Felodipine/metoprolol: a review of the fixed dose controlled release formulation in the management of essential hypertension

The main objective of fixed dose combination therapy for hypertension is to improve blood pressure (BP) control with lower, better tolerated dosages of 2 antihypertensives rather than higher dosages of a single agent. Felodipine and metoprolol lower BP via different, but complementary, mechanisms and controlled release formulations of these 2 drugs are available as a fixed dose combination, felodipine/metoprolol. In clinical trials in patients with hypertension, felodipine/metoprolol was significantly more effective than placebo and the respective monotherapies administered at the same dosages. Mean BP was reduced to < 155/90 mm Hg in patients treated with combination therapy and controlled in approximately 70% of patients. In one study that titrated dosages to effect, fewer felodipine/metoprolol than felodipine or metoprolol monotherapy recipients required dosage increases to achieve BP control (45 vs 60 and 67%, respectively). Data from double blind comparative studies show that the antihypertensive efficacy of felodipine/metoprolol 5 to 10/50 to 100 mg/day is significantly greater than that of enalapril monotherapy or captopril plus hydrochlorothiazide and equivalent to nifedipine/atenolol and amlodipine. In comparisons with enalapril, fewer felodipine/metoprolol than enalapril recipients required dosage titration to achieve BP control. Compared with amlodipine, felodipine/metoprolol significantly reduced mean 24-hour average BP (8.9/5.5 vs 14.4/9.5 mm Hg after 6 weeks; p < 0.001). Both treatments preserved diurnal rhythm. Long term follow-up studies show that the antihypertensive effect of felodipine/metoprolol occurs mostly during the first month of treatment with small additional decreases in BP being observed in the second and third months, and a relatively constant effect thereafter. According to a validated questionnaire, quality of life was relatively similar during 12 weeks treatment with felodipine/metoprolol, enalapril or placebo. In a retrospective pharmacoeconomic analysis conducted in Sweden, felodipine/metoprolol was more cost effective than enalapril as initial treatment for hypertension. Peripheral oedema, headache and flushing were the most commonly reported adverse events with felodipine/metoprolol and felodipine monotherapy, whereas dizziness, fatigue, headache and respiratory infection were more frequent with metoprolol monotherapy. Dose-dependent adverse events such as oedema may occur less often in patients taking lower dosages in combination than in those taking higher dosages of felodipine monotherapy. Thus, patients with hypertension treated with felodipine/metoprolol experience greater control of BP, with less need for dosage titration, than those treated with felodipine, metoprolol or enalapril monotherapy. Importantly this greater efficacy does not appear to be associated with a higher incidence of adverse events relative to monotherapy. Additionally, in short term studies felodipine/metoprolol had a similar (minimal) effect on QOL to enalapril monotherapy but was more cost effective.     

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)     

Bioequivalence, pharmacokinetic and pharmacodynamic response to combined extended release formulations of felodipine and metoprolol in healthy volunteers

Objective: The primary aim of this study was to investigate whether bioequivalence is achieved for a new fixed combination of extended-release (ER) felodipine and controlled-release (CR/ZOK) metoprolol␣compared with the free combination of felodipine ER metoprolol CR/ZOK. The second aim was to study whether there was an interaction in pharmacokinetics and pharmacodynamics between felodipine and metoprolol when administered as ER formulation. Methods: Two four-way cross-over studies were performed in 36 young subjects and 24 elderly subjects with frequent measurement of drug plasma concentrations, blood pressures and heart rate. The pharmacokinetic analysis included enantioselective analysis in six subjects. Results: Bioequivalence between the fixed combination and the free combination was observed for the two drugs (mean difference 27%) except for a minor deviation regarding C_max of metoprolol in the elderly. No significant interaction was shown except for a small increase (6%) of metoprolol AUC in the younger subjects. Mean plasma S-/R-enantiomer ratios were almost identical for the different treatments. Blood pressure and heart rate was significantly reduced for the fixed combination compared with felodipine ER in the younger and the elderly subjects. No significant difference regarding pharmacodynamics was detected between the fixed combination and the corresponding free combination. Conclusion: The fixed combination consistently provides fairly constant and effective felodipine and metoprolol concentrations after once-daily administration of one tablet. It is clinically interchangeable with the free combination of metoprolol CR/ZOK tablets and felodipine ER tablets. Finally, felodipine and metoprolol do not interact on a pharmacokinetic level when administered as the fixed combination. Received: 29 October 1996 / Accepted in revised form: 21 March 1997     

Antihypertensive efficacy and tolerability of a fixed combination of metoprolol and felodipine in comparison with the individual substances in monotherapy. The Swedish/United Kingdom Study Group.

