Ind) combination in elderly and very elderly patients (65-85 years) with mild to moderate systolic and diastolic hypertension (SDH) or isolated systolic hypertension (ISH) were investigated vs placebo. This trial was a multinational randomized double-blind study with doubling of active drug dosage in nonresponders. Intention to treat analysis was performed in 383 patients (age 72.4 years; ISH 32%). 58.5% remained on their initial dosage. Per/Ind decreased supine diastolic and systolic blood pressure (sDBP/sSBP) by 13.2+/-8.0 mm Hg and 22.5+/-13.9 mm Hg (P <.0001) versus placebo -7.3+/-9.0 mm Hg and -12.3+/-15.2 mm Hg, respectively. In ISH (n = 123), Per/Ind decreased sSBP by 23.0+/-11.8 mm Hg (P <.0001). Overall response and normotension rates was 81.3% with Per/Ind (P <.0001). Adverse event rates (including hypokalemia) were similarly low in both groups. Analysis in the over-75 year subgroup showed similar safety and efficacy results. Fixed low-dose Per/Ind is a safe and effective treatment of hypertension including isolated systolic hypertension in the elderly.     

Effects of isradipine or enalapril on blood pressure in salt-sensitive hypertensives during low and high dietary salt intake. MIST II Trial Investigators

This large multicenter study, tested the antihypertensive effects of isradipine, a dihydropyridine calcium channel blocker and enalapril, an angiotensin-converting enzyme inhibitor, in salt-sensitive hypertensive patients under low and high salt intake diets. After a 3-week (weeks -9 to -6) of ad lib salt diet, those patients who had a sitting diastolic blood pressure (SDBP) of > or =95 but < or =115 mm Hg qualified to enter a 3-week (weeks -6 to -3) placebo run-in low salt diet (50 to 80 mmol Na+/day). Then high salt (200 to 250 mmol Na+/day) was added to the placebo treatment for 3 weeks (weeks -3 to 0). Those patients who demonstrated an increase in SDBP > or =5 mm Hg from the low to high salt diet were considered salt sensitive and were randomized into a 4-week (weeks 0 to 4) double-blind treatment period of either isradipine 2.5 to 10 mg twice a day, enalapril 2.5 to 20 mg twice a day, or placebo. Then they entered a 3-week (weeks 4 to 7) placebo washout phase of low salt diet (50 to 80 mmol Na+/day). After week 7 and while the low salt diet was continued the patients were restarted on their double-blind treatment for 4 more weeks (weeks 7 to 11) and the study was completed. Of 1,916 patients screened, 464 were randomized into the double-blind treatment phase and 397 completed the study. Both isradipine and enalapril decreased the sitting systolic blood pressure (SSBP) and SDBP during the high salt diet, to a similar degree, whereas enalapril caused a greater reduction in SSBP and SDBP than isradipine during the low salt diet (11.3 +/- 1.2/7.7 +/- 0.7 mm Hg v 7.7 +/- 0.9/4.8 +/- 0.6 mm Hg, mean +/- SEM, respectively, P < .02). Within drugs, the effect of isradipine on blood pressure (BP) was higher during the high than the low salt diet (14.9 +/- 1.5 v 7.6 +/- 1.3 mm Hg for SSBP and 10.1 +/- 0.6 v 4.8 +/- 0.9 mm Hg for SDBP, P < .001), but enalapril exerted a similar effect during both diets. Because salt restriction lowered both SSBP and SDBP, the lowest BP achieved with both drugs were during the salt restriction phase.     

