The antihypertensive and metabolic effects of low and conventional dose cyclopenthiazide in type II diabetics with hypertension.

The antihypertensive efficacy and metabolic effects of cyclopenthiazide 125 micrograms were compared with cyclopenthiazide 500 micrograms in patients with non-insulin dependent diabetes and hypertension in a double blind, randomized crossover study. After a 6-week placebo period 24 patients with non-insulin dependent diabetes mellitus, stabilized on diet or oral hypoglycaemic agents, who had a mean diastolic blood pressure between 90 and 120 mmHg after receiving placebo for 6 weeks were given 125 micrograms or 500 micrograms cyclopenthiazide for 12 weeks. Patients then received placebo for a further 6-week period, following which they received the alternate treatment dosage for 12 weeks. There were no differences between doses in their antihypertensive effects. While 500 micrograms significantly reduced systolic and diastolic blood pressures, only diastolic pressure was significantly reduced by 125 micrograms from pre-treatment values. The higher dose of cyclopenthiazide had greater effects on measures of diabetic control than did the 125 micrograms dose and the rise in blood glucose after 12 weeks' treatment with 500 micrograms was significantly different from pre-treatment values. Cyclopenthiazide 125 micrograms had significantly less effect on triglycerides, potassium and urate, than did 500 micrograms. Cyclopenthiazide 500 micrograms resulted in a significant fall in serum potassium from pre-treatment values. There were no intertreatment differences in the other variables measured. Cyclopenthiazide 125 micrograms is as effective as 500 micrograms in reducing diastolic blood pressure in mildly hypertensive non-insulin dependent diabetic patients. The higher dose had more pronounced adverse effects on glucose control and serum concentrations of triglycerides, potassium and urate.     

Low-dose Cyclopenthiazide in the Treatment of Hypertension: A One-year Community-based Study

After an 8-week placebo period, 73 patients whose diastolicblood pressures were between 90 and 110 mmHg were randomly assignedto receive 125 µg (low dose) or 500 µg of cyclopenthiazide(standard dose) for a period of one year. Blood pressure wasmeasured in the patient's home by the same observer at two-weeklyintervals during an 8-week placebo run-in period, every 4 weeksfor a further 12 weeks and at 24, 36 and 52 weeks thereafter.Serum potassium, urate, glucose, glycosylated haemoglobin, totaland HDL cholesterol, and apolipoproteins were measured at theend of the placebo period and at 4, 8, 24 and 52 weeks of activetreatment. Twelve of the 73 patients had an inadequate antihypertensiveresponse—five on the higher dose and seven on the lowerdose. One patient receiving 500 µg was withdrawn becauseof adverse effects. In the remaining 60 patients, systolic anddiastolic blood pressures were significantly reduced when comparedwith pretreatment values in both treatment groups throughoutthe one year period. The decreases in blood pressure were notsignificantly different from each other (p>0.65). Three patientson 500 µg required potassium supplements. Maximum decreasesin the serum potassium of 0.52 mmol/l(500 µg dose) and0.14 mmol/l(125 µg dose) were observed at 24 weeks oftreatment in the remaining 57 patients. The differences betweenthe two doses at this time were statistically significant (p< 0·05), as were the increases in serum urate observedat 4, 8 and 24 weeks (p<0.05). Five hundred micrograms ofcyclopenthiazide increased total serum cholesterol at eightand 24 weeks (0.35, 0.36 mmol/l respectively) when comparedwith pretreatment values (p<0.01) and almost achieved statisticalsignificance when compared with the corresponding low dose value(p = 0.066). This study confirms that 125 µg of cyclopenthiazideis a useful antihypertensive agent with a favourable metabolicprofile which is maintained in the long term.     

