Ramipril and felodipine: a comparison of the efficacy and safety of monotherapy versus combination therapy

A multinational, double-blind, randomised study was conducted to investigate the efficacy and safety of a low-dose combination of the angiotensin converting enzyme inhibitor, ramipril, and the calcium antagonist, felodipine ER, in 642 patients with mild to moderate hypertension [supine diastolic blood pressure (DBP) = 95-115 mm Hg]. After a 4-week single-blind placebo run-in, patients were randomly allocated to once-daily felodipine extended release (ER; 2.5 mg), ramipril (2.5 mg) or felodipine ER/ramipril (2.5/2.5 mg) for 12 weeks. In the intention-to-treat analysis, mean DBP decreased significantly (p < 0.0001) after felodipine ER, ramipril and the combination (-9.1, -9.8 and -11.4 mm Hg, respectively). The decrease was significantly greater with the combination than with felodipine ER monotherapy (p = 0.02). The number of responding patients (final DBP < or = 90 mm Hg or a decrease of > or = 10 mm Hg) was also higher with the combination than with felodipine ER or ramipril monotherapy (65.1%, 53.1%, 55.7%, respectively). There were no differences between the three groups with respect to the incidence of adverse events overall or those considered treatment-related. There were fewer cases of peripheral oedema with combination therapy than with felodipine ER monotherapy. Thirty-three patients (5.1%) withdrew from the study because of adverse events, but there was no clear pattern with regard to the specific events leading to withdrawal. There were no clinically relevant changes in laboratory or clinical safety variables. Ramipril/felodipine ER 2.5/2.5 mg is an appropriate starting dosage when initiating combination antihypertensive therapy.     

Double-blind, parallel, comparative multicentre study of a new combination of diltiazem and hydrochlorothiazide with individual components in patients with mild or moderate hypertension

OBJECTIVE: To compare the antihypertensive efficacy and tolerability of a new combination preparation of diltiazem (150 mg) and hydrochlorothiazide (12.5 mg) with the individual constituents in patients with mild/moderate hypertension. DESIGN: Multi-centre, double-blind, randomised parallel group study. PATIENTS: Seventy-one patients with essential hypertension were recruited to the study. TREATMENT: Following completion of the placebo run-in period 63 patients fulfilled the prerandomisation criteria and entered the 10 week treatment period. Patients were randomised to receive either the combination preparation (D 150 mg/H 12.5 mg), diltiazem (150 mg) or hydrochlorthiazide (12.5 mg). The dosage was increased in three patients who had not attained target blood pressure (BP) control after 6 weeks. OUTCOME MEASURES: Response to treatment assessed by change from baseline in clinic and 24 h ambulatory BP. RESULTS: The proportion of patients achieving target BP (a reduction in resting supine diastolic blood pressure (DBP) to below 90 mm Hg or a reduction of 10 mm Hg from baseline) was 80% in the combination group, 55% in the diltiazem group, and 38% in the hydrochlorothiazide group. The respective figures for reduction in supine DBP from baseline were 13.5 mm Hg, 11.2 mm Hg and 5.9 mm Hg. A similar treatment order appeared throughout each of the efficacy variables. BP control throughout the 24 h dosing interval was demonstrated by ambulatory BP monitoring. Each treatment was well tolerated. CONCLUSION: This study provides clear evidence of the efficacy of combination therapy with diltiazem and hydrochlorothiazide in the management of patients with hypertension.     

A multifactorial trial design to assess combination therapy in hypertension. Treatment with bisoprolol and hydrochlorothiazide

