Control of blood pressure in hypertensive patients with felodipine extended release or nifedipine retard.

1. This multicentre hospital study compared the antihypertensive efficacy and the tolerability of once daily felodipine extended release (ER) with twice daily nifedipine retard (R) in hypertensive patients inadequately controlled on metoprolol monotherapy. 2. One hundred patients, aged 20-70 years, whose seated diastolic blood pressure was 100-115 mmHg after 4 to 6 weeks of metoprolol (200 mg day-1) monotherapy, were randomised, double-blind, to receive felodipine ER 10 mg once daily or nifedipine R 20 mg twice daily for 8 weeks. The dosage of felodipine or nifedipine was doubled if seated diastolic blood pressure exceeded 95 mmHg, 2 or 4 weeks after randomisation. Metoprolol 200 mg once daily was taken throughout the trial. 3. Fifty-one patients received felodipine ER and 49 nifedipine R; 46 and 45 respectively completed the 8 week trial. About half of patients on each treatment needed the higher dose. The baseline characteristics of the felodipine and nifedipine groups were generally well balanced. 4. Seated diastolic blood pressure was reduced by 17 mmHg for felodipine (24 h post-dose) and by 9 mmHg for nifedipine (12 h post-dose), a difference between treatments of 8 mmHg (95% confidence interval 5 to 12 mmHg, P less than 0.0001). The attained blood pressures at the end of the study (felodipine 90 +/- 10, mmHg, mean +/- s.d.; nifedipine 95 +/- 10) were also significantly different (95% confidence interval for the 5 mmHg difference, -9 to -1 mmHg, P less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

The antihypertensive efficacy and tolerability of a low dose combination of ramipril and felodipine ER in mild to moderate essential hypertension

1. The antihypertensive efficacy and tolerability of a low dose combination of the angiotensin converting enzyme inhibitor ramipril (2.5 mg) and the extended release formulation of the dihydropyridine calcium channel antagonist felodipine (5 mg) were assessed in a double-blind, double dummy placebo controlled, randomised, crossover study in 20 patients (mean age 55.4 years; range 46-69) with uncomplicated mild to moderate hypertension (supine diastolic > 90 mmHg < 115 mmHg after 4 weeks of single-blind wash-out on placebo). The four randomised, double-blind, crossover study phases evaluated the response to 4 weeks of once daily treatment with placebo, monotherapy with each drug and the combination. Noninvasive ambulatory blood pressure monitoring (Spacelabs 90207) was performed for 24 h at the end of each phase. 2. The mean 24 h ambulatory blood pressure (mmHg) was 147.9/92.0 following placebo, 141.3/87.8 following monotherapy with ramipril 2.5 mg, 136.8/85.8 following monotherapy with felodipine ER 5 mg and 131.1/82.6 following the combination of ramipril 2.5 mg and felodipine ER 5 mg. All active treatment phases significantly reduced mean 24 h ambulatory diastolic pressure by comparison with placebo. The antihypertensive efficacy of the combination was additive. 3. The coadministration of ramipril did not attenuate the incidence of headache attributable to felodipine ER.     

Felodipine ER formulation in the treatment of mild hypertension: efficacy and tolerability vs placebo.

1. Felodipine is a new calcium-antagonist dihydropyridine derivative with a high degree of selectivity for smooth muscle of arteriolar resistance vessels, as opposed to cardiac cells. 2. In this double-blind, cross-over study the antihypertensive efficacy and tolerability of the new extended release (ER) formulation of felodipine 10 mg, once daily, in patients with mild essential hypertension was evaluated. After a 4-week single-blind placebo period 28 patients (15 males; mean age 48 +/- 12 years) were randomized to receive felodipine 10 mg ER once daily or placebo for 4 weeks and the alternative treatment for a further 4 weeks. Supine blood pressure and heart rate were measured in the out-patients department every 2 weeks, 22-24 h after the last drug administration. 3. Felodipine 10 mg ER induced a significant reduction in blood pressure in comparison with placebo (from 149 +/- 16/97 +/- 6 to 140 +/- 12/89 +/- 6 mm Hg). Heart rate remained unchanged. Seven patients dropped-out; five during felodipine ER administration and two during placebo. 4. A once daily dose of felodipine ER significantly reduces blood pressure in mild hypertensive patients 22-24 h after administration. It is well tolerated and the adverse events are related to its pharmacodynamic effects.     