The Antihypertensive and Metabolic Effects of Low and Conventional Dose Cyclopenthiazide in Type II Diabetics with Hypertension

The antihypertensive efficacy and metabolic effects of cyclopenthiazide125 µg were compared with cyclopenthiazide 500 µgin patients with non-insulin dependent diabetes and hypertensionin a double blind, randomized crossover study. After a 6-weekplacebo period 24 patients with non-insulin dependent diabetesmellitus, stabilized on diet or oral hypoglycaemic agents, whohad a mean diastolic blood pressure between 90 and 120 mmHgafter receiving placebo for 6 weeks were given 125 µgor 500 µg cyclopenthiazide for 12 weeks. Patients thenreceived placebo for a further 6-week period, following whichthey received the alternate treatment dosage for 12 weeks. Therewere no differences between doses in their antihypertensiveeffects. While 500 µg significantly reduced systolic anddiastolic blood pressures, only diastolic pressure was significantlyreduced by 125 µg from pre-treatment values. The higherdose of cyclopenthiazide had greater effects on measures ofdiabetic control than did the 125 µg dose and the risein blood glucose after 12 weeks' treatment with 500 µgwas significantly different from pre-treatment values. Cyclopenthiazide125 µg had significantly less effect on triglycerides,potassium and urate, than did 500 µg. Cyclopenthiazide500 µg resulted in a significant fall in serum potassiumfrom pre-treatment values. There were no intertreatment differencesin the other variables measured. Cyclopenthiazide 125 µgis as effective as 500 µg in reducing diastolic bloodpressure in mildly hypertensive non-insulin dependent diabeticpatients. The higher dose had more pronounced adverse effectson glucose control and serum concentrations of triglycerides,potassium and urate.     

Clinical Efficacy and Safety of Lower-Dose Indapamide Therapy in the Treatment of Patients with Mild to Moderate Hypertension

Previous clinical studies with indapamide, an indoline antihypertensive drug with diuretic and vasodilating activities, have shown a dose relationship associated with potassium loss. Two placebo-controlled, randomized, double-blind, parallel clinical studies were, therefore, done to evaluate the safety and efficacy of a low dose (1.25 mg) of indapamide and to determine if an improved safety profile could be produced while maintaining efficacy with a 1.25-mg dose in patients with mild to moderate essential hypertension. Four hundred seventeen (417) adult patients with mild to moderate essential hypertension (sitting diastolic blood pressure greater-than-or-equal 95 mmHg and less-than-or-equal 110 mmHg) were enrolled in two clinical studies; 209 patients were randomized to indapamide 1.25 mg and 208 patients to placebo. Patients received single-blind placebo for a 4-week washout period followed by an 8-week double-blind treatment period during which patients received either indapamide 1.25 mg or placebo. The primary efficacy endpoint was the mean change from baseline to week 8 in sitting diastolic blood pressure. Secondary efficacy variables were the proportion of patients whose sitting diastolic blood pressure had decreased greater-than-or-equal 10 mmHg and/or had a sitting diastolic blood pressure of less-than-or-equal 90 mmHg (treatment success) at all visits and at endpoint, mean changes from baseline in sitting diastolic blood pressure at designated timepoints and at endpoint, and mean changes from baseline in standing diastolic blood pressure and in sitting and standing systolic blood pressure at all visits and at endpoint. Results of these trials were pooled in order to have a larger patient population in an attempt to detect trends not readily apparent with a smaller sample size. In the primary analysis, indapamide produced statistically significantly (p = 0.0001) greater reductions in sitting diastolic blood pressure than placebo after 8 weeks of therapy. In the secondary analysis, the percentage of indapamide-treated patients who achieved treatment success after 8 weeks of therapy was statistically significantly (p < 0.0001) higher compared to placebo-treated patients. In addition, indapamide produced a statistically significantly (p = 0.0001) superior reduction compared to placebo in sitting systolic and standing systolic and diastolic blood pressure after 8 weeks of therapy. The incidence of drug-related adverse events between patients in the indapamide and placebo groups was similar. There were no clinically meaningful differences in laboratory values, including serum potassium, between the patients in the indapamide and placebo groups. Low-dose (1.25 mg) indapamide proved to be safe and effective in the treatment of mild to moderate hypertension.     