Efficacy of a once-daily formulation of carvedilol for the treatment of hypertension

Beta-blockers with pharmacologic effects that differ from conventional agents might add to antihypertensive treatment options. This study evaluated a new once-daily formulation of the beta-/alpha1-blocker, carvedilol controlled-release (CR), in hypertensive patients off treatment or while still taking up to 2 (non-beta-blocker) agents. After a 4-week run-in phase, patients were randomized either to placebo (n=76) or carvedilol CR 20 mg (n=82), 40 mg (n=76), or 80 mg (n=86) once daily. After 6 weeks of treatment, ambulatory blood pressure monitoring was repeated to measure the primary end point of changes in mean 24-hour diastolic blood pressure. During treatment, 24-hour diastolic blood pressure fell in the placebo and carvedilol CR 20-mg, 40-mg, and 80-mg groups by (mean +/- SE) 0.4+/-0.9, 4.4+/-0.9, 7.9+/-0.9, and 9.6+/-0.9 mm Hg, respectively (P< or =.001, trend test for all carvedilol CR doses with placebo). Corresponding 24-hour systolic blood pressure changes were 0.6+/-1.4, 6.8+/-1.3, 10.1+/-1.4, and 12.5+/-1.3 mm Hg, respectively (P< or =.001, trend test). Diastolic blood pressure trough-to-peak ratios (placebo-corrected) based on ambulatory blood pressure monitoring (trough = mean of 20- to 24-hour post-dose readings; peak = mean of 3- to 7-hour post-dose readings) for 20-mg, 40-mg, and 80-mg doses were 0.73, 0.64, and 0.65, respectively. Adverse events, including clinical chemistry values, were similar in the drug-treated and placebo groups. Carvedilol CR has a clinically meaningful defined dose-dependent antihypertensive effect that persists throughout a 24-hour period.     

Combined treatment of severe essential hypertension with the new angiotensin converting enzyme inhibitor ramipril

Ramipril is a newly synthesized angiotensin converting enzyme inhibitor without a sulfhydryl group in the molecule but with a prolonged duration of action. Efficacy, tolerance and safety of this drug were evaluated in 10 patients with severe essential hypertension. After a treatment period of at least 4 weeks with the conventional antihypertensive drug combination of a diuretic and a beta-blocking agent with the vasodilator dihydralazine, their systolic and diastolic blood pressures averaged 161 +/- 6 and 111 +/- 2 mm Hg, respectively. Because diastolic blood pressure during this drug regimen was still greater than 105 mm Hg in all patients, the patients received ramipril initially at single daily doses of 5 mg in addition to their previous medication. The first dose of 5 mg ramipril resulted in a moderate but significant decrease in systolic and diastolic blood pressure in 9 of the 10 patients to 142 +/- 5 and 104 +/- 4 mm Hg (p less than 0.01), respectively, between 3 and 6 hours after drug administration. In 1 patient blood pressure was unresponsive to ramipril and 1 patient complained of nausea and vomiting within the first week of treatment with ramipril. Within the following 8-week treatment period with a once-daily intake of 5 or, if necessary, 10 mg of ramipril, diastolic blood pressure normalized in the remaining 8 patients to less than 90 mm Hg. Systolic and diastolic blood pressure averaged 130 +/- 5 and 83 +/- 2 mm Hg, respectively, at the end of the 8-week treatment period with ramipril. Severe hypotension and reflex tachycardia were not observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of candesartan cilexetil in patients with severe systemic hypertension. Candesartan Cilexetil Study Investigators.