A dose-finding, placebo-controlled study on extended-release felodipine once daily in treatment of hypertension

Hypertensive patients received a beta-blocker plus placebo once daily for 4 weeks. If their diastolic blood pressure (DBP) was then 95-115 mm Hg, they were randomized to receive, in addition to the beta-blocker, placebo (n = 36), felodipine-extended release (ER) 10 mg (n = 36), or felodipine-ER 20 mg (n = 37) in a 4-week double-blind parallel-group trial. All medication was administered once daily and, when BP was measured 24 h after the last dose, felodipine-ER 10 mg reduced DBP by 14 +/- 9 mm Hg (mean +/- SD) from a mean of 103 mm Hg and felodipine-ER 20 mg reduced DBP by 18 +/- 9 mm Gg from 101 mm Hg. The reductions in DBP with both doses of felodipine were greater than reductions with placebo (5 +/- 8 mm Hg, from 102 mm Hg--both p less than 0.001). At the end of the study, 21% of patients receiving placebo had a DBP less than or equal to 90 mm Hg. In contrast, 69% of patients receiving felodipine-ER 10 mg and 82% receiving 20 mg attained this level. More than 90% of patients receiving 10 mg felodipine-ER once daily had a reduction in DBP greater than 5 mm Hg 24 h postdose. Felodipine-ER was well tolerated. Felodipine-ER once daily is an effective antihypertensive drug for patients who require therapy in addition to a beta-blocker; the tolerability in this study was good, and a starting dose greater than 10 mg once daily is not indicated.     

A placebo-controlled dose-response study of felodipine extended release in hypertensive patients

This placebo-controlled study assessed antihypertensive effect and tolerability of two dose levels of an extended release (ER) formulation of felodipine (Plendil), given once daily to patients in primary health care. The patients had mild to moderate hypertension and were randomized to receive felodipine ER (FER) 20 mg (n = 50), FER 10 mg (n = 50), or placebo (n = 51) in a 4-week, double-blind, parallel-group multicenter study. After 4 weeks, the 24-h reduction in supine diastolic BP (DBP) was greater (p less than 0.01) in both FER groups (7 +/- 6 and 8 +/- 5 mm Hg) than in the placebo group (4 +/- 6 mm Hg). The 24-h reduction in supine systolic BP (SBP) was greater (p less than 0.01) in the FER 20-mg group (14 +/- 11 mm Hg), but not in the FER 10-mg group, than in the placebo group (8 +/- 11 mm Hg). No significant difference in blood pressure (BP) was found between FER 10 and 20 mg. Heart rate (HR) did not differ between any of the groups, nor did body weight or routine laboratory parameters. During felodipine treatment, 17 patients (12 receiving FER 20 mg) were withdrawn mostly because of vasodilatory side effects such as headache and ankle edema. We conclude that FER 10 mg and 20 mg once daily had an antihypertensive 24-h effect and that FER 10 mg may be more suitable as initial dose.     

Control of hypertension in elderly patients with felodipine and metoprolol: a double-blind, placebo-controlled clinical trial.

1. Forty-nine patients aged 65-80 years, whose Phase V diastolic blood pressure (dBP) was above 95 mmHg after 4 weeks open treatment with metoprolol 50 mg twice daily were randomized to receive, double-blind, the calcium antagonist felodipine (n = 32) 2.5 mg twice daily or placebo (n = 17) in addition to metoprolol for 2 weeks. If the dBP remained greater than 95 mmHg, the dose of felodipine or placebo was doubled for a further 2 weeks; if the dBP was still greater than 95 mmHg, the dose of felodipine was doubled again to 10 mg twice daily or the corresponding placebo dose given. The duration of the double-blind period was 6 weeks, all patients receiving metoprolol 50 mg twice daily throughout. 2. At the end of the double-blind period, the seated dBP was reduced from 103 +/- 5 (mean +/- s.d.) to 88 +/- 7 mmHg (P less than 0.001) by felodipine and from 105 +/- 100 +/- 11 mmHg (NS) by placebo. The differences between these reductions (P less than 0.01) and between the final dBPs (P less than 0.001) were significant. Eighty-nine per cent of patients receiving felodipine and 33% of those receiving placebo (P less than 0.001) had controlled (dBP less than or equal to 95 mmHg) BPs. Half (14/27 completing) of the patients receiving felodipine required 2.5 mg throughout; 9/27 needed 5 mg and 4/27 10 mg twice daily. Adverse events occurred with equal frequency in the two groups, but the profile was different.(ABSTRACT TRUNCATED AT 250 WORDS)     