A Study of the Efficacy and Safety of Moexipril in Mild to Moderate Hypertension

This placebo-controlled, double-blind, multicenter study examined the efficacy, safety, and tolerability of the angiotensin-converting enzyme inhibitor, moexipril, in lowering blood pressure in mildly to moderately hypertensive patients. Patients were initially randomized into four groups, two of which received moexipril 7.5 mg per day and two received moexipril 15 mg per day, for first 12 weeks of treatment. Patients then entered a withdrawal phase with one of the groups in each dose category continuing that dose of moexipril and one receiving placebo for 12 more weeks. From 223 patients randomized initially, 190 completed the 12-week withdrawal phase. In the two dosage groups from baseline to 12 weeks, sitting diastolic blood pressure decreased from 101.1 to 92.8 mm Hg for the 7.5-mg group and from 100.7 to 91.3 mm Hg for the 15-mg group (p < 0.05 baseline to week 12 in both groups) with a significant difference between those groups attained at week 12 only (p = 0.03). By the end of the withdrawal phase (24-week evaluation), the group that continued to receive 7.5 mg moexipril decreased diastolic blood pressure by 8.2 mm Hg, whereas the corresponding placebo group decreased diastolic blood pressure by 3.7 mm Hg. Although the difference between these two groups was not significant at the 24-week end point, all other time points differed significantly between groups at p less-than-or-equal 0.017. Similarly, whereas the corresponding placebo group had a mean reduction in diastolic blood pressure of 4.6 mm Hg, the group that continued 15 mg of moexipril showed a mean diastolic blood pressure reduction of 10.6 mm Hg (p < 0.001 between groups). No comparison between the two moexipril dosage groups was significant, however, during the withdrawal phase. These results during medication withdrawal indicate that moexipril is effective in significantly lowering diastolic blood pressure.     

Diurnal blood pressure in patients with mild-to-moderate hypertension treated with once-daily benazepril hydrochloride

This study evaluated the blood pressure effects of administration of once daily oral benazepril hydrochloride, a new angiotensin-converting enzyme (ACE) inhibitor, for mild-to-moderate hypertension. After a 2 to 4 week placebo baseline period, patients with diastolic blood pressure between 95 and 114 mm Hg, were randomized to receive either placebo or benazepril hydrochloride, 5, 10, 20, or 40 mg, once daily in double-blind fashion for 28 days. Blood pressure was measured predose and at 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 hours after the dose during inpatient observation days at the end of the placebo baseline period, and on the first and last day of the double-blind treatment period; and 24 hours after the dose at weekly outpatient visits. All doses of benazepril hydrochloride resulted in clinically important reductions in diastolic and systolic blood pressures that lasted between 12 and 24 hours after both the first dose, and following the last dose after 4 weeks of treatment. The findings indicate that benazepril hydrochloride may be clinically useful as once-daily monotherapy in many patients with hypertension.     

The Antihypertensive Properties of the Angiotensin-Converting Enzyme Inhibitor Moexipril Given Alone or in Combination with a Low Dose of a Diuretic

The antihypertensive characteristics of the angiotensin-converting enzyme inhibitor moexipril were evaluated in 413 patients with baseline setting diastolic blood pressures between 95 and 114 mm Hg. The study was double blind, with patients randomized to placebo or to differing doses of moexipril alone or in combination with a low dose of hydrochlorothiazide. Compared with placebo, moexipril 3.75 mg daily was not different, but single daily doses of 7.5, 15, and 30 mg were significantly more effective (as measured at trough, approximately 24 h after dosing) in decreasing the diastolic blood pressuring during an 8-week treatment period. The dose-response relationship indicated that no additional blood-pressure-lowering effect occurred above 15 mg daily. Hydrochlorothiazide 12.5 mg was not significantly more effective than placebo, but the combinations of the diuretic with moexipril doses of 3.75, 7.5, and 15 mg all produced significant antihypertensive actions. Interestingly, the 3.75-mg moexipril--hydrochlorothiazide combination was equally as efficacious as the higher doses. The combinations were all more effective than their respective moexipril and hydrochlorothiazide monotherapies. There were no meaningful laboratory changes except for decreased potassium concentrations in the patients on diuretic alone; this effect was attenuated in the low-dose moexipril combination. Only 14 of the 413 patients who entered the double-blind study period (3%) discontinued treatment because of adverse experiences. Thus, moexipril is a well-tolerated drug that has clear antihypertensive efficacy as a single agent in once-daily doses of 7.5--30 mg. When combined with hydrochlorothiazide 12.5 mg, it is effective in daily doses as low as 3.75 mg.     