BACKGROUND: The safety and effectiveness of different dosages and combinations of antihypertensive agents can be efficiently studied using a multifactorial trial design. In consultation with the Cardio-Renal Division of the Food and Drug Administration, we conducted a randomized, double-blind, placebo-controlled, 3 x 4 factorial trial of bisoprolol, a beta 1-selective adrenergic blocking agent, and hydrochlorothiazide. METHODS: A total of 512 patients with mild to moderate essential hypertension were randomized to once-daily treatment with bisoprolol (0, 2.5, 10, or 40 mg), hydrochlorothiazide (0, 6.25, or 25 mg), and all possible combinations. Diastolic and systolic blood pressures were monitored during this 12-week trial. RESULTS: The effects of bisoprolol and hydrochlorothiazide were additive with respect to reductions in diastolic and systolic blood pressures over the dosage ranges studied. The addition of hydrochlorothiazide (or bisoprolol) to therapy with bisoprolol (or hydrochlorothiazide) produced an incremental reduction in blood pressure. Dosages of hydrochlorothiazide as low as 6.25 mg/d contributed a significant antihypertensive effect. A hydrochlorothiazide dosage of 6.25 mg/d produced significantly less hypokalemia and less of an increase in uric acid levels than a dosage of 25 mg/d. The low-dose combination of bisoprolol, 2.5 mg/d, and hydrochlorothiazide, 6.25 mg/d, reduced diastolic blood pressure to lower than 90 mm Hg in 61% of patients and demonstrated a safety profile that compared favorably with that of placebo. CONCLUSIONS: The utility of factorial design trials to characterize dose-response relationships and to test the potential interactions between various antihypertensive agents has been demonstrated. The combination of low dosages of bisoprolol and hydrochlorothiazide may be a rational alternative to conventional stepped-care therapy for the initial treatment of patients with mild to moderate hypertension.     

Low-dose reserpine/thiazide combination in first-line treatment of hypertension: efficacy and safety compared to an ACE inhibitor

The concept of initiating treatment of mild-to-moderate hypertension with a low-dose combination of reserpine and the thiazide clopamide in comparison to monotherapy with an ACE inhibitor was investigated. A total of 127 adult outpatients with diastolic blood pressure between 100 and 114 mmHg were randomized into this double-blind, parallel group study. After a 2-week wash-out period and a subsequent 2-week placebo run-in period, they were allocated to once-daily treatment with 0.1 mg reserpine plus 5 mg clopamide (R/C), or 5 mg enalapril. If diastolic blood pressure was not normalized after 3 weeks of therapy (i.e. DBP < 90 mmHg), the dosage was doubled from week 4 to 6. The primary efficacy variables were the change from baseline in mean sitting diastolic and systolic blood pressure (DBP/SBP) after 3 weeks of therapy. Secondary variables included the change in DBP and SBP after 6 weeks of therapy, the BP normalization rates at 3 and 6 weeks and, concerning tolerability, the rates of adverse events after 6 weeks of therapy. An intent-to-treat analysis was performed. The reserpine/ clopamide and enalapril groups did not differ with regard to demographic and baseline characteristics (mean age 57 or 58 years, respectively; 63% or 56% males, respectively; mean SBP/DBP after the 2-week placebo period = 156 mmHg/104 mmHg in both groups). After 3 weeks of treatment with one capsule daily, mean SBP/DBP reduction from baseline (24 h after last medication intake) in the R/C combination group was -19.6/ -17.0 mmHg, in the enalapril group -6.1/ -9.5 mmHg (between-group comparison: 2p < 0.01 for both parameters). The normalization rates for DBP (< 90 mmHg) were 64.1% (R/C) and 28.6% (enalapril) (2p < 0.01). Adverse events that were considered possibly or definitely drug-related by the investigator were noted in 11 patients (17.2%) in the R/C group and in 9 patients (14.3%) in the enalapril group (NS). Two patients in the enalapril group discontinued the study prematurely due to adverse events (cough; skin eruption). In the treatment of mild-to-moderate hypertension, a low-dose combination of reserpine and clopamide once a day is considerably more effective than, and as tolerable as, 5-10 mg of enalapril once a day. These findings suggest that treatment with a combination of different antihypertensives with different modes of action in low doses is a rational alternative to conventional monotherapy in the first-line treatment of hypertension. Besides, the "old" reserpine-diuretic regimen also in these days appears to be a rational alternative to "modern" monotherapies.     

Valsartan and hydrochlorothiazide in patients with essential hypertension. A multiple dose, double-blind, placebo controlled trial comparing combination therapy with monotherapy