Persistence of anti-hypertensive effect after missed dose of perindopril

AIMS: To assess the persistence of the antihypertensive effect of the ACE-inhibitor perindopril after one missed dose. METHODS: After a placebo run-in period, 10 hypertensive patients were started on perindopril 4 mg once daily in the morning, increased to 8 mg once daily after 4 weeks if office diastolic BP >85 mmHg. 24 h BP monitoring was performed at the end of the placebo run-in period and during active treatment in week 9 and 10 on either active treatment or a placebo-day using a double-blind, randomized, cross-over design. RESULTS: Office BP decreased from 155+/-3/100+/-2 mmHg at the end of placebo to 139+/-3/89+/-2 mmHg (P<0.05 vs placebo) after 8 weeks of active treatment. After 2 months of active treatment, 24 h ABP showed significant decreases in day BP by -11+/-1/-7+/-1 mmHg and in night BP by -11+/-2/-7+/-1 mmHg while on active treatment. During the placebo-day, daytime BP showed decreases by -10+/-1/-5+/-1 and night BP by -8+/-2/-6+/-1 mmHg (NS vs active treatment day). CONCLUSIONS: Perindopril 4-8 mg day-1 causes a persistent decrease in BP during the 24 h dosing interval, which is mostly maintained over the 24-48 h after dosing.     

Felodipine extended release in mild to moderate hypertension

A multi-centre study was carried out to examine the antihypertensive effect and adverse event profile of felodipine in an extended-release (ER) formulation given once daily as monotherapy. Doses of 5 mg, 10 mg or 20 mg felodipine ER were compared with placebo in 183 patients with mild or moderate hypertension. All antihypertensive medication was discontinued on entering a 4-week placebo run-in period. If, at the end of the run-in period, supine diastolic blood pressure was in the range greater than 95 less than 120 mmHg, patients were randomly allocated to double-blind treatment with felodipine, 5 mg, 10 mg or 20 mg, or placebo, to be taken once daily for 4 weeks. Supine and standing blood pressure, heart rate and body weight were measured every 2 weeks during the trial. Assessments were made 24 hours after intake of the study drug. Adverse events were recorded at each review. Over the 4-week treatment period, a dose-related decrease in supine diastolic blood pressure was observed, this reduction occurring already during the first 2 weeks of active treatment. In the placebo group and the felodipine 5 mg, 10 mg and 20 mg groups, supine blood pressure (systolic/diastolic) decreased by 7/6 mmHg, 9/8 mmHg, 12/10 mmHg and 14/11 mmHg, respectively. Supine diastolic blood pressure reduction in the felodipine 10 mg group and both systolic and diastolic blood pressure reductions in the 20 mg group were significantly greater than with placebo. Standing diastolic blood pressure reduction was significantly greater in all three dose groups on felodipine compared with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antihypertensive effect of lisinopril assessed by 24-hour ambulatory monitoring: a double-blind, placebo-controlled, cross-over study.