Safety and Efficacy of Once-Daily Captopril Plus Hydrochlorothiazide versus Nifedipine Gastrointestinal Therapeutic System in Black Patients with Mild to Moderate Hypertension

The safety and efficacy of captopril plus hydrochlorothiazide (HCTZ) were compared to nifedipine gastrointestinal therapeutic system (GITS) in 145 randomly assigned black patients with mild to moderate hypertension. Following a 4-week placebo lead-in, patients received captopril plus HCTZ 25/15 mg or nifedipine GITS 30 mg for up to 12 weeks. Upward dose titration was permitted at weeks 3 and 6. Mean seated systolic and diastolic blood pressures decreased 16.1 ± 13.5 mm Hg and 11.5 ± 7.4 mm Hg, respectively, with captopril plus HCTZ. Statistically similar decreases were observed with nifedipine GITS: systolic, 19.3 ± 12.2 mm Hg; diastolic, 13.8 ± 7.2 mm Hg. There were no clinically significant between-group differences in serum chemistries. Edema was reported in 20.3% of nifedipine GITS patients versus 1.4% of captopril plus HCTZ patients (p = 0.001). The two regimens were equally effective in controlling blood pressure in black patients; however, a higher incidence of edema occurred with nifedipine GITS compared to captopril plus HCTZ.     

The effects of the long-acting angiotensin-converting enzyme inhibitor cilazapril on casual, exercise, and ambulatory blood pressure

We assessed blood pressure (BP) and heart rate (HR) responses in a double-blind, randomized study comparing cilazapril, a long-acting, nonsulfhydryl-group converting enzyme inhibitor, with placebo in 18 patients with mild to moderate (sitting diastolic BP, 95 to 114 mm Hg) essential hypertension. The BP and HR parameters were evaluated at rest (casual, 24 hours after administration), during treadmill exercise testing (Bruce protocol), and with 24-hour noninvasive ambulatory BP monitoring. These assessments were made after a 4-week drug washout period and after 8 to 12 weeks of therapy. After 8 weeks of therapy with cilazapril (mean dose 3.6 +/- 0.9 mg/day), casual BP decreased 19/11 mm Hg (p less than 0.01), whereas placebo lowered BP by 4/5 mm Hg (difference not significant) compared with the baseline period. The casual HR was modestly (7 beats/min) but significantly (p less than 0.05) lowered by cilazapril monotherapy. Exercise BP was reduced by cilazapril (reduction at peak HR, 23/11 +/- 10/5 mm Hg; p less than 0.05), and exercise HR was unchanged. Compared with baseline, the duration of exercise was improved with cilazapril but not with placebo (1.0 minute vs -0.2 minute; p less than 0.05). Twenty-four-hour mean, awake, and sleep BPs were reduced with cilazapril with the most impressive reduction occurring during the awake period (19/12 mm Hg; p less than 0.01). These data demonstrate that cilazapril lowers casual, exercise, and ambulatory BP with a modest but significant improvement in exercise time. Thus cilazapril may be particularly effective in the physically active hypertensive patient.     

A placebo-controlled comparison of the efficacy and tolerability of candesartan cilexetil, 8 mg, and losartan, 50 mg, as monotherapy in patients with essential hypertension, using 36-h ambulatory blood pressure monitoring

