Biochemical, endocrine, and mineral effects of indapamide in black women

Black women with established essential hypertension, without renal insufficiency or diabetes mellitus, were withdrawn from their usual antihypertensive therapy for 2-3 weeks prior to entry into a study to evaluate pertinent biochemical and mineral effects of indapamide treatment. Twenty patients with a sitting diastolic blood pressure greater than 90 mm Hg had baseline measurements of plasma total cholesterol, HDL cholesterol, triglycerides, glucose, uric acid, potassium, magnesium, calcium, selenium, renin, norepinephrine, whole blood ionized calcium, and glycosylated hemoglobin. Low-density lipoprotein (LDL) cholesterol was calculated by the Friedewald equation. The patients were placed on a fixed daily dose of 2.5 mg indapamide. Blood pressure and blood tests were repeated at 4, 8, and 12 weeks of treatment. The systolic and diastolic blood pressure were both lowered significantly at week 12. Plasma renin activity was significantly increased. There was no significant change in norepinephrine, glucose, glycosylated hemoglobin, uric acid, ionized calcium, calcium, triglycerides, potassium, magnesium, or selenium. Total cholesterol increased with an increase in both high-density lipoprotein (HDL) and LDL cholesterol; however, these increases did not alter significantly either the total/HDL cholesterol or LDL/HDL cholesterol ratios. It is concluded that 2.5 mg of indapamide per day effectively lowers blood pressure with no significant adverse metabolic effects.     

Antihypertensive effects of captopril in combination with diuretics in spontaneously hypertensive rats

To examine the antihypertensive effects of captopril, when used in combination with diuretics, an oral dose of the agent (30 mg/kg) was given to spontaneously hypertensive rats pretreated for 1 week with trichlormethiazide (TCTZ), hydrochlorothiazide (HCTZ), furosemide, or water. One-week treatment with diuretics did not lower blood pressure, but potentiated the anti-hypertensive action of captopril in magnitude as well as duration. The degree of potentiation was in the following order: furosemide greater than or equal to HCTZ greater than TCTZ. Plasma renin concentration (PRC) prior to the administration of captopril was highest in the furosemide group, followed by the HCTZ, TCTZ, and control groups, in this order. When data from four groups were taken together, the reduction of blood pressure following captopril administration was closely related to PRC before administration. These data suggest that repeated administration of diuretics renders the maintenance of blood pressure more dependent on the renin-angiotensin system without affecting blood pressure and that this situation underlies the potentiation of the antihypertensive action of captopril by combined use of diuretics. There was no qualitative difference between furosemide and thiazides in the potentiation of anti-hypertensive action of captopril.     

A comparison of fosinopril and hydrochlorothiazide with hydrochlorothiazide in non-insulin-dependent diabetes mellitus patients with mild to moderate hypertension

A multicentre, randomised, double-blind, parallel-group study of the tolerability and antihypertensive efficacy of once-daily fosinopril 20 mg/hydrochlorothiazide 12.5mg (FOS/HCTZ) compared with once-daily hydrochlorothiazide 25mg (HCTZ) was conducted in 142 patients with non-insulin-dependent diabetes mellitus (NIDDM) and mild to moderate essential hypertension. After 12 weeks of treatment, both groups had statistically significant mean changes from baseline in seated diastolic and systolic blood pressures (FOS/HCTZ, -15.0mm Hg; HCTZ, -11.9mm Hg for seated diastolic blood pressure). The difference between treatment groups was statistically significant (p < 0.001). In addition, normalisation of seated diastolic blood pressure was achieved in 85% of FOS/HCTZ patients compared with 71% of HCTZ patients. A statistically significant difference (p < 0.05) in favour of FOS/HCTZ was observed for the total number of favourable responses (normalisation or >/=10mm Hg reduction in seated diastolic blood pressure) at week 12 and for the end-point analysis. One FOS/HCTZ patient and 5 HCTZ patients discontinued treatment because of adverse events. No clinically significant changes in serum glucose, potassium or cholesterol were observed. A slight but statistically significant increase in fasting triglycerides occurred with FOS/HCTZ compared with HCTZ (+26.1 vs +13.5 mg/dl, respectively; p < 0.05). These results show that the combination of fosinopril and hydrochlorothiazide has considerable potential as an effective antihypertensive regimen that does not significantly alter glucose or lipid metabolism in patients with NIDDM.     