The efficacy, tolerability, and safety of the potent angiotensin II receptor blocker candesartan cilexetil were evaluated in 217 adult patients (68% men, 41% black) with severe systemic hypertension on background therapy with hydrochlorothiazide (HCTZ) in a 4-week, multicenter, randomized, double-blind, placebo-controlled study. Patients with sitting diastolic blood pressure (BP) > or =110 mm Hg during the placebo run-in received HCTZ 12.5 mg once daily for 1 week. Those with sitting diastolic BP >95 mm Hg after the HCTZ run-in were randomized (2:1) to receive candesartan cilexetil 8 mg once daily (n = 141) or placebo (n = 76), plus HCTZ 12.5 mg. After 1 week of double-blind treatment, patients with sitting diastolic BP > or =90 mm Hg were uptitrated to candesartan cilexetil 16 mg once daily or matching placebo, plus HCTZ 12.5 mg; 84% required uptitration. Primary efficacy measurement was a change in trough (24+/-3 hours after treatment) sitting diastolic BP from the end of the HCTZ run-in to double-blind week 4. Mean changes in systolic and diastolic BP were significantly greater with candesartan cilexetil than with placebo, -11.3/-9.1 mm Hg versus -4.1/-3.1 mm Hg, p <0.001/p <0.001, respectively. Patients with higher sitting diastolic BP at the end of the HCTZ run-in tended to have greater decreases in BP (p <0.05). Most patients (53%) receiving candesartan cilexetil were responders (diastolic BP <90 mm Hg or > or =10 mm Hg decrease) and 32% were controlled (diastolic BP <90 mm Hg). Tolerability and safety profiles were similar in the candesartan and placebo groups. In conclusion, candesartan cilexetil 8 to 16 mg once daily was an effective and well-tolerated therapy for lowering BP when added to HCTZ 12.5 mg in a diverse population of patients with severe systemic hypertension in the United States.     

Chronic dietary tyrosine supplements do not affect mild essential hypertension

The blood pressure and plasma norepinephrine response to oral tyrosine, the precursor of norepinephrine, supplementation (2.5 g t.i.d.) of regular meals was examined in 13 untreated patients with mild essential hypertension. Using a randomized double-blind crossover design, each 2-week treatment was followed by a 2-week supplement-free interval. Supine and standing blood pressure and plasma norepinephrine levels were measured at the beginning and end of each 2-week treatment. Plasma tyrosine levels increased (p less than 0.001) from 71.2 +/- 8.0 nM/ml at baseline to 152.8 +/- 17.4 nM/ml 2 hours after the tyrosine supplement. Blood pressure under control conditions was 144 +/- 3 Hg systolic, 91 +/- 2 mm Hg diastolic (109 +/- 2 mm Hg mean) after 30 minutes in the supine position and 148 +/- 4 mm Hg systolic, 102 +/- 3 mm Hg diastolic (117 +/- 3 mm Hg mean) after 5 minutes of standing. Plasma norepinephrine levels were 191 +/- 18 pg/ml in the supine subjects and 390 +/- 33 pg/ml in the standing subjects. No difference in systolic, diastolic, or mean blood pressure, heart rate, or plasma norepinephrine levels were seen between the beginning and end of each period or between groups. Individual changes in blood pressure showed no correlation with individual changes in norepinephrine levels. These results indicate that the addition of a tyrosine supplement to the usual diet of mild hypertensive subjects has no beneficial effect on blood pressure.     

Effect of the HMG-CoA reductase inhibitors on blood pressure in patients with essential hypertension and primary hypercholesterolemia

Certain hydroxymethylglutaryl coenzyme A reductase inhibitors, ie, statins, may cause vasodilation by restoring the endothelial dysfunction that frequently accompanies hypertension and hypercholesterolemia. Several studies have found that a blood pressure reduction is associated with the use of statins, but conclusive evidence from controlled trials is lacking. After an 8-week placebo and diet run-in period, 30 persons with moderate hypercholesterolemia and untreated hypertension (total cholesterol 6.29+/-0.52 mmol/L, systolic and diastolic blood pressure 149+/-6 and 97+/-2 mm Hg) were randomized in a double-blind manner to placebo or pravastatin (20 to 40 mg/d) in a crossover design. In 25 participants who completed the 32-week trial, pravastatin decreased total and LDL cholesterol (both -1.09 mmol/L, P=0.001), systolic and diastolic blood pressure (-8 and -5 mm Hg, both P=0.001), and pulse pressure (-3 mm Hg, P=0.011) and blunted the blood pressure increase caused by the cold pressor test (-4 mm Hg, P=0.005) compared with placebo. It also reduced the level of circulating endothelin-1 (P=0.001). The blood pressure results were virtually unchanged in stratified analyses according to gender and age and in intention-to-treat analyses that included the 5 patients who dropped out of the study. When the participants were taking either placebo or pravastatin, blood pressure was not significantly correlated with total or LDL cholesterol or with circulating endothelin-1. Pravastatin decreases systolic, diastolic, and pulse pressures in persons with moderate hypercholesterolemia and hypertension. This antihypertensive effect may contribute to the documented health benefits of certain statins.     