In this double-blind, randomized, parallel-group study, the aim was to compare the efficacy and tolerability of a new fixed combination of felodipine and metoprolol with the individual components in monotherapy. After a placebo period of 4 weeks, 159 patients with mild to moderate essential hypertension were randomized to extended-release formulations of either felodipine plus metoprolol 10 + 100 mg (FM), felodipine 10 mg (F), or metoprolol 100 mg (M) once daily if supine diastolic blood pressure greater than 95 mm Hg. After 12 weeks of active treatment, the reductions in supine blood pressure (24 h after dosing) were 20/14, 13/10, and 11/8 mm Hg for FM, F, and M, respectively. The difference in change was 7/4 mm Hg (p = 0.004/p = 0.006) and 8/5 mm Hg (p = 0.0002/p less than 0.0001) for the fixed combination and F or M, respectively. Blood pressure control (diastolic blood pressure less than 90 mm Hg after 12 weeks) was significantly better for the combination than for F and M, i.e., 71%, 49% (p = 0.008), and 34% (p = 0.004), respectively. Adverse experiences were those to be expected from previous studies with felodipine and metoprolol and did not differ in frequency between groups. It can be concluded that a fixed combination of metoprolol and felodipine has a clinically relevant and significantly better blood pressure reduction 24 h postdose than the individual substances in monotherapy, without decreased tolerability.     

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.     

Ramipril/felodipine extended-release fixed-dose combination: a review of its use in the management of essential hypertension

Ramipril/felodipine extended release (ER) [Triapin and Triapin Mite, Unimax] is a once-daily fixed-dose combination of the ACE inhibitor ramipril and the ER formulation of the dihydropyridine calcium channel antagonist felodipine. It is indicated in adult patients with essential hypertension whose blood pressure (BP) is inadequately controlled with ramipril or felodipine monotherapy. In this patient population, commercially available fixed-dose combinations (i.e. 2.5 mg/2.5 mg and 5 mg/5 mg) of ramipril and felodipine ER are more effective at controlling hypertension than the individual components used as monotherapy at the same dosages. Likewise, the 5 mg/5 mg combination is as effective as felodipine ER 10 mg, and more effective than ramipril 10 mg administered as monotherapy. The addition of low-dose ramipril plus felodipine ER (fixed-dose or combination of individual components) to the existing antihypertensive regimen also appears to provide adequate BP control and renal protection in hypertensive patients with non-diabetic chronic renal disease. In these patients, the low-dose combination of ramipril and felodipine ER was as effective as standard-dose felodipine ER, but more effective than standard-dose ramipril, in providing diastolic BP (DBP) control, and as effective as standard-dose ramipril, but more effective than standard-dose felodipine ER, in slowing the rate of regression of glomerular filtration. The ramipril/felodipine ER combination is as well tolerated as ramipril or felodipine ER monotherapy administered at the same dosages, and is better tolerated than felodipine ER monotherapy given at twice the dosage used in the combination. Overall, ramipril/felodipine ER appears to be an effective option for the treatment of adults with essential hypertension that is poorly controlled with monotherapy. In addition, a fixed, low-dose combination of ramipril/felodipine ER is a potential alternative to monotherapy for the initial management of essential hypertension.     

Plasma concentration-effect relationships of intravenous and extended-release oral felodipine in hypertensive patients.

Felodipine, a dihydropyridine calcium antagonist, was given double-blind in a crossover design comparing once-daily doses of 20 mg felodipine extended-release (ER) tablets with placebo in 12 hypertensive patients. A 2-h intravenous infusion was given after a placebo washout. After oral felodipine, blood pressure (BP) was significantly lower than after placebo, both after the first dose and after 2 weeks of treatment. Supine BP 24 h after the first dose of placebo and felodipine was 159/97 and 153/92 mm Hg (p less than 0.01/0.05), respectively. Corresponding BPs at 2 weeks were 158/99 and 144/89 mm Hg (p less than 0.01/0.01). Approximately 75% of the maximal and 60% of the trough effect at steady state were obtained already after the first dose. The plasma concentration (CpF) vs. time curve after felodipine ER was relatively flat. After oral felodipine, a linear correlation was found between BP reduction and logarithmic CpF. After intravenous administration, CpF correlated well with a hyperbolic function. These data indicate that there is an almost linear relation between BP reduction and log CpF in the range from 2-20 nmol/L, and that little additional effect is to be expected above approximately 20 nmol/L. No hysteresis was found for the relationship between CpF and BP reduction. The absolute bioavailability of felodipine ER was 22%.     