The antihypertensive effect of the angiotensin-converting enzyme (ACE) inhibitor lisinopril administered in a single dose of 20 mg was evaluated by ambulatory blood pressure monitoring (ABPM) in a double-blind, placebo-controlled, cross-over study. Twenty-four patients (21 men and 3 women, mean age 52 +/- 6 years) with mild to moderate hypertension were included in the study and randomly assigned to two consecutive treatments with lisinopril 20 mg and placebo, each administered for 4 weeks. On the last day of each treatment, BP was assessed by noninvasive 24-h ABPM. BP was significantly lower after lisinopril than after placebo in a 24-h period (mean 24-h systolic BP (SBP) with lisinopril 120 +/- 7 mm Hg and with placebo 135 +/- 9 mm Hg; mean day SBP with lisinopril 125 +/- 3 mm Hg and with placebo 142 +/- 5 mm Hg; mean night SBP with lisinopril 112 +/- 4 mm Hg and with placebo 124 +/- 6 mm Hg; mean 24-h diastolic BP (DBP) with lisinopril 76 +/- 6 mm Hg, and with placebo 87 +/- 8 mm Hg; mean day DBP with lisinopril 80 +/- 3 mm Hg and with placebo 93 +/- 4 mm Hg; mean night DBP with lisinopril 69 +/- 2 mm Hg and with placebo 79 +/- 5 mm Hg, p less than 0.001). Mean 24-h, mean day, and mean night heart rate (HR) did not differ significantly between placebo and lisinopril treatments. Repeated-measures analysis of variance (ANOVA) showed a significant influence on SBP (p less than 0.001) and DBP (p less than 0.001) throughout the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Smooth blood pressure control obtained with extended-release felodipine in elderly patients with hypertension: evaluation by 24-hour ambulatory blood pressure monitoring

OBJECTIVE: To assess, by smoothness index (SI), distribution of the antihypertensive effect of extended-release (ER) felodipine over 24 hours in elderly patients with hypertension. METHODS: After a 4-week washout phase, 35 elderly patients (mean age 69 +/- 4 years) with mild-to-moderate hypertension received 2 weeks' treatment with ER felodipine 5mg once daily. The dosage of ER felodipine was doubled to 10 mg/day and given for a further 2 weeks in non-responders (sitting clinic blood pressure > 140/90mm Hg). The study had an open-label design with no placebo control. After each period, clinic and ambulatory blood pressures were measured. Trough-to-peak (T/P) ratio was computed by dividing the blood pressure (BP) change at trough (22 to 24 hours after drug intake) by the change at peak (2 adjacent hours with a maximal BP reduction between the second and eighth hour after drug intake). SI was calculated as the ratio between the average of the 24, hourly, treatment-induced BP changes and its standard deviation. RESULTS: After the initial 2-week treatment period, clinic and 24-hour ambulatory BP values were higher in non-responders (145 +/- 11/87 +/- 8 and 135 +/- 17/80 +/- 6mm Hg, respectively) than in responders (133 +/- 6/81 +/- 3 and 130 +/- 9/77 +/- 7mm Hg). In non-responders, clinic and 24-hour BP values were lowered after a further 2 weeks of treatment with ER felodipine 10 mg/day (128 +/- 11/78 +/- 6 and 128 +/- 12/75 +/- 5mm Hg). SI was high in responders (0.8 +/- 0.8/0.7 +/- 0.7 for systolic/diastolic BP) and low in non-responders (0.5 +/- 0.6/0.3 +/- 0.6) during the first 2-week treatment period. It increased in non-responders after an additional 2 weeks of treatment with ER felodipine 10 mg/day (1.0 +/- 0.8/0.7 +/- 0.6). Median T/P ratios were 0.73 and 0.61 (systolic BP and diastolic BP) in responders and 0.41 and 0.61 in non-responders after 2 weeks of treatment. At variance with SI, T/P ratios did not increase in non-responders after doubling the dosage of ER felodipine (0.34 and 0.18). ER felodipine did not increase 24-hour heart rate. A total of nine adverse events were recorded in six patients (17%), but no patients withdrew from the study. CONCLUSION: ER felodipine 5 to 10 mg/day smoothly and safely reduces 24-hour ambulatory BP in elderly patients with hypertension.     

Genetic polymorphisms of the urea transporter gene are associated with antihypertensive response to nifedipine GITS