Plasma lipid profiles and antihypertensive agents: effects of lisinopril, enalapril, nitrendipine, hydralazine, and hydrochlorothiazide

Previous studies have documented potentially adverse effects of diuretics and beta-blocking agents on plasma lipid profiles. This study was designed to establish the effects on lipid profiles of the angiotensin-converting enzyme inhibitors lisinopril and enalapril, alone and in combination with hydrochlorothiazide (HCTZ), the calcium-channel blocker nitrendipine, HCTZ, and hydralazine. After a two-week, single-blind, placebo phase, 77 patients with essential hypertension were given active agent as monotherapy in a double-blind fashion for 8-20 weeks. The dose of each agent was titrated to achieve diastolic blood pressure less than 90 mm Hg. At the end of placebo and treatment phases, plasma was analyzed for triglycerides, total cholesterol, and high-(HDL), and low-density lipoprotein (LDL) cholesterol. Overall, few changes in lipid contents were noted. Total cholesterol decreased during therapy with hydralazine but increased in patients receiving the combination of lisinopril and HCTZ. HDL cholesterol was depressed in those taking HCTZ alone and in combination with lisinopril. LDL cholesterol was lowered during therapy with hydralazine but was otherwise unaffected by all other agents. None of the agents evaluated significantly affected triglyceride concentrations. Thus, monotherapy with lisinopril, enalapril, and nitrendipine do not affect plasma lipid concentrations. Hydralazine lowers total and LDL cholesterol. If these findings are confirmed in trials with larger numbers of patients, these effects on lipid profiles may influence choice of agent in the therapy of essential hypertension.     

Double-blind placebo-controlled trial of terazosin effect on blood pressure and urinary output of dopamine in hypertensive patients.

In a parallel, double-blind study, 12 untreated hypertensive patients received terazosin (2-4 mg/day for 4 weeks), and 12 received placebo during the same period. Systolic and diastolic blood pressure decreased significantly in the terazosin group, from 150 +/- 5.0 mmHg systolic and 99.6 +/- 2.0 diastolic before treatment, to 134.0 +/- 7.0 systolic and 85.6 +/- 3.0 mmHg diastolic at week 4 of treatment. No significant blood pressure changes occurred in the placebo group. Blood pressure decrease showed a positive correlation (r = .62 and r = .52 for systolic and diastolic blood pressure, respectively) with the patient's age (P less than .05). Total plasma cholesterol decreased 18% in the terazosin group (P less than .05) and 9% in the placebo group (P greater than .05). Urinary dopamine excretion decreased significantly from 692.8 +/- 180.0 to 330.5 +/- 52.0 micrograms/24 hours in the terazosin group (P less than .05) and showed a nonsignificant increase in the placebo group. Compared with 22 age- and sex-matched healthy volunteers, urinary dopamine excretion in the hypertensive group before treatment was not statistically different (779.3 +/- 83.1 micrograms/24 hours). Dopamine excretion was higher in untreated hypertensive men and in male healthy volunteers compared with women. The decrease of urinary dopamine excretion observed under terazosin treatment could be due to a decrease of kidney dopamine synthesis or release induced by blood pressure reduction, or secondarily to the blockade of kidney alpha 1-receptors, modulating dopamine excretion. No significant changes were observed in urinary excretion of noradrenaline and adrenaline.     

Olmesartan medoxomil/amlodipine/hydrochlorothiazide: fixed-dose combination in hypertension