This double-blind, randomised, controlled study compared the efficacy of candesartan cilexetil 8 mg (n = 87) and losartan 50 mg (n = 89), once daily for 6 weeks, relative to placebo (n = 80) in patients with mild-to-moderate essential hypertension (diastolic blood pressure (DBP): 95-115 mmHg). Ambulatory BP measurements were done every 15 min over 36 h. At the end of the 6-week treatment, the mean change in DBP between the baseline and the 0-24-h period after the last dose of study medication was greater in patients receiving candesartan cilexetil 8 mg (-7.3 mmHg +/- 6.9 mmHg) compared with losartan 50 mg (-5.1 mmHg +/- 4.9 mmHg) (p < 0.05) or placebo (0.3 mmHg +/- 6.5 mmHg) (p < 0.001). The mean change in systolic BP (SBP) during this time was greater in patients receiving candesartan cilexetil 8 mg (-10.8 mmHg +/- 11.3 mmHg), or losartan 50 mg (-8.8 mmHg +/- 8.9 mmHg) than placebo (1.2 mmHg +/- 9.9 mmHg) (p < 0.001). Candesartan cilexetil 8 mg was associated with a greater reduction in DBP and SBP, relative to placebo, when compared with losartan 50 mg, during both daytime and night-time, and between 12 and 24 h after dosing (p < 0.001). Both active treatments were well tolerated. In patients with mild-to-moderate essential hypertension, candesartan cilexetil 8 mg therefore had greater, more consistent antihypertensive efficacy throughout the day and the night, and long-lasting efficacy after the last dose, compared with losartan 50 mg. This greater efficacy is maintained with an excellent tolerability associated with members of the angiotensin Il type 1-receptor blocker class.     

The efficacy of telmisartan compared with perindopril in patients with mild-to-moderate hypertension

In this study, efficacy of the angiotensin II type 1 receptor blocker telmisartan given as monotherapy was compared with that of perindopril monotherapy in patients with mild-to-moderate hypertension. After a 2-week, single-blind, placebo run-in period, 60 patients were randomised to double-blind, once-daily treatment with telmisartan 80 mg or perindopril 4 mg for 6 weeks. Clinic and ambulatory blood pressure measurements and clinical laboratory evaluation were performed at the end of the placebo run-in and active treatment phases. Both telmisartan and perindopril significantly (p < 0.0001) reduced clinic systolic blood pressure (SBP) and diastolic blood pressure (DBP) compared with baseline values. Also, both drugs significantly (p < 0.0001) reduced 24-h mean ambulatory SBP and DBP compared with baseline. Comparison of the mean hourly antihypertensive activities showed that the reduction in mean ambulatory DBP for the last 8 h of the dosing interval was significantly greater (p < 0.05) in telmisartan-treated patients. A 24-h mean DBP of <85 mmHg was observed in 66.6% of the telmisartan-treated patients but in only 46.6% of the perindopril-treated patients (p < 0.05). It is concluded that telmisartan and perindopril both produce significant reductions in clinic SBP and DBP, but the mean reduction in ambulatory DBP during the last 8 h of the dosing interval is greater in patients treated with telmisartan.     

Nitrendipine does not impair long-term glucose control in hypertensive noninsulin-dependent diabetic patients

The subjects, 15 noninsulin-dependent diabetic hypertensive patients (mean age, 61 years) and 15 nondiabetic hypertensive patients (mean age, 60 years), received placebo for four weeks and then 20 to 40 mg of nitrendipine once daily for 24 weeks. At the end of the placebo period their blood pressures were greater than or equal to 160 mmHg systolic or greater than or equal to 95 mmHg diastolic. Blood pressures declined significantly during treatment in both patient groups; after 24 weeks, 13 of 15 diabetic patients and 12 of 15 nondiabetic patients were normotensive (diastolic blood pressure less than 90 mmHg). Meanwhile, heart rate, indices of glycemic control (serum glucose, hemoglobin A1c, fructosamine, and C-peptide levels), and serum lipids (cholesterol, high-density cholesterol, triglycerides, apolipoprotein A1 and B levels) did not change. It is concluded that nitrendipine does not impair glucose or lipid metabolism in diabetic hypertensive patients.     