Nifedipine GITS has diuretic and natriuretic properties, which may enhance its antihypertensive efficacy. We assessed contributions of polymorphisms in the urea transporter-A gene (SLC14A2) to interindividual variations in blood pressure (BP) response to nifedipine treatment. 405 subjects from a single Chinese county received a single oral dose of 30 mg nifedipine GITS (gastrointestinal therapeutic system) daily for 16 days. We genotyped two SNPs in SLC14A2 and found significant associations for the Val227Ile (rs1123617) and Ala357Thr (rs3745009) polymorphisms with BP response to nifedipine treatment. After treatment, subjects with either Ala357/Thr357 or Thr357/Thr357 genotypes had significantly smaller mean changes in systolic BP (SBP) (beta +/- SE = -2.87 +/- 1.24 mmHg, p = 0.020) and diastolic BP (DBP) (beta +/- SE = -1.69 +/- 0.62 mmHg, p = 0.006) compared to those with the Ala357/Ala357 genotype. Subjects with either Val227/Ile227 or Ile227/Ile227 genotypes had significantly larger mean changes in SBP (beta +/- SE = 3.13 +/- 1.19, p = 0.009) and DBP (beta +/- SE = 1.50 +/- 0.60 mmHg, p = 0.013) compared with those with the Val227/Val227 genotype after treatment. Subjects carrying both the Ala357/Ala357 genotype in the Ala357Thr polymorphism and either Val227/Ile227 or Ile227/Ile227 genotypes in the Val227Ile polymorphism had the highest mean change in SBP and DBP. Our study supports the conclusion that polymorphisms in the SLC14A2 gene can predict the antihypertensive efficacy of nifedipine GITS.     

The effects of mibefradil and enalapril on 24-hour blood pressure control and left ventricular mass in patients with mild to moderate hypertension: double-blind, randomized trial

In this prospective, double-blind, monocenter drug trial, 48 primary care patients with mild to moderate essential hypertension were randomized to mibefradil, 50 mg, titrated to 100 mg, or enalapril, 20 mg, titrated to 2 x 20 mg. Ambulatory 24-h blood pressure measurements (ABPM) and echocardiography were performed at baseline and after 12 weeks' treatment. Complete data from 43 patients were analyzed. Mibefradil (n = 22; titration, 13 patients) reduced mean 24-h ABP from 159+/-14/102+/-7 mm Hg to 140+/-10/89+/-7 mm Hg after 12 weeks. Enalapril (n = 21; titration, six patients) reduced baseline ABP from 156+/-12/100+/-9 mm Hg to 140+/-17/89+/-10 mm Hg (12 weeks). Trough-to-peak ratios in DBP were 86% for mibefradil and 75% with enalapril. Left ventricular mass (LVM) decreased from 199+/-65 to 193+/-62 g [M-mode modified American Society of Echocardiography (ASE)] and from 184+/-65 to 173+/-50 g (truncated ellipsoid method) after 12 weeks in response to mibefradil (p > 0.2), and from 212+/-50 to 196+/-57 g and from 182+/-39 to 170+/-40 g (mean +/- SD, p < 0.02) with enalapril. Mibefradil matched enalapril in 24-h ABP control. Enalapril reduced LVM significantly after 12 weeks (p < 0.02). Mibefradil did not significantly reduce LVM after 12 weeks.     

Clinical equivalence of two tablet formulations of felodipine

Objective: This study was performed to assess whether a new formulation of felodipine extended release (FER) tablets with a 9 mm diameter is similar to the presently used 11 mm diameter FER formulation with respect to antihypertensive effect and tolerability in patients with essential hypertension. A randomised, double-blind, placebo controlled, three-way cross-over study design was used. Patients: Twenty-four patients with a supine diastolic blood pressure (DBP) of 95–115 mmHg after a 4-week placebo run-in period were given FER 5 mg 9 mm tablets, FER 5 mg 11 mm tablets and placebo in randomised order. The tablets were given once daily and each double-blind treatment period lasted for two weeks. Methods: Twenty-four hour ambulatory blood pressure monitoring was performed at the end of each treatment period. The primary effect variable was mean DBP over 24 hours. Nineteen patients had 24-hour blood pressure data valid for analysis using an analysis of variance with patient, treatment, period and carry-over as factors. Results: Both formulations of FER 5 mg tablets significantly reduced the mean 24-hour DBP compared to placebo. The 9 and 11 mm tablets resulted in, on average, 4.7 and 3.4 mmHg lower mean 24-hour DBP than placebo. There was, however, no significant difference between the two different FER formulations. Both FER formulations were well tolerated and similar to placebo in this respect. Conclusion: Both FER 5 mg tablet formulations (9 and 11 mm diameter), given once daily, were clinically equivalent with respect to antihypertensive effect and tolerability in patients with mild to moderate essential hypertension.     

IS ISOLATED SYSTOLIC HYPERTENSION A WHITE COAT’ PHENOMENON IN THE ELDERLY?