The antihypertensive agents olmesartan medoxomil, amlodipine and hydrochlorothiazide (HCTZ) are now available as a fixed-dose combination tablet (olmesartan medoxomil/amlodipine/HCTZ). In a 12-week, randomized, double-blind, multicentre trial (TRINITY) in adults with moderate to severe hypertension, olmesartan medoxomil?+?amlodipine?+?HCTZ triple combination therapy produced significantly greater least squares mean reductions from baseline in seated diastolic blood pressure (BP) [primary endpoint] and seated systolic BP than olmesartan medoxomil/amlodipine, olmesartan medoxomil/HCTZ or amlodipine?+?HCTZ. Furthermore, significantly more patients achieved BP goals and targets with the triple combination regimen than with any of the dual combination regimens at week 12, with olmesartan medoxomil?+?amlodipine?+?HCTZ also demonstrating benefit over the dual regimens in terms of ambulatory BP control. According to subgroup analyses of the TRINITY trial, olmesartan medoxomil?+?amlodipine?+?HCTZ was more effective in reducing BP and achieving BP goals than each of the dual therapies, irrespective of hypertension severity, age, sex, race or diabetes mellitus status. Data from a number of smaller clinical studies indicated that olmesartan medoxomil?+?amlodipine?+?HCTZ triple combination therapy provides antihypertensive efficacy in patients whose BP is not adequately controlled with olmesartan medoxomil?+?amlodipine. Olmesartan medoxomil?+?amlodipine?+?HCTZ was generally well tolerated in the TRINITY study, with adverse events usually being mild or moderate in severity.     

厄贝沙坦氢氯噻嗪初始治疗2级高血压80例临床观察

目的 评价厄贝沙坦氢氯噻嗪片初始治疗2级高血压的疗效及安全性.方法 采用自身对照,开放单一治疗试验设计方法,对80例新发2级高血压病人口服厄贝沙坦氢氯噻嗪片1片,4周时血压不达标则剂量加倍,观察8周,记录治疗前后诊所血压及24h动态血压的变化,观察不良反应,以评价疗效与安全 性.结果 厄贝沙坦氢氯噻嗪片治疗1周后血压即...     

Dose-ranging study to delineate the additive antihypertensive effect of guanabenz and captopril

This open crossover study in eight hypertensive patients defined a possible additive effect of oral guanabenz and captopril and determined a safe and effective dose range. Each group of four patients received placebo followed by ascending doses (on alternate days) of either guanabenz (2, 4, 8 mg) or captopril (6.25, 12.5, 25 mg) as initial monotherapy and were subsequently crossed over to the alternate monotherapy. Guanabenz and captopril were given concomitantly in increasing doses--the highest dose for both groups being 8 mg guanabenz/25 mg captopril. When guanabenz and captopril were given concomitantly, blood pressure decreased, both from the values during placebo administration and from the lead-in values recorded before each dose. Mean supine systolic and diastolic blood pressures after combination therapy decreased significantly (P less than .05) in a dose-related manner at most evaluations. The authors conclude that guanabenz and captopril have an additive effect when administered in combination to patients with hypertension.     

厄贝沙坦与氢氯噻嗪联用在肾性高血压大鼠体内药动学-药效学关系研究

目的:应用药动学-药效学结合模型研究厄贝沙坦与氢氯噻嗪联用在肾性高血压大鼠体内单剂量及多剂量用药时的药动学-药效学关系。方法:将SD大鼠制备成2肾1夹型肾性高血压模型,给大鼠单剂量或多剂量灌胃给药,分别于第1天和第8天连续的预定时间点测定血药浓度,同时测定动脉收缩压(SBP)和动脉舒张压(DBP)等药物效应,建立效应室药动学-药效学结合模型并计算相关的药动学和药效学参数。对单用、联用及单剂量、多剂量的药动学-药效学规律进行定量研究。结果:厄贝沙坦的药动学特征呈二室模型,氢氯噻嗪在非稳态和稳态条件下均未改变厄贝沙坦的药动学参数,而在稳态条件下,厄贝沙坦可增高氢氯噻嗪的血药浓度及曲线下面积。厄贝沙坦和氢氯噻嗪联用降压效应优于单用的效应。药物效应和效应室浓度之间符合Sigmoid-Emax药效学模型。单剂量下药物效应与血药浓度间存在滞后现象,多剂量下滞后现象消失。Emax、EC50、Keo等药效学参数在厄贝沙坦组和两药联用组之间的差异有统计学意义。结论:建立了PK-PD定量数学模型研究厄贝沙坦和氢氯噻嗪联用在大鼠体内单剂量和多剂量用药后药动学-药效学(暴露-反应)关系的规律,并提供了相关的药动学和药效学参数,可为临床合理用药提供参考依据。     