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)     

Pharmacokinetic interaction between cyclosporine and the dihydropyridine calcium antagonist felodipine

Objective: In a double blind, randomised, placebo-controlled, cross-over study 12 healthy male volunteers were allocated to receive felodipine + placebo, cyclosporine + placebo, and felodipine + cyclosporine in order to investigate the interaction between the calcium channel blocker felodipine and cyclosporine as it affects the pharmacokinetics of felodipine, dehydrofelodipine, and cyclosporine, and 24-hour blood pressure measurements. Methods: Single doses of cyclosporine (capsules, 5 mg/kg body weight) and of felodipine (extended release (ER) tablets 10 mg) were given at a 1–2 week interval. Plasma drug concentrations were followed for 2 days after drug intake. Results: For cyclosporine, C_max was increased after combined treatment (16%) compared to cyclosporine alone, but felodipine did not influence other kinetic parameters of cyclosporine. For felodipine, combined treatment with cyclosporine and felodipine increased AUC and C_max (58% and 151%, respectively) and lowered mean residence time (24%) significantly compared to felodipine alone. For the metabolite dehydrofelodipine, too, AUC and C_max were increased after the combined treatment (43% and 94%, respectively). Mean 24-hour systolic and diastolic blood pressures were significantly lower after felodipine, both when felodipine was given alone (121/68 mmHg) and in combination with cyclosporine (122/68 mmHg) compared to cyclosporine alone (127/73 mmHg). Conclusion: A combined single dose of cyclosporine and felodipine in healthy subjects increased the AUC and C_max of felodipine suggesting a cyclosporine-induced decrease in the first-pass metabolism of felodipine, whereas the AUC of cyclosporine was only slightly increased by felodipine. Received: 28 August 1995/Accepted in revised form: 18 December 1995     

非洛地平缓释片对原发性高血压左室肥厚的影响

目的：观察非洛地平缓释片对高血压左室肥厚的逆转作用。方法：应用动脉血压及彩色多普勒超声心动图测定26例高血压并左室肥厚患者口服非洛地平缓释片（5～10mg/d),24周后血压及左室形态结构变化。结果：治疗后血压明显下降（P＜0．01）,舒张期室间隔厚度及左室后壁厚度,左室重量指数均明显减少（P＜0．01）。结论：非洛地平缓释片不但能有效降低血压,而且能逆转左室肥厚。     

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.     

非洛地平和美托洛尔联用大鼠经皮给药的协同降压作用

目的：研究非洛地平和美托洛尔联用经皮给药对自发性高血压大鼠的协同降压作用，为其复方经皮给药系统的研制提供药理学依据。方法：50只自发性高血压大鼠随机分为10组（均为单次给药）：空白对照组，非洛地平-美托洛尔剂量分别为1-10、3—30、9—90mg／kg的复方透皮贴剂治疗组，非洛地平剂量分别为1、3、9mg／kg和美托洛尔剂量分别为10、30、90mg／kg的单方透皮贴剂治疗组。以无创性尾套法测定给药后大鼠的血压和心率，评价两药联用的协同降压作用。结呆：非洛地平和美托洛尔联用经皮给药对收缩压和舒张压的降低作用均显著高于两药各自单用（P〈0．05），对心率有降低作用但显著低于单用美托洛尔（P〈0．05）。单方与复方药物经皮给药对血压及心率的作用强度和持续时间均具有剂量依赖性（P〈0．05）。结论：作用机制不同的非洛地平和美托洛尔联用，协同和互补作用明确，该透皮给药复方制剂可以提高血压控制率、治疗安全性和病人用药依从性。     

A double-blind comparison of felodipine and hydrochlorothiazide added to metoprolol to control hypertension