OBJECTIVE: This study compares the antihypertensive efficacy and tolerability of valsartan, a novel angiotensin II antagonist, given with hydrochlorothiazide (HCTZ) vs placebo or vs valsartan or HCTZ alone. DESIGN: 871 adult out-patients with essential hypertension participated in this double-blind study. Patients were randomised in equal number to receive either combination therapy of valsartan (80 mg or 160 mg) and HCTZ (12.5 mg or 25 mg), or valsartan (80 mg or 160 mg) or HCTZ (12.5 mg or 25 mg) alone, or placebo. Patients were treated once daily for 8 weeks and assessed at 2, 4 and 8 weeks after randomisation. MAIN OUTCOME MEASURES: The primary efficacy variable was change from baseline in mean sitting diastolic blood pressure (MSDBP) at end-point. The secondary variable was change in mean sitting systolic blood pressure (MSSBP) from baseline to end-point. RESULTS: All active treatments produced a statistically significant difference in MSDBP (P < 0.001) from baseline to end-point compared with placebo. Similar results were obtained for MSSBP. All combination regimens produced a statistically significantly greater reduction in MSDPB and MSSBP than the corresponding monotherapies. Dizziness and headache were the most common treatment-related adverse experiences reported. Hypokalaemia, associated with the use of thiazide diuretics, was more commonly reported in the higher dose HCTZ 25 mg groups. CONCLUSIONS: Valsartan 80 mg and 160 mg act additively with HCTZ 12.5 mg or 25 mg to lower MSDBP and MSSBP in patients with essential hypertension. The addition of HCTZ to valsartan 80 mg or 160 mg was well tolerated.     

Vectorcardiographic evaluation of myocardial infarct size: departure parameters are superior to conventional spatial parameters

OBJECTIVE: To measure the effects of losartan and amlodipine on peripheral capillary microcirculation in hypertension. SETTING: Medical out-patient clinic, Basel, in a university teaching hospital. METHODS: After a 4-week placebo run-in period 20 patients aged 50 +/- 8 (range 36-65) years with mild-to-moderate hypertension were randomly allocated to receive active treatment with losartan 50 mg titrated to losartan 50 mg/hydrochlorothiazide (HCT) 12.5 mg, or amlodipine 5 mg titrated to 10 mg for a 12 week period. Titration was performed if diastolic blood pressure (BP) was > or=90 mm Hg after 6 weeks of treatment. BP measurements as well as video capillary microscopy of the finger nailfold at the end of the placebo period and after 12 weeks of active treatment were compared. Capillary blood cell velocity was measured at rest and immediately, 1 min and 2 min after local finger cooling. RESULTS: After 3 months of treatment with amlodipine (n = 10) and losartan titrated to losartan-HCT (n = 10) sitting BP decreased significantly from 160 +/- 7/103 +/- 4 mm Hg and 147 +/- 7/98 +/- 6 mm Hg to 131 +/- 10/86 +/- 7 mm Hg and 134 +/- 17/89 +/- 9 mm Hg, respectively (P < 0.01). After local finger cooling the area under the curve (AUC) of capillary blood cell velocities was 1.13 +/- 0.58 mm (median +/- s.d.) at baseline and increased to 1.94 +/- 1.15 (P < 0.05) in losartan/losartan-HCT treated patients. In amlodipine treated patients the increase in AUC of capillary blood cell velocity did not reach the level of statistical significance (1.59 +/- 1.36 to 2.14 +/- 1.05 mm). CONCLUSION: This small trial shows that the area under the curve of capillary blood cell velocity increases in hypertensive patients treated with both losartan/losartan-HCT and amlodipine compared with baseline values.     

A case report of two siblings with familial leukoencephalopathy in normotensive male adults with alopecia and lumbago

The aim of the study was to examine the hypotensive efficacy and tolerance of bisoprolol in elderly patients. Sixty patients (40 <65 years and 20 >65 years) with mild-to-moderate essential hypertension (diastolic blood pressure (DBP) between 95 and 109 mm Hg) were included in the study. After a 2-week run-in period on placebo, patients began bisoprolol therapy (5 mg/d) for 12 weeks. After 4 weeks the dose was increased to 10 mg/d in those with a DBP > or =95 mm Hg. Additionally, in 10 patients over 65 years old, 24-h ambulatory BP monitoring (ABPM) was performed, after placebo and after bisoprolol (5 mg) administration. The hypotensive efficacy of bisoprolol in the elderly and younger patients was similar. Before and after treatment the mean difference of systolic BP (SBP) was 19.6 +/- 12.5 mm Hg and DBP 9.6 +/- 6.2 mm Hg in the younger patients and 16.1 +/- 13.6 mmHg and 9.5 +/- 6.0 mmHg in the elderly patients. Bisoprolol produced a similar reduction in heart rate (23.1% vs 17.1%) in the estimated groups. The tolerance of bisoprolol was good in both groups. There were no significant differences in adverse drug reactions between the groups.     