1. Repeated clinic blood pressure measurement was compared with non-invasive ambulatory blood pressure (ABP) monitoring in 10 elderly subjects with isolated systolic hypertension (ISH) and 11 normotensive controls (NT). 2. Subjects were assessed on four occasions at weekly intervals. None was receiving antihypertensive or vasoactive medication. 3. Mean clinic blood pressure was consistently higher than mean daytime ABP in both clinical groups. This effect was greater for systolic (SBP) than diastolic blood pressure (DBP) and in the ISH group compared with the NT group. The reproducibility of the clinic minus ABP difference was high in both groups; the mean +/- s.d. of the differences was 26 +/- 15/9 +/- 2 mmHg in the ISH group and 7 +/- 18/8 +/- 9 mmHg in the controls. 4. ABP readings were normally distributed for both SBP and DBP in both groups. In the ISH group, the frequency distribution of SBP readings was shifted to the right whilst the distribution of DBP readings overlapped that of the NT subjects. 5. These results suggest a pressor response may largely account for the elevated SBP seen in elderly subjects with sustained ISH based on casual readings.     

An oral yohimbine/L-arginine combination (NMI 861) for the treatment of male erectile dysfunction: a pharmacokinetic, pharmacodynamic and interaction study with intravenous nitroglycerine in healthy male subjects

AIMS: Interaction of phosphodiesterase type 5 inhibitors for the treatment of erectile dysfunction with organic nitrates could lead to severe hypotension. NMI 861 is a combination of 7.7 mg yohimbine tartrate and 6 g l-arginine glutamate. A similar oral combination, which contains the same amount of yohimbine and L-arginine, has been shown to improve erectile function in previous studies. METHODS: In two placebo-controlled, randomized, double-blind, two-way crossover design studies we aimed to assess first the pharmacokinetics and pharmacodynamics of a single oral dose of NMI 861 administered in 16 healthy male subjects, and then the pharmacodynamics of orally administered NMI 861 in combination with intravenous nitroglycerine (GTN) in 12 healthy male subjects. Systolic (SBP) and diastolic (DBP) blood pressures, pulse rate and adverse events were measured in each study. RESULTS: NMI 861 was well tolerated by all subjects with no significant adverse reactions reported. For L-arginine, mean C(max) +/- SEM (range) was 42 +/- 2.2 (28-63) microg ml(-1) and t(max) (range) was 0.88 (0.50-1.5) h. AUC and t(1/2) were not calculated for L-arginine because of the presence of endogenous concentrations and the contribution from food sources. For yohimbine, mean C(max) was 42 +/- 11 (2.8-128) ng ml(-1); t(max) was 0.57 (0.25-1.0) h; mean AUC(0,8 h) was 65 +/- 24 (5.4-332), ng ml(-1) h and t(1/2) was 1.0 +/- 0.34 (0.40-6.0) h. There was a small but significant difference in the mean change from baseline for SBP from 0 to 6 h after NMI 861 treatment compared with placebo (0.8 +/- 1.4 vs-4.1 +/- 2.1 mmHg, respectively; 95% CI 0.0, 9.8 mmHg (P = 0.047)). There was no significant difference in SBP between treatments for the studied periods 6-12 h and 12-24 h. There was no significant difference in DBP or pulse between NMI 861 and placebo treatments for the three studied time periods. In the study designed to investigate the interaction of organic nitrate with NMI 861, subjects were infused intravenously with increasing doses of GTN (15 min each dose) at 2.5, 5, 10, 20 and 40 microg min(-1) starting 40 min after a single oral dose of either NMI 861 or placebo. There was no significant difference in the hypotensive response induced by GTN between the NMI 861 and placebo treatments. The mean maximum changes from baseline during GTN infusion for subjects administered with either NMI 861 or placebo were a decrease of 16.9 +/- 3.4 vs 13.6 +/- 2.4 mmHg (mean difference between treatments -3.3 mmHg, 95% CI -12.7, 6.0 mmHg (P = 0.460)) for SBP, a decrease of 14.7 +/- 2.0 vs 14.0 +/- 2.0 mmHg for DBP (mean difference -0.7 mmHg, 95% CI -8.2, 6.8 mmHg (P = 0.835)), and an increase of 11.8 +/- 1.9 vs 14.1 +/- 2.4 beats min(-1) for pulse, respectively (mean difference -2.3 beats min(-1), 95% CI -9.3, 4.5 beats min(-1) (P = 0.464)). CONCLUSIONS: Acute oral administration of NMI 861 was found to be well tolerated and bioavailable in healthy male subjects and no significant hypotensive interaction with intravenous GTN was detected at the doses investigated.     