Summary Seventy-six uncomplicated hypertensive patients treated in General Practice, whose seated diastolic blood pressure (Phase V) (dBP) remained 95 mmHg after a minimum of 4 weeks treatment with metoprolol 50 mg b.i.d. as antihypertensive monotherapy, were randomized to receive the selective calcium antagonist felodipine 5 mg b.i.d. or hydrochlorothiazide 12.5 mg b.i.d. in addition to metroprolol 50 mg b.i.d. The trial duration was 8 weeks, the dose of the felodipine or hydrochlorothiazide being doubled after 4 weeks if control of BP (dBP <90 mmHg) was not achieved on the initial doses.Over the trial period of 8 weeks, felodipine reduced dBP from 102 to 85 mmHg and hydrochlorothiazide from 101 to 91 mmHg; the dBP reduction in the felodipine group was greater than that in the hydrochlorothiazide group (17 vs 9 mmHg) and the attained dBP lower in the felodipine group. About half of the patients in each group required the higher dose.Both regimes were effective and well tolerated. In the dosages used, felodipine was a slightly more effective antihypertensive drug than hydrochlorothiazide when added to metoprolol. There was no apparent difference in the tolerability of the two regimes.     

Pharmacokinetic interactions between felodipine and metoprolol

Summary This double-blind, cross-over study in healthy male subjects evaluated the pharmacokinetics of felodipine and metoprolol given both separately and in combination. During three, five-day study periods, felodipine 10 mg b.d., metoprolol 100 mg b.d. and a combination of the two, were given in random order. There was at least a 7-day washout period between each pharmacokinetic study day. Plasma levels of unchanged felodipine and metoprolol were measured for 24 h after the last dose, on the 5th day of each treatment period.Eight subjects, aged 19–22 years, completed the study. Both felodipine and metoprolol, given alone and in combination, were well tolerated.None of the felodipine pharmacokinetic variables (t_max, C_max, C_min, AUC (0–12) and t_1/2) changed significantly when felodipine and metoprolol were given in combination. C_max and AUC (0–12) for metoprolol increased significantly when metoprolol and felodipine were combined, although t_max, C_min and t_1/2 for metoprolol remained unchanged. The changes in metoprolol pharmacokinetics induced by felodipine are small and unlikely to be clinically important.     

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)     

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.     

Comparison of benazepril-amlodipine and captopril-thiazide combinations in the management of mild-to-moderate hypertension

OBJECTIVE: To compare the efficacy and tolerability of benazepril 10 mg + amlodipine 5 mg combination (BZ+AM) versus captopril 50 mg + hydrochlorothiazide 25 mg (CP+HT) combination. MATERIAL: 405 outpatients with mild-to-moderate arterial hypertension not adequately controlled by a monotherapy with ACE inhibitors or calcium channel blockers or diuretics entered this multicenter, double-blind, randomized, parallel-group study. METHOD: After a 2-week placebo run-in, 397 patients with sitting diastolic (D) blood pressure (BP) > 95 mmHg and/or sitting systolic (S) BP > 160 mmHg were randomized to receive either BZ+AM (201 patients) or CP+HT (196 patients) once daily for 12 weeks. Main outcome measure was sitting DBP and SBP values at the end of active treatment. The response rate was defined as the proportion of patients with either a final sitting DBP < 90 mmHg or decreased by at least 10 mmHg or a sitting SBP < 150 mmHg or decreased by at least 20 mmHg from baseline. RESULTS: The DBP and SBP values obtained with BZ+AM were, respectively, 2.7 and 3.7 mmHg lower than those obtained with CP+HT (both p < 0.001 vs. CP+HT). The response rate in the BZ+AM group (94.8%) was better than that observed in the CP+HT group (86.0%, p = 0.004). The incidence of adverse events was similar with the 2 treatment regimens (17.9% for both). CONCLUSIONS: These data suggest a higher antihypertensive efficacy of the fixed combination BZ 10 mg+AM 5 mg as compared with CP 50 mg+HT 25 mg.     