The impact of ibuprofen on the efficacy of antihypertensive treatment with hydrochlorothiazide in elderly persons

BACKGROUND: Nonsteroidal antiinflammatory drugs (NSAIDs) may alter blood pressure through their inhibitory effects on prostaglandin biosynthesis. Such potential hypertensive effects of NSAIDs have not been adequately examined in the elderly, who are the largest group of NSAID users. METHODS: We performed a randomized, double-blind, two-period crossover trial of ibuprofen (1800 mg per day) vs placebo treatment in patients older than 60 years of age with hypertension controlled with hydrochlorothiazide. While continuing their usual thiazide dosage, subjects were randomized to a 4-week treatment period (ibuprofen or placebo) followed by a 2-week placebo wash-out period and a second 4-week treatment period with the alternative therapy. Supine and standing systolic and diastolic blood pressures were measured weekly. RESULTS: Of 25 randomized subjects, 22 completed the study protocol (mean age = 73 +/- 6.7 years). Supine systolic blood pressure and standing systolic blood pressure were increased significantly with ibuprofen treatment, compared with placebo. Mean supine systolic blood pressures were 143.8 +/- 21.0 and 139.6 +/- 15.9 mmHg on ibuprofen and placebo, respectively (p = .004). Mean standing systolic blood pressures were 148.1 +/- 19.9 and 143.4 +/- 17.9 mmHg on ibuprofen and placebo, respectively (p = .002). CONCLUSION: We conclude that 1800 mg per day of ibuprofen does induce a significant increase in systolic blood pressure in older hypertensive patients treated with hydrochlorothiazide. NSAID therapy may negatively impact the control of hypertension in elderly patients.     

Main results of the losartan versus amlodipine (LOA) study on drug tolerability and psychological general well-being. LOA Study Group

OBJECTIVE: To compare two losartan regimens (with and without hydrochlorothiazide) and amlodipine in treating mild-to-moderate hypertension regarding their blood-pressure-lowering effect, drug tolerability and quality of life. DESIGN: A 12-week, randomized, double-blind, parallel-group, multi-centre study. After 4 weeks of placebo, patients with a diastolic blood pressure (DBP) in the range 95-115 mmHg were allocated randomly to be administered 50 mg losartan (increased to 100 mg if the DBP was 90 mmHg or more after 6 weeks), 50 mg losartan (plus 12.5 mg hydrochlorothiazide under the above conditions), or 5 mg amlodipine (increased to 10 mg under the above condition). The tolerability of the treatment and the quality of life were evaluated by spontaneous reporting, active questioning and the Psychological General Well-Being (PGWB) index. STUDY POPULATION: In total 898 hypertensives, mainly referred from primary health care (mean age 57.8 years) of whom 52% were men. RESULTS: Administration of 50 mg losartan (plus 12.5 hydrochlorothiazide if necessary) and of 5 mg amlodipine (or 10 mg if necessary) lowered the blood pressure as well as or better than did 50 mg losartan (or 100 mg if necessary). The incidence of 'any discomfort' and 'swollen ankles' increased with amlodipine but not with losartan treatment. The opposite was found for 'dizziness upon standing'. The incidence of drug-related adverse events and the number of patients withdrawn from therapy were higher with amlodipine than they were with losartan treatment. The PGWB index at week 12 indicated that improvements from baseline had occurred in some domains for the losartan groups whereas it remained unchanged for the amlodipine group. CONCLUSION: Both losartan and amlodipine were effective in lowering the blood pressure and were tolerated well. Administration of 50 mg losartan (plus 12.5 mg hydrochlorothiazide if necessary) and of 5 mg amlodipine (or 10 mg if necessary) lowered the blood pressure equally well or better than did 50 mg losartan (or 100 mg if necessary). Drug-related adverse effects and withdrawal from the study were more common for the amlodipine group. The clinical significance of the improvements in the PGWB index with losartan needs to be studied further.     