Effect of three months' treatment with irbesartan on blood and pulse pressure of hypertensive type 2 diabetic patients: open, observational study in 31,793 patients

OBJECTIVES: In hypertensive diabetics the cardiovascular risk is substantially increased. Therefore, an effective reduction of both blood pressure and pulse pressure is of particular importance for these patients. The aim of the prospective observational study in hypertensive type 2 diabetics was to assess the effect of a switch from the previous antihypertensive therapy to the angiotensin-II-receptor antagonist irbesartan (alone or in combination with HCTZ) on the reduction of blood pressure and pulse pressure, the reduction of diabetic nephropathy (microalbuminuria), and tolerability. METHODS: 8714 general practitioners included 31,793 type 2 diabetics aged at least 18 years in an open observational study. After inclusion in to the study the patients received irbesartan 300 mg as monotherapy or in combination with hydrochlorothiazide 12.5 mg (HCTZ). Main outcome measures for efficacy were the reduction of systolic (SBP) and diastolic (DBP) blood pressures, reduction of pulse pressure, and blood pressure responder (reduction in DBP > or = 10 mmHg or diastolic < 90 mmHg), diastolic normalization (DBP < 90 mmHg) and overall normalization rates (SBP < 140 mmHg and DBP < 90 mmHg) after 3 months. Further outcome measures included the reduction of microalbuminuria or proteinuria, and adverse events (AEs) as a measure of tolerability. RESULTS: Thirty-eight per cent of patients received irbesartan 300 mg and 61% irbesartan in combination with HCTZ. Mean systolic blood pressure was reduced by 22.5 mmHg, diastolic blood pressure by 10.7 mmHg (baseline values: 160.2 and 93.2 mmHg). Pulse pressure fell on average by 11.6 mmHg. 83.4% of the patients were responders, with an overall normalization rate of 42.7% (SBP < 140 mmHg and DBP < 90 mmHg), respectively 73.8% (DBP < 90 mmHg). The antihypertensive benefit was achieved irrespective of the previous medication. Mean albuminuria decreased by about 27.7 mg/L. Only 0.3% of patients experienced adverse events. CONCLUSIONS: In type 2 diabetics with hypertension and either uncontrolled or no previous antihypertensive therapy a change to treatment with irbesartan or irbesartan/HCTZ for 3 months resulted in a distinct reduction of systolic and diastolic blood pressures, with concomitant effective reductions of pulse pressure and microalbuminuria.     

Efficacy and safety of valsartan 160/HCTZ 25 mg in fixed combination in hypertensive patients not controlled by candesartan 32 mg plus HCTZ 25 mg in free combination

ABSTRACT

Objective: Free combination hypertension medication is associated with a lower compliance and less persistence compared to fixed combination therapy and can, there­fore, be associated with insufficient blood pressure reductions. This non-randomized study investigated whether valsartan 160?mg/ hydrochlorothiazide 25?mg (Val 160/HCTZ 25) in fixed dose combination could provide additional blood pressure control in hypertensive patients not adequately controlled by the free combination of candesartan 32?mg plus HCTZ 25?mg.

Research design and methods: One hundred and ninety-seven patients with a mean sitting diastolic blood pressure (MSDBP) between 100 and 110?mmHg entered a 4-week treatment phase with 32?mg of candesartan in free combination with 25?mg of HCTZ once daily. One hundred and thirty-eight patients with uncontrolled BP at Week 4, entered a second 4-week treatment phase with Val160/ HCTZ 25 once daily.

Main outcome measures: The primary efficacy parameter was the reduction in MSDBP at trough between Week 4 and Week 8 in the intent-to-treat population.

Results: At baseline, MSDBP was 103.0 ± 2.8?mmHg. After Week 4, MSDBP had decreased to 93.8 ± 4.5?mmHg. Subsequent treatment with Val 160/HCTZ 25 for 4 weeks reduced MSDBP to 88.7 ± 8.6?mmHg. This represented an additional decrease in MSDBP of 5.1 ± 7.9?mmHg (?p < 0.0001). Val 160/ HCTZ 25 reduced mean sitting systolic BP by 3.4 ± 13.0?mmHg (?p = 0.0029).