Effects of BAYl 5240, a fixed combination of low dose nifedipine and acebutolol on hypertension: Comparison with standard dose nifedipine

116 patients from 4 clinics participated in a double blind study to assess the efficacy of (BAY l 5240), a nifedipine-acebutolol fixed combination (10 mg + 100 mg), as compared to nifedipine 20 mg in essential hypertension. During the 10 week study, the mean recumbent blood pressure decreased 1 to 3 h after treatment from 175.5/105.2 to 148.3/88.0 mmHg in the BAY l 5240 group and from 174.3/102.9 to 150.3/86.5 mmHg in the nifedipine group. The results also showed a comparable decrease in the mean systolic (SBP) and diastolic (DBP) blood pressures before treatment (24 h after last tablet) and after physical exertion before and after either drug given for 4 weeks. Doubling of the dose for 4 additional weeks produced a moderate and similar additional decrease in blood pressure. The results show the possibility of treating essential hypertension with a low dose of a beta-adrenergic blocking agent in combination with 10 mg nifedipine. Both regimens were well tolerated. One patient in the BAY l 5240 group and 2 in the nifedipine group, all treated by the same investigator, were withdrawn from the study because of headache during the nifedipine pre-period.     

Antihypertensive efficacy of manidipine and enalapril in hypertensive diabetic patients

Recent studies showed that in diabetic hypertensive patients, administration of angiotensin-converting enzyme (ACE)-inhibitors or calcium antagonists can effectively lower blood pressure (BP) and prevent diabetes-related cardiovascular complications with no adverse metabolic effects. We sought to assess the antihypertensive and metabolic effects of the new dihydropyridine calcium antagonist manidipine (M) in patients with diabetes mellitus and essential hypertension as compared with the ACE inhibitor enalapril (E). After 3 weeks of placebo, 101 (62 men; age range, 34-72 years) hypertensives with type II diabetes mellitus were randomized to M 10-20 mg or E 10-20 mg, od, for 24 weeks. At the end of the placebo period and the active-treatment phase, BP was measured with a mercury sphygmomanometer (office, O) and over the 24 h by ambulatory (A) monitoring. ABP recordings were analyzed to obtain 24-h, day (6 a.m. to midnight), and night (midnight to 6 a.m.) average systolic (S) and diastolic (D) BP and heart rate (HR) values. Homogeneity of the antihypertensive effect over the 24 h was assessed by the smoothness index [SI: i.e., the ratio between the average of the 24 hourly BP changes after treatment and the corresponding standard deviation (the higher the SI, the more uniform is the BP control by treatment over the 24 h]. The O SBP and DBP were significantly (p < 0.01) and similarly reduced by M (16 +/- 10 and 13 +/- 6 mm Hg, n = 49) and E (15 +/- 10 and 13 +/- 6 mm Hg, n = 45). The percentage of patients whose O DBP was reduced < or = 85 mm Hg (i.e., the value indicated to be the optimal DBP goal in diabetic hypertensives) was similar for M (37%) and E (40%). The reduction of 24-h BP also was similar between M (n = 38) and E (n = 38) for both drugs (systolic, 6 +/- 11 and 8 +/- 10 mm Hg; diastolic, 5 +/- 8 and 5 +/- 7; NS, M vs. E). The antihypertensive effect was distributed in a similar homogeneous fashion throughout the dosing interval, as shown by the similar SI values (M, 0.6 +/- 1.2 for SBP and 0.6 +/- 0.9 for DBP; E, 0.6 +/- 0.8 for SBP and 0.5 +/- 0.7 for DBP; NS, M vs. E). O and A HR were unchanged by either treatment. Markers of glucose and lipid metabolism and renal function were not significantly modified by treatment both with M and with E. In the diabetic hypertensives, M was as effective and metabolically neutral as the ACE-inhibitor E.     