Blood pressure responses to whole-body cold exposure: effect of carvedilol

OBJECTIVE: The aim of this study was to test the effects of carvedilol on blood pressure (BP) and heart rate (HR) during whole-body cold exposure in hypertensive and normotensive subjects. METHODS: Ten hypertensive and twelve normotensive subjects were exposed to cold (-15 degrees C, wind 3.5 m/s) three times for 15 min with a 1-week interval between the exposures. The study design was made according to a randomised double-blind, crossover method. Before the cold exposures the subjects ingested carvedilol or placebo once a day (carvedilol 12.5 mg/day for 2 days and then 25 mg/day for 5 days) for 1 week. The systolic (SBP) and diastolic (DBP) blood pressure and HR were measured every 3 min during the test procedures using an indirect ambulatory blood pressure monitor device (ABPM-02, Meditech Co.). RESULTS: In the hypertensive group, the cold exposure increased SBP/DBP from 119/75 mmHg to 143/96 mmHg during carvedilol treatment (P<0.001) and from 132/85 mmHg to 159/106 mmHg during placebo (P<0.001). In the normotensive group the cold exposure increased SBP/DBP from 112/72 mmHg to 142/93 mmHg during carvedilol treatment (P<0.001) and from 121/75 mmHg to 147/98 mmHg during placebo (P<0.001). In the hypertensive group, the levels of SBP, DBP and MAP (mean arterial pressure) were significantly lower with carvedilol than with placebo during the cold exposure although carvedilol did not affect the cold-induced rise of the BP. The BPs were lower also with carvedilol in the normotensive group than the placebo during the cold exposure, but the differences were smaller than in the hypertensive group. Carvedilol decreased the BP more the higher the initial mean SBP/DBP was with placebo during the cold exposure. CONCLUSION: Carvedilol reduced the BP during the cold exposure, especially in the hypertensive subjects but also in normotensive ones, without effect on the cold-induced rise of the BP.     

厄贝沙坦单用及合用治疗轻、中度原发性高血压60例

目的 :比较国产厄贝沙坦单用以及与非洛地平或雷米普利合用对轻、中度原发性高血压的降压疗效。方法 :6 0例轻、中度高血压病人 ,经 2wk安慰剂导入期后 ,单服厄贝沙坦 15 0mg ,qd。 4wk后随机分 2组 ,分别联合服用非洛地平 5mg ,qd ,或雷米普利 5mg ,qd ,均为 4wk。治疗前及治疗后 4wk和 8wk行 2 4h动态血压监测 ,并测治疗前后坐位血压。结果 :厄贝沙坦单用 4wk后 ,坐位血压和2 4h动态血压均下降 (P <0 .0 5或P <0 .0 1) ,收缩压和舒张压的谷峰比值为 0 .82和 0 .86。厄贝沙坦与非洛地平或雷米普利合用 4wk后 ,坐位血压总有效率从 4 0 %增加为 89%和 70 % ;动态血压显示联合用药降压作用较明显。结论 :厄贝沙坦单用有长效的降压作用 ,与非洛地平或雷米普利联合用药有叠加降压作用     

Comparison of the efficacy and acceptability of nicardipine and propranolol, alone and in combination, in mild to moderate hypertension.

1. We evaluated the relative efficacies and tolerability of various low-dose combinations of nicardipine and propranolol in patients with mild-moderate essential hypertension (DBP Phase V of greater than 90-125 mmHg; WHO Grades I and II) in order to select the best one. 2. Sixty patients completed the double-blind, balanced, randomised three-way cross-over protocol, with each phase lasting 4 weeks, and in which twice daily nicardipine 40 mg or propranolol 80 mg was compared with four twice daily combinations of nicardipine (20 or 30 mg) plus propranolol (40 or 80 mg). 3. At 'peak' effect time (i.e., 2 h post-dosing) all four treatment combinations were significantly more effective than propranolol, with effects ranging from 9-23 mmHg (systolic) and 5-15 mmHg (diastolic). Only the two 30 mg nicardipine combinations with propranolol were more effective than nicardipine monotherapy, further reducing BP by 8-13 mmHg (systolic) and 5-7 mmHg (diastolic); there were no significant differences between them. 4. 'Trough' diastolic pressures were not different between treatments and 'trough' BP control was sub-optimal on all treatments. 5. 70% of patients on nicardipine monotherapy, 33% of those on propranolol monotherapy and 30% of patients during the placebo run-in complained of symptoms. In terms of complaint rates, there was little to choose between the four combinations (27-33%). Serum potassium and creatinine levels were elevated following propranolol monotherapy by 0.19 mmol 1-1 and 6.5 mumol 1-1 respectively (P less than 0.01 for both) and following the nicardipine 30 mg/propranolol 80 mg combination. Nicardipine monotherapy elevated serum T4 levels by an average of 0.57 ng dl-1 (P less than 0.05). 6. The twice daily combination of nicardipine 30 mg plus propranolol 40 mg was therefore the optimum one in terms of its efficacy and tolerability. Further studies need to be performed to test the hypothesis that a higher dose of propranolol might ameliorate troublesome vasodilator side effects. However, none of the treatments studied was ideal for clinical use in the twice daily dosage used in this study.