Divalproex sodium in migraine prophylaxis: a dose-controlled study

Objective : To evaluate the efficacy and safety of divalproex sodium (DVPX) when used as prophylactic monotherapy in patients with migraine. Design : Multicenter, double-blind, placebo-controlled, parallel group. Patients were previously untreated or had failed no more than two adequate trials of prophylactic therapy. During the 4-week (single-blind) baseline, patients received placebo and completed a headache diary. Patients with two or more migraine attacks during the baseline were randomized to receive a DVPX daily dose of 500, 1000, or 1500 mg, or to placebo. The experimental phase (EP) lasted 12 weeks, the first 4 weeks for dose escalation to randomized dose, and the remaining 8 weeks for maintenance at that dose. The primary efficacy variable was 4-week migraine attack frequency during the EP. Results : One-hundred-and-seventy-six patients (44 placebo, 132 DVPX) were randomized; 171 provided efficacy data and 137 completed the study. During the EP, after adjustment for differences in baseline migraine attack frequencies, mean reductions in the DVPX groups were 1.7 (500 mg), 2.0 (1000 mg) and 1.7 (1500 mg) migraine attacks per 4 weeks compared to a mean reduction of 0.5 migraine attacks in the placebo group ( p 0.05 vs placebo). Forty-four to 45% of DVPX-treated patients, compared to 21% of patients in the placebo group achieved 50% reduction in their migraine attack frequencies ( p 0.05 vs placebo). The recommended initial dose of DVPX in migraine prophylaxis is 500 mg per day, although some patients may benefit from higher doses. Adverse events were similar in the DVPX and placebo treatment groups except for nausea, dizziness and tremor, in which incidence rates were significantly higher in the DVPX 1500 mg group (nausea was also higher in 500 mg group) than in the placebo group. Conclusion : Divalproex sodium is an effective prophylactic treatment in migraine and is generally well tolerated.     

The effect of high-dose short-term ibuprofen on antihypertensive control with hydrochlorothiazide

The effect of high-dose ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID), on the blood pressure of treated hypertensive patients was evaluated in a randomized, placebo-controlled, double-blind, crossover trial with 24-hour ambulatory blood pressure monitoring. Twelve middle-aged black women with essential hypertension, controlled with 50 mg hydrochlorothiazide per day, randomly received 3200 mg ibuprofen and a placebo for 8 days. Each treatment phase was separated by a 1-week washout period. Ambulatory blood pressure monitoring (ABPM), body weight, and 24-hour urinary excretion of sodium, creatinine, and prostaglandin E2 (PGE2) were determined at the end of each treatment phase. Mean (+/- SEM) 24-hour systolic and diastolic blood pressures were 122/85 (+/- 2.9/1.7) and 125/85 (+/- 3.0/1.1) during the placebo and ibuprofen phases, respectively. Mean ABPM during six consecutive 4-hour periods also revealed no significant differences between placebo and ibuprofen. We conclude that 3200 mg ibuprofen per day for up to 1 week induced little change in blood pressure in hypertensive who are receiving hydrochlorothiazide.     

Influence of dosage and duration of therapy on the rate of response to methyclothiazide in essential hypertension

One hundred twenty patients with essential hypertension were studied to determine whether patients who had not responded to the usual dose of a thiazide (methyclothiazide, 5 mg daily during a six-week drug trial) would respond to a higher dose (10 mg daily). The 14-week study was divided into three periods: (1) a two-week placebo period; (2) a six-week single-blind trial; and (3) a six-week period for double-blind dose comparison. Among the 77.3 percent of patients who responded to the drug, diastolic blood pressure was reduced to 90 mm Hg or lower. Two types of thiazide responders were identified-early and late. The early responders (50 percent of study patients), showed a significant reduction in diastolic blood pressure within four weeks; the late responders (27.3 percent) showed a modest reduction in diastolic blood pressure during the first four weeks of therapy, followed by a plateau lasting about two weeks, then a further significant reduction in blood pressure during the ensuing six weeks. Hypokalemia was more common in early responders. There were no significant differences in late response among patients who continued on the usual dose of methyclothiazide compared to those whose dosage was doubled, suggesting that the late response was not due to increasing the dose of the drug.     

Candesartan cilexetil: comparison of once-daily versus twice-daily administration for systemic hypertension. Candesartan Cilexetil Study Investigators.