Ultrastructural immunolocalization of bone sialoprotein in guinea-pig osteoarthritis

OBJECTIVE: To compare the efficacy and tolerability of mibefradil and amlodipine in patients with uncomplicated mild-to-moderate essential hypertension. DESIGN: A double-blind, randomised, parallel group multicentre trial. METHODS: 239 patients received 50 mg mibefradil or 5 mg amlodipine for 4 weeks, followed by a forced titration to 100 mg mibefradil or 10 mg amlodipine for an additional 8 weeks. Patients then entered a 4-week withdrawal period either on therapy or switched to placebo. RESULTS: Statistically equivalent reductions in trough sitting diastolic blood pressure (SDBP) were observed after 12 weeks of once-daily treatment with 50/100 mg mibefradil (-11.5 +/- 8.2 mm Hg) and 5/10 mg amlodipine (-13.2 +/- 7.9 mm Hg). The number of patients with normalised SDBP (< or = 90 mm Hg) increased 23.3% in the mibefradil group and 19.5% in the amlodipine group (approximately 74% in both groups). Patients on mibefradil or amlodipine during the withdrawal period had significantly larger decreases in SDBP than those on placebo. Patients on mibefradil had a decrease in heart rate of 5.5 bpm. Patients on amlodipine had no change in heart rate; however, cessation of amlodipine was associated with a decrease in heart rate. CONCLUSIONS: Mibefradil was as effective as amlodipine in reducing BP; both compounds were effective treatments of hypertension.     

Antihypertensive effects of combined lisinopril and hydrochlorothiazide in elderly patients with systodiastolic or systolic hypertension: results of a multicenter trial

This study was aimed at evaluating the antihypertensive effect of lisinopril and hydrochlorothiazide administered in the fixed combination of 20 and 12.5 mg, respectively, on clinic and 24-h blood pressure in elderly patients (age, 68.8 +/- 5.8 years, mean +/- SD) with mild-to-moderate essential systodiastolic or isolated systolic hypertension. After a washout period of 4 weeks, patients received once daily lisinopril combined with hydrochlorothiazide for a 6-week period. At the end of the washout and treatment periods, clinic blood pressure was assessed 24 h after dosing, and 24-h ambulatory blood pressure was monitored, taking blood pressure readings every 15 min. Pretreatment clinic blood pressure was 171.3 +/- 14.0/103.7 +/- 5.1 mm Hg (systolic/diastolic) in the group with systodiastolic hypertension (n = 405) and 179.6 +/- 9.4/83.6 +/- 5.4 mm Hg in the group with isolated systolic hypertension (n = 165). The corresponding 24-h average blood pressures were 144.1 +/- 13.9/88.7 +/- 8.4 mm Hg (n = 114) and 150.7 +/- 15.5/80.8 +/- 9.4 mm Hg (n = 40). Clinic blood pressure was significantly reduced by treatment in both groups. This was the case also for ambulatory blood pressure, which was reduced by 9.6 +/- 0.9%/9.9 +/- 0.9% in systodiastolic and by 11.8 +/- 1.3%/8.5 +/- 1.5% in isolated patients with systolic hypertension (p < 0.05 at least for all differences). The antihypertensive effect was similar in patients older and younger than 70 years. In all groups, it was manifest both during the day and the nighttime and was still significant after 24 h. Thus single daily administration of combined lisinopril-hydrochlorothiazide effectively reduces blood pressure in elderly patients with hypertension.     

Centralized i.v. team provides inpatient and home-care treatment

AIM: The study of the effects of the inhibitor of angiotensin converting enzyme ramipril (tritace) on the 24-h profile of blood pressure (BP) in patients with mild and moderate arterial hypertension. MATERIALS AND METHODS: Ramipril was given to 21 males aged 45-68 years with essential hypertension stage II (WHO criteria) with stable elevated diastolic blood pressure (95-114 mm Hg) in a single dose 2.5-10 mg/day. Captopril controls received 100 mg twice a day. BP was monitored using "SpaceLabs Medical" unit (model 90207, USA). RESULTS: Compared to placebo, ramipril lowered systolic and diastolic blood pressure both for the 24-h period and in the day time; captopril lowered only diastolic BP in the day time. Side effects of long-term application of ramipril occurred 2 times less frequently than in application of captopril. CONCLUSION: Long-term treatment with ramipril in the above regimen provides more effective control of BP than captopril in the above doses in patients with mild and moderate hypertension.     