Antihypertensive efficacy of Irbesartan/HCTZ in men and women with the metabolic syndrome and type 2 diabetes

This subgroup analysis of the Irbesartan/Hydrochlorothiazide (HCTZ) Blood Pressure Reductions in Diverse Patient Populations (INCLUSIVE) trial evaluated the efficacy and safety of irbesartan/HCTZ fixed combinations in adults with uncontrolled systolic blood pressure (SBP) (140-159 mm Hg; 130-159 mm Hg for type 2 diabetes mellitus [T2DM]) after >or=4 weeks of antihypertensive monotherapy. Treatment was sequential: placebo (4-5 weeks), HCTZ 12.5 mg (2 weeks), irbesartan/HCTZ 150/12.5 mg (8 weeks), and irbesartan/HCTZ 300/25 mg (8 weeks). In the intent-to-treat analysis, mean change from baseline (end of placebo phase) off all previous therapy to Week 18 (study end) in T2DM patients (n=227) was -18.2+/-14.1 mm Hg for SBP (primary end point; p<0.001) and -8.7+/-8.2 mm Hg for diastolic blood pressure (p<0.001). Mean SBP/diastolic blood pressure changes in patients with the metabolic syndrome (n=345) were -21.0+/-14.3/-10.4+/-8.5 mm Hg (p<0.001). Overall, 56% (95% confidence interval, 49%-62%) of T2DM and 73% (95% confidence interval, 68%-77%) of metabolic syndrome patients achieved SBP goal (<140 mm Hg; <130 mm Hg for T2DM). Goal attainment rates were significantly higher among women with the metabolic syndrome than men. Treatments appeared to be well tolerated. Irbesartan/HCTZ fixed combinations achieved SBP goals in over half of the T2DM patients and nearly three quarters of patients with the metabolic syndrome, with SBP uncontrolled on antihypertensive monotherapy.     

Antihypertensive effect of sustained-release isosorbide dinitrate for isolated systolic systemic hypertension in the elderly

A double-blind, randomized trial was performed in 40 patients, mean age (+/- standard deviation) 80 +/- 4 years, with isolated systolic systemic hypertension to evaluate the antihypertensive effect of oral sustained-release isosorbide dinitrate (ISDN), 20 to 40 mg twice daily, vs placebo. After 12 weeks of treatment, supine systolic blood pressure (BP) decreased from 192 +/- 10 to 162 +/- 12 mm Hg with ISDN (p less than 0.001) and from 189 +/- 10 to 175 +/- 15 mm Hg with placebo (p less than 0.001). On the basis of variance analysis, the decrease in systolic BP was significantly lower with ISDN (27 mm Hg) than with placebo (13 mm Hg). Similar results were observed for supine and erect systolic BP measured at 8 AM and 4 PM, 8 and 12 hours after drug intake. No significant differences in diastolic BP, heart rate or side effects occurred. After the ISDN tapering off-period (2 weeks), systolic BP increased significantly but did not change with placebo. The study provided evidence that in elderly patients with systolic hypertension, sustained-release ISDN induced a selective and sustained decrease in systolic BP, antihypertensive effect was observed 8 and 12 hours after drug administration, and no tolerance phenomenon was noted.     

Efficacy of once daily nitrendipine in mild hypertension: comparison with placebo.