This randomized, double-masked, placebo-controlled, forced-titration, parallel-arm study was designed to compare the blood pressure (BP)-lowering effect of candesartan cilexetil, a potent antagonist of the angiotensin II receptor subtype AT1, administered once daily with that of the same agent administered twice daily at the same total daily dose of 16 mg. After a 4- to 5-week placebo run-in period, 277 patients with a sitting diastolic BP of 95 to 109 mm Hg were randomly allocated to receive placebo (n = 92) or candesartan cilexetil 8 mg once daily for 4 weeks, followed by forced titration to either 16 mg once daily (n = 91) or 8 mg twice daily (n = 94) for 4 weeks. At 8 weeks, mean reductions in trough sitting diastolic BP were similar for the once- and twice-daily treatment groups (9.4 and 10.3 mm Hg, respectively). After 8 weeks of treatment, no statistically significant differences were observed in diastolic or systolic BP, peak or trough BP, or sitting or standing BP between the 2 active-treatment groups. The rates of positive responses (defined as a trough sitting diastolic BP of <90 mm Hg or a decrease in BP of > or =10 mm Hg) were also similar (approximately 60%) in the once- and twice-daily candesartan cilexetil groups. Furthermore, placebo-corrected trough-to-peak ratios for sitting diastolic BP exceeded 75% for both candesartan cilexetil regimens, indicating a persistent 24-hour duration of drug effect. Ambulatory BP monitoring performed in a subset of patients (n = 44) confirmed the consistent 24-hour BP-lowering effect and preservation of diurnal variation with once-daily dosing. No significant between-group differences were observed in the incidence or severity of clinical or laboratory adverse events. The results of this study suggest that identical daily doses of candesartan cilexetil administered once or twice daily have comparable efficacy and tolerability and that no additional clinical benefit is derived from twice-daily administration.     

Efficacy/safety of olmesartan medoxomil versus losartan potassium in patients by stage 1 or 2 hypertension

An exploratory subgroup analysis of a prospective, randomized, double-blind, forced-titration study comparing the efficacy and safety of once-daily olmesartan medoxomil (OM) and losartan potassium (LOS) in patients with stage 1 or stage 2 hypertension is reported. After a 3- to 4-week placebo run-in period, eligible patients received once-daily OM (weeks 1-4, 20 mg; weeks 5-8, 40 mg), placebo plus OM (weeks 1-2, placebo; weeks 3-4, OM 20 mg; weeks 5-8, OM 40 mg), or LOS (weeks 1-4, 50 mg; weeks 5-8, 100 mg). A subset of patients underwent ambulatory blood pressure (BP) monitoring. Efficacy endpoints by hypertension stage were mean change from baseline in seated cuff diastolic BP (SeDBP) at week 8 (primary); seated cuff systolic BP (SeSBP) at week 4 and week 8, and SeDBP at week 4 (secondary); and the change from baseline in mean 24-hour ambulatory BP at week 8, and BP target achievement (tertiary). At week 8, patients with stage 1 and stage 2 hypertension had least-squares mean SeDBP reductions from baseline of 9.9 and 9.5 mm Hg, respectively, for OM treatment, and 6.9 and 7.3 mm Hg for LOS treatment (P = 0.0095 and P = 0.0035, respectively). Overall, 63.6% of patients with stage 1 hypertension treated with OM versus 47.3% treated with LOS (P = 0.0095) achieved an SeBP of < 140/90 mm Hg, while 36.1% of patients with stage 2 hypertension treated with OM versus 25.2% treated with LOS (P = 0.0022) achieved an SeBP of < 140/90 mm Hg. At week 8, OM-treated patients with stage 2 hypertension had a significantly greater reduction in least-squares mean 24-hour ambulatory BP versus LOS-treated patients. Olmesartan and LOS were well tolerated, and the most common treatment-emergent adverse event was headache. Once-daily, maximum doses of OM in patients with stage 1 or stage 2 hypertension achieved superior BP reductions versus LOS, with similar tolerability.     