Evaluation of the tolerance and effectiveness of Diltiazem LP 300 mg in hypertensive patients with chronic renal insufficiency

31 male and female patients, between the ages of 18 and 65 years, presenting mild-to-moderate hypertension (DBP between 95 and 114 mmHg) and stable chronic renal failure (creatinine clearance between 60 and 25 ml/min) after a preinclusion placebo phase were included in a multicentre open study designed to evaluate the clinical, electrocardiographic and laboratory safety, as well as the antihypertensive efficacy of Diltiazem 300 mg Retard, as monotherapy for 3 months, or combined with a diuretic (furosemide) or angiotensin converting enzyme inhibitor (captopril) for 45 days. After an 8-day placebo run-in period, the study consisted of a 45-day phase of strict monotherapy with Diltiazem 300 mg Retard, followed by a final 45-day phase during which either monotherapy was continued (if safety was satisfactory and supine DBP < or = 90 mmHg), or two-agent combination therapy was instituted (when supine DBP was between 91 and 115 mmHg), 6 clinical evaluations were performed during the 3 months of this trial. Overall, 21 patients (mean age: 50 +/- 14 years) completed the study until the 3rd month: 13 remained on monotherapy, and 8 required two-agent combination therapy. Supine and standing systolic and diastolic blood pressures and heart rate were significantly decreased. The number of responding patients controlled (supine DBP < or = 90 mmHg) progressed between D10 (40%) and D90 (57%). The observed adverse events and reasons for drop-outs from the trial for adverse events were mostly related to the vasodilator effects of Diltiazem. The cardiac safety was good, with no significant variation of the PR interval on the ECG (0.15 +/- 0.03 sec on D-8, 0.17 +/- 0.02 sec on D90). No marked modification of blood and urinary laboratory constants (serum electrolytes, blood glucose, liver function tests) was observed during this trial. Renal function, evaluated by creatinine clearance, was not altered by treatment (40.5 +/- 15.2 ml/min on D0, 41.7 +/- 16.9 ml/min on D90). Overall, this study confirmed the good clinical, laboratory and electrocardiographic safety as well as the antihypertensive efficacy of Diltiazem 300 mg Retard administered as monotherapy for 3 months or possibly in combination for 45 days, in hypertensive patients with chronic renal failure.     

A randomised crossover comparison of reserpine and sustained-release nifedipine in hypertension

OBJECTIVE: To compare the effectiveness of the combination of hydrochlorothiazide (HCT) plus sustained-release nifedipine with the combination of HCT plus reserpine in lowering high blood pressure (BP) unresponsive to HCT monotherapy. DESIGN: An open, randomised crossover drug trial. SETTING: Outpatients' clinic in Parirenyatwa Hospital, Harare, a tertiary referral centre. SUBJECTS: 32 Black patients of both sexes with newly diagnosed or previously treated hypertension aged between 21 and 65 years who had a BP > 140/95 after receiving HCT 25 mg daily for four weeks were studied. INTERVENTION: Patients were kept on HCT 25 mg daily and were randomised to receive either reserpine 0.25 mg daily or nifedipine (Adalat Retard) 20 mg bd for four weeks. This was followed by a two week washout period during which patients received HCT 25 mg daily only. After the washout period patients were crossed over to the alternative treatment for four weeks. Patients were kept on HCT 25 mg daily throughout the trial. MAIN OUTCOME MEASURES: The main outcome measure was the fall in BP which was taken as the difference between the BP at baseline and the BP at the end of each treatment period. Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) measurements were taken. RESULTS: Both second line drugs were effective in lowering SBP and DBP and there was no significant difference between them. Nifedipine reduced SBP by 18.9 mmHg (95% CI 12.1 to 25.7) and DBP by 9.6 mmHg (95% CI 7.2 to 12.0). Reserpine reduced SBP by 15.9 mmHg (95% CI 8.4 to 23.4) and DBP by 11.1 mmHg (95% CI 7.5 to 14.6). However, only two patients attained the target DBP of < or = 90 mmHg after each active treatment period. CONCLUSION AND RECOMMENDATIONS: Since both agents were equally effective in reducing both SBP and DBP and reserpine is much cheaper than nifedipine, it is recommended that for a developing country like Zimbabwe, the combination of HCT and reserpine at the above doses should be used as the first step to treat mild to moderate hypertension without evidence of end organ damage. However, further trials should compare BP lowering effects as well as end organ protection offered by the trial drugs.     