Effect of a new calcium antagonist, tiapamil, in hypertension of the elderly.

The antihypertensive effect of a single oral dose of tiapamil (450 mg) and placebo were compared in a single blind randomized cross-over study in 10 71-86 year old hypertensive patients. Blood pressure (BP) and heart rate (HR) were recorded every 15 min for 12 h by an automatic device. Tiapamil led to a decrease in mean daytime systolic (SBP) and diastolic (DBP) BP from 171 +/- 12/98 +/- 10 mm Hg to 159 +/- 11/90 +/- 9 mm Hg (P less than 0.001) without significant variation in HR. Thereafter patients received tiapamil 450 twice daily; by the seventh day of treatment mean daytime SBP and DBP were 155 +/- 13/85 +/- 14 mm Hg (P less than 0.001 vs placebo). The hourly mean values of SBP recorded for 8/12 h (first tiapamil day) and 10/12 h (seventh tiapamil day) were significantly lower than the corresponding values after placebo. We conclude that tiapamil in the elderly exerts a sustained antihypertensive effect lasting 12 h or more, with only minor variations in HR. This effect predominates on systolic pressure and is significant from the first dose.     

The effects of KT3-671, a new angiotensin II (AT 1) receptor blocker in mild to moderate hypertension

AIMS: To compare the antihypertensive effect, and tolerability and safety of once daily doses of KT3-671 with that of placebo in patients with mild to moderate uncomplicated essential hypertension. METHODS: A randomised, multicentre, double blind, parallel-group comparison of KT3-671 with placebo. Hypertensive patients [Ambulatory Blood Pressure Monitoring (ABPM), mean daytime DBP > 90 mmHg, Office sitting mean DBP 95-114 after a 7-28 day washout period] entered a 2-week, single blind, run-in phase. Patients eligible for the double-blind phase were randomised to receive KT3-671 40 mg, 80 mg, 160 mg or placebo once daily over 4 weeks. The primary end-point was trough mean sitting office DBP. The study had 90% power to detect a 5 mmHg change between treatments and placebo at the 5% level of significance. The secondary end-points were 24 hour, daytime and night time mean ABPM. RESULTS: Office DBP was significantly lower with KT3-671 40 mg but not the other 2 dosage groups (-3.2; 95% CL -6.1 : -0.3 P < 0.03). Office SBP was significantly reduced with all dosage groups (40 mg -5.9, 95% CL -11 : -0.9; 80 mg -4.9, 95% CL -9.9 : 0.1 and 160 mg -5.7, 95% CL -10.8 : -0.7 P < 0.05). All doses of KT3-671 reduced systolic and diastolic ABPM. The number of patients with treatment related adverse events were comparable to placebo (38.8% KT3-671 vs 32.8% placebo). There was some evidence of a dose-response relationship with fall in nocturnal ABPM. CONCLUSIONS: Oral KT3-671 was well tolerated. KT3-671 reduced office systolic BP at all doses and diastolic BP at some of the doses. Due to greater precision and power, the falls in mean ambulatory systolic and diastolic pressure were all significantly lower than placebo.     

Effect of the calcium antagonist benidipine hydrochloride on 24-h ambulatory blood pressure in patients with mild to moderate hypertension in a double-blind study against placebo

The effects of benidipine hydrochloride (benidipine, CAS 91559-74-5), a dihydropyridine calcium antagonist, on the 24-h ambulatory blood pressure were studied by a double-blind test against placebo in 8 patients with essential hypertension. The mean resting systolic (SBP) and diastolic (DBP) blood pressures were 173 mmHg and 104 mmHg, respectively, at the time of patients enrollment. Blood pressure was measured every 30 min for 24 h after a single oral administration of either benidipine (4 mg/day) or the placebo. The mean through/peak (T/P) ratios were calculated from blood pressure measurements obtained using 2-h moving averages, and the smoothness index (SI) was calculated by subtracting the effect of the placebo from that of benidipine at each interval. The mean SBP and DBP fell to 135 and 88 mmHg, respectively, after dosing, which gave T/P ratios of 82% and 64%, respectively. The SIs for SBP and DBP were 1.82 and 0.76, respectively. These findings indicate that benidipine maintained a satisfactory and durable antihypertensive effect by once-a-day dosing.