EFFICACY OF RAMIPRIL VERSUS ENALAPRIL IN PATIENTS WITH MILD TO MODERATE ESSENTIAL HYPERTENSION

SUMMARY This double-blind, randomised, cross-over study investigated the antihypertensive efficacy of ramipril and enalapril was completed by 30 patients with mild-to-moderate essential hypertension. After a four-week placebo run-in phase, the patients received either 2.5mg ramipril or 10mg enalapril once daily for four weeks. The dosages were increased to 5mg ramipril and 20mg enalapril for a further four weeks. After a placebo washout phase of four weeks, the patients were crossed over to the alternative treatment. The decrease in average 24-hour ambulatory diastolic blood pressure from week 0 to week 8 was 1.6mmHg greater with ramipril than enalapril (90% confidence interval 0.6-2.7mmHg). The corresponding reduction in for systolic blood pressure was also greater with ramipril than enalapril by 2.4mmHg (90% confidence interval: 0.5-4.2mmHg). For the difference in the drop of 24-hour ambulatory diastolic blood pressure between ramipril and enalapril the lower level of the 90% confidence interval (CI) is above the clinically relevant difference of -3mmHg. This is an indication that ramipril (2.5 and 5mg dose) is at least as effective as enalapril (10 and 20mg dose) in decreasing blood pressure in patients with mild-to-moderate essential hypertension. The duration of adequate antihypertensive effect was relatively long for both ramipril and enalapril; however, ramipril tended to have a more prolonged antihypertensive effect. Ramipril had a higher diastolic and systolic trough/peak ratio than enalapril, resulting in a more uniform antihypertensive effect over the 24-hour treatment period. Both ramipril and enalapril were well tolerated and the two treatment groups had similar safety profiles.     

Metabolic effects of dobutamine in normal man.

1. Dobutamine in 5% (w/v) D-glucose was infused at sequential doses of 2, 5 and 10 micrograms min-1 kg-1, 45 min at each dose, into eight healthy male subjects, and the effects were compared with those produced by infusion of the corresponding volumes of 5% (w/v) D-glucose alone. 2. The energy expenditure increased and was 33% higher than control (P less than 0.001) at 10 micrograms of dobutamine min-1 kg-1. The respiratory exchange ratio decreased from 0.85 (SEM 0.02) before infusion to 0.80 (SEM 0.01) at 10 micrograms of dobutamine min-1 kg-1, but did not alter during the placebo infusion (P less than 0.001). 3. Plasma noradrenaline concentrations were lower during the dobutamine infusion compared with during the infusion of D-glucose alone (P less than 0.025). Plasma dopamine concentrations remained below 0.1 nmol/l throughout both infusions. 4. Compared with during the placebo infusion, the blood glucose concentration decreased (P less than 0.001), the plasma glycerol and free fatty acid concentrations increased by 150 and 225%, respectively (both P less than 0.001), and the plasma potassium concentration decreased from 3.8 (SEM 0.07) to 3.6 (SEM 0.04) mmol/l (P less than 0.01) during dobutamine infusion. The plasma insulin concentration increased at 2 and 5 micrograms of dobutamine min-1 kg-1 (P less than 0.001) with no further rise at 10 micrograms of dobutamine min-1 kg-1. 5. Compared with during the placebo infusion, the systolic and diastolic blood pressures and the heart rate increased during dobutamine infusion (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

A Study Design for Comparing the Effects of Missing Daily Doses of Antihypertensive Drugs

In this double-blind, 6-week study comparing once-daily oral betaxolol and atenolol, the study design allowed the effects of simulated drug noncompliance to be examined. Overall similar blood pressure and heart rate responses were seen in 114 patients with mild-to-moderate hypertension. Similarly, there was no statistically significant difference in percentage of patients achieving goal diastolic blood pressure reductions at the end of 6 weeks of active therapy (betaxolol, 87%, 46/53; atenolol, 82%, 44/54), and safety results overall were similar. However, when patients randomly received placebo for two consecutive treatment days in either the fifth or sixth week of the study to simulate the effect of missing doses, magnitude and duration of effect on systolic blood pressure (p = 0.006), diastolic blood pressure (p = 0.02) and heart rate (p = 0.001) were significantly greater for betaxolol than atenolol as calculated from 28-h ambulatory blood pressure monitoring data. Although betaxolol and atenolol monotherapy are equally effective in controlling blood pressure when taken consistently, the blood pressure and heart rate response with betaxolol is significantly superior for at least 24 h after missing a dose, an important consideration related to patient noncompliance. These results are compatible with the different elimination half-lives of each drug.