Quality of life before and during antihypertensive treatment: a comparative study of celiprolol and atenolol

BACKGROUND: The well-being of hypertensive patients may be adversely affected by the disease itself, its complications, and other concomitant processes such as anxiety, sedation, and side effects of the prescribed drugs. Some recently developed antihypertensive agents have been suggested to be devoid of these deleterious effects on well-being expressed as quality of life. OBJECT: We compared the effect on quality of life of a standard cardioselective beta-blocker atenolol to the effect of celiprolol as a representative of a new class of selective beta-blockers with vasodilatory properties. One-hundred-thirty-two patients with mild to moderate hypertension were eligible to enter a 28-week double-blind parallel-group study, consisting of a 4-week run-in period on placebo and a 24-week period on dosage-adjusted treatment with either atenolol or celiprolol. RESULTS: Both systolic and diastolic blood pressure were assessed, as was quality of life perception by a selected test battery including the Quality of Life Questionnaire of Bulpitt and Fletcher [1990]. During celiprolol treatment, supine blood pressure fell from 167/101 (range 120-200/95-116) to 150/92 mm Hg (p < 0.0001). This antihypertensive effect was at least as good with celiprolol as with atenolol. Quality of life perception was comparable for the 2 drugs, although some adverse effects were more frequent during atenolol than during celiprolol, particularly after prolonged treatment. Also patient compliance was better for celiprolol than for atenolol. CONCLUSIONS: Our results show that the selective beta-blocker with vasodilatory property celiprolol is at least as effective as atenolol and that it has additional advantage in terms of enhancement of some quality of life variables.     

A case of intraplacental choriocarcinoma associated with placental hemangioma

Disorders in peripheral microcirculation are observed in arterial hypertension and may be improved by antihypertensive treatment. In this pilot study the authors measured capillary blood cell velocity in the finger nailfold in 14 patients (mean age 50 +/- 14 years, range 30-71 years; 9 men, 5 women) with mild-to-moderate essential hypertension. After a 3-week placebo period, patients received double-blind randomized treatment with either 0.2- to 0.4-mg moxonidine (n=7) or 2.5- to 5.0-mg cilazapril (n=7). Finger nailfold video capillaroscopy was performed at baseline and after 8 weeks of treatment. Blood pressure was measured by conventional office technique. Capillary blood cell velocity, 1 minute after local finger cooling, increased in the Moxonidine group (0.65 +/- 0.53 mm/sec to 1.13 +/- 0.77 mm/sec; p<0.05) after 8 weeks treatment compared to the baseline. The increase in the Cilazapril group from 0.79 +/- 0.45 mm/sec to 0.93 +/- 1.03 mm/sec did not reach a level of statistical significance. Blood pressure decreased from 151 +/- 8/101 +/- 5 to 147 +/- 6/98 +/- 7 mmHg in the Moxonidine group and from 164 +/- 12/102 +/- 6 to 140 +/- 9/93 +/- 9 mmHg in the cilazapril group. Moxonidine increased nailfold capillary blood cell velocity 1 minute after local finger cooling in patients with mild-to-moderate hypertension. This improvement of the peripheral microcirculation may be associated with reversal of vascular dysfunction in hypertension.     

Low-dose antihypertensive therapy with 1.5 mg sustained-release indapamide: results of randomised double-blind controlled studies. European study group

OBJECTIVE: In accordance with international recommendations on the need to decrease doses of antihypertensive drugs, a low-dose (1.5 mg) sustained-release (SR) formulation of indapamide was developed to optimize the drug's efficacy : safety ratio. The aim of this work was to evaluate the benefit of a low-dose diuretic by consolidating the efficacy and safety results of two clinical trials with a similar design. PATIENTS AND METHODS: Clinical data were obtained in two European randomized double-blind studies with 690 mild to moderate hypertensive patients (95 mmHg < or = supine diastolic blood pressure < or = 114 mmHg using a mercury sphygmomanometer) treated respectively for 2 and 3 months, with a mean age of 53 and 57 years, 44 and 57% males, mean supine diastolic blood pressure of 100.6 and 102.5 mmHg and mean supine systolic blood pressure of 161.0 and 164.5 mmHg. RESULTS: The first study, a dose-finding study with indapamide SR at 1.5, 2 and 2.5 mg versus placebo and the immediate-release (IR) formulation of indapamide, showed that the 1.5 mg dosage of the new indapamide formulation had an improved antihypertensive efficacy : safety ratio. The second study confirmed the equivalence of blood pressure reductions with 1.5 mg indapamide SR and 2.5 mg indapamide IR, and better acceptability with 1.5 mg indapamide SR, particularly in the number of patients with serum potassium levels < 3.4 mmol/l, which was reduced by more than 50%. The long-term efficacy of 1.5 mg indapamide SR was observed through a 9-month open-treatment follow-up to the second study. CONCLUSION: The 1.5 mg SR formulation of indapamide has an improved antihypertensive efficacy : safety ratio, which is in accordance with international recommendations for the use of low-dose antihypertensive drugs and diuretics in first-line therapy of hypertension.     