A randomized, double-blind, parallel group study was carried out to compare the antihypertensive efficacy of nitrendipine with that of placebo in 80 mild hypertensives. The dose of nitrendipine was initially 10 mg once daily and was doubled to 20 mg once daily after four weeks in patients who responded poorly (33% of patients on nitrendipine and 49% of patients on placebo required doubling of dose). Blood pressure was assessed 20 to 24 h after dosing. Mean (+/- standard error) reductions in supine systolic and diastolic blood pressures for patients who completed 10 weeks of therapy were significantly greater for the nitrendipine group than for the placebo group (systolic blood pressure 18.1 +/- 2.7 mmHg versus 4.2 +/- 2.5, P less than 0.0001; and diastolic blood pressure 10.6 +/- 1.1 mmHg versus 6.6 +/- 1.3, P = 0.002). A comparison of mean reductions in standing systolic and diastolic blood pressures produced similar results. Goal of therapy (diastolic blood pressure no more than 90 mmHg or reduction of at least 10 mmHg) was achieved in 71% of nitrendipine-treated and 45% of placebo-treated patients (P less than 0.05). Nine of 80 patients randomized to therapy dropped out during treatment (nitrendipine: four adverse experiences and one moved from the area; placebo: two adverse experiences, and drug ineffective in two). Overall, the incidence of adverse experiences considered by the physician to be related to treatment was higher in the placebo group (32%) than in the nitrendipine group (23%). Only flushing had a higher incidence in the nitrendipine group; however, the overall incidence was low (9%).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Antihypertensive effect of diltiazem in a slow-release formulation for mild to moderate essential hypertension

The antihypertensive efficacy and frequency of adverse reactions following administration of diltiazem in a new slow-release formulation were compared with placebo in 34 patients with mild to moderate essential hypertension in a randomized, double-blind, crossover study. After 6 weeks of treatment with diltiazem (240 or 360 mg/day), average supine blood pressure (BP) decreased from 165 +/- 21/101 +/- 5 mm Hg at baseline to 152 +/- 16/93 +/- 4 mm Hg compared with 160 +/- 19/100 +/- 7 mm Hg with placebo (p less than 0.01/p less than 0.001). Standing BP decreased from 162 +/- 20/107 +/- 6 mm Hg at baseline to 150 +/- 14/101 +/- 5 mm Hg compared to 159 +/- 18/107 +/- 8 mm Hg with placebo (p less than 0.01/p less than 0.001). The supine heart rate after diltiazem was 65 +/- 7 beats/min and after placebo 69 +/- 9 beats/min (p less than 0.01). There were no hematologic side effects. Only minor differences between diltiazem and placebo were observed in some of the biochemical laboratory values. Four patients were withdrawn due to side effects during treatment with diltiazem and 2 with placebo. Diltiazem in a slow-release formulation given twice a day lowered blood pressure significantly as monotherapy in patients with mild to moderate hypertension and was well tolerated.     

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.     

Antihypertensive efficacy of once daily MK-521, a new nonsulfhydryl angiotensin-converting enzyme inhibitor

The effects of the new nonsulfhydryl-containing oral converting-enzyme inhibitor MK-521 on blood pressure, heart rate, angiotensin-converting enzyme activity, plasma renin activity and plasma aldosterone concentration were assessed in 10 hypertensive patients. After a 2-week no-treatment period, patients received placebo and then 14 days each: MK-521 20 mg once daily, hydrochlorothiazide 50 mg once daily and the latter 2 in combination. During the last day of each treatment, the mean (+/- standard deviation) time-averaged (1- to 12-hour) standing diastolic blood pressure decreased from 106 +/- 8 (placebo) to 95 +/- 10 mm Hg with MK-521, 95 +/- 13 mm Hg with hydrochlorothiazide (p less than 0.05 vs placebo) and 88 +/- 11 mm Hg with the combination (p less than 0.05 vs all other treatments). The antihypertensive effect of MK-521 was maintained 24 hours after dosing. Heart rate did not change significantly after MK-521 treatment. MK-521 caused a marked suppression of converting enzyme activity for over 24 hours; plasma renin activity increased significantly after each active treatment and MK-521 significantly decreased the hydrochlorothiazide-induced elevation of plasma aldosterone concentration. In this short-term trial, MK-521 was well tolerated.