Laparoscopic repair of chronic traumatic diaphragmatic hernia: case report and review of the literature

This study compared the efficacy and tolerability of nisoldipine coat core (CC) 10-40 mg o.d. and hydrochlorothiazide (HCTZ) 25-50 mg o.d. Patients with mild-to-moderate essential hypertension received either nisoldipine CC 10 mg o.d. or HCTZ 25 mg o.d. Treatment was titrated at two-weekly intervals as necessary. The primary efficacy endpoint was a defined reduction in diastolic blood pressure (DBP). Response rates were similar for both the nisoldipine CC- and HCTZ-treated groups (74% and 70%, respectively). Secondary efficacy endpoints were reductions in both diastolic and systolic blood pressures (SBP). At treatment endpoint, the change from baseline in SBP was 16.2 mmHg for the nisoldipine CC group and 14.9 mmHg for the HCTZ group. Both drugs were well tolerated, and adverse events were generally minor and typical of these antihypertensive agents. Drug-related adverse events were greater in the nisoldipine CC- than the HCTZ-treated patients (50% and 37%, respectively). Nisoldipine CC was shown to demonstrate antihypertensive efficacy similar to HCTZ in the treatment of mild-to-moderate hypertension.     

Effect of betaxolol on blood pressure and heart rate in mild to moderate hypertension

The efficacy and safety of daily 20 mg betaxolol monotherapy was investigated in mild-moderate essential hypertension in a four week long, open label, single blind trial (with a placebo run-in). Twenty one patients of both sexes were enrolled. The systolic blood pressure in the supine position decreased from 158 to 142 mmHg, the diastolic blood pressure from 101 to 89 mmHg. The mean systolic values of the 24 hours ambulatory blood pressure monitoring decreased from 136 to 126 mmHg, the mean diastolic values from 87 to 80 mmHg. All decreases in blood pressure were significant. The reduction of the heart rate (80/min vs 63/min) was also significant. The decrease in blood pressure during daytime was significant, during night it was moderate. The blood pressure- and heart rate reducing effect of betaxolol was detectable however in the second half of the night, before wake-up. No side effect was recorded.     

Evaluation of the efficacy and tolerability of a low-dose combination of isradipine and spirapril in the first-line treatment of mild to moderate essential hypertension

To investigate the concept of initiating therapy with low doses of a calcium antagonist and an ACE inhibitor, a fixed combination of isradipine 2.5 mg plus the ACE inhibitor spirapril 3 mg was compared with its components, with the full-dose monotherapies (isradipine 5 mg or spirapril 6 mg), and with placebo. After a 2-week wash out phase in pretreated patients and a subsequent 2-week placebo period, 405 patients with a diastolic blood pressure (DBP) between 100 and 114 mmHg were randomly allocated to 12-week once-daily double-blind treatment in one of the six treatment arms. In patients whose blood pressure was not normalized (defined as DBP< or =90 mmHg) after 6 weeks of treatment, the dosage of either medication was doubled or, in the placebo group, was switched to the fixed combination. After week 6, the mean reductions from baseline in sitting systolic/diastolic blood pressure 24 hours after dosing (trough) for the fixed combination or the monotherapies isradipine 5 mg, isradipine 2.5 mg, spirapril 6 mg, spirapril 3 mg, and placebo were 10.4/8.7, 10.0/9.4, 6.5/6.7, 10.0/8.3, 7.0/5.8, and 2.2/4.7 mmHg, respectively. The blood pressure changes obtained with the low-dose fixed combination were essentially identical to those observed with the full-dose monotherapies, thus showing an additive effect of low-dose isradipine and spirapril. In terms of tolerability, the lowest rate of any adverse events was found in the combination group. In this group, typical adverse events of calcium antagonists, such as headache, flushing, ankle edema, or palpitations, were observed only in 5%, 2%, 1%, and 0%, respectively, dry cough, considered typical for ACE inhibitors, was observed in only 1% of the combination group. In conclusion, the low-dose components isradipine 2.5 mg and spirapril 3 mg were shown to have an additive effect when combined, exerting a blood pressure-lowering effect comparable with the full doses and a trend to a better tolerability profile in comparison with the standard doses. Thus, low-dose combination therapy with these drugs appears to be a rational alternative to conventional monotherapy in the first-line treatment of hypertension.