Conclusions: The fixed dose combination of valsartan 160/HCTZ 25?mg provided a statistically and clinically significant additional BP reduction in patients not controlled by the free combination of candesartan 32?mg and HCTZ 25?mg.     

Tolerability and efficacy of fosinopril and hydrochlorothiazide compared with amiloride and hydrochlorothiazide in patients with mild to moderate hypertension

This 6-month multicentre, randomised, double-blind, parallel group clinical trial compared the tolerability and antihypertensive efficacy of a once-daily combination of fosinopril 20mg/hydrochlorothiazide 12.5mg (FOS/HCTZ) with a combination of amiloride 5mg/hydrochlorothiazide 50mg (AMI/HCTZ) in 217 patients with mild to moderate essential hypertension. Adverse events related to hypotension or to specifically targeted clinical laboratory values were observed infrequently with FOS/HCTZ compared with AMI/HCTZ: with FOS/HCTZ, only 4 of 104 patients (3.9%) experienced such events, compared with 16 of 113 (14.1%) in the AMI/HCTZ group (p < 0.001). While statistically significant differences were found between the two treatment groups for changes from baseline in serum potassium, cholesterol, triglyceride and glucose values, the metabolic profile was uniformly unfavourable towards the AMI/HCTZ group; for example, reductions in potassium and elevations in cholesterol, triglyceride and glucose were more pronounced with the AMI/HCTZ group than with the FOS/HCTZ group. Both antihypertensive regimens produced statistically significant reductions from baseline in seated diastolic blood pressure that were equivalent at most points of measurement during double-blind treatment. Therapeutic response rates were high (>/=95%) and were similar for both regimens throughout the study. Because the relative risk for adverse events was markedly less over the long term with FOS/HCTZ than with AMI/HCTZ, the combination of fosinopril and hydrochlorothiazide may offer significant tolerability advantages over amiloride plus hydrochlorothiazide for such patients.     

Antihypertensive and metabolic effects of single and combined atenolol regimens.

The antihypertensive and metabolic effects of placebo (PL), a fixed combination of hydrochlorothiazide (25 mg) and triamterene (50 mg) (HCTZ/TRI), atenolol (25 mg) (Atc-25), atenolol (50 mg) (Ate-50) and their combination with HCTZ/TRI given once daily, were tested on 256 patients with mild-to-moderate essential-hypertension. After 3 weeks of PL monotherapy, 43 patients were randomized to PL (group 1), 41 patients to HCTZ/TRI (group 2), 44 patients to Ate-25 (group 3), 42 patients to Ate-50 (group 4), 43 patients to Ate-25/HCTZ/TRI (group 5), and 43 patients to Ate-50/HCTZ/TRI (group 6) in a double-blind parallel design study and were followed for 4 weeks. At the end of week 7, those patients who were randomized to groups 5 and 6 were allowed to continue for an additional 12 weeks, if their arterial pressure was satisfactorily controlled. Complete blood counts, blood chemistries, urinalyses, and electrocardiograms were done initially and during the study. Monotherapy with HCTZ/TRI, Ate-25, and Ate-50 had significant and equal antihypertensive effects compared with placebo. (P less than .01). However, the combination of Ate-25/HCTZ/TRI and Ate-50/HCTZ/TRI resulted in further reduction of arterial pressure with the effect being greatest with Ate-50/HCTZ/TRI (P less than .001). Patient groups 3 through 6 had also slower heart rates compared with groups 1 and 2 (P less than .01). Mild, but statistically significant, increases in BUN, glucose, triglycerides, and uric acid were noted in groups 2, 5, and 6 (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Once vs twice daily administration of a fixed combination of captopril plus hydrochlorothiazide in essential hypertension: a double-blind crossover study in known responders to a standard combination.

The purpose of this randomized, double-blind, crossover trial was to compare the hypotensive effects of a fixed combination of captopril (C) 50 mg and hydrochlorothiazide (HCTZ) 25 mg (C 50/HCTZ 25) once daily with those of a fixed combination of C 25 mg and HCTZ 12.5 mg (C 25/HCTZ 12.5) twice daily. We studied 199 patients (108 M, 91 F) with mild to moderate essential hypertension whose BP was already controlled by the co-administration of C 25 mg and HCTZ 12.5 mg twice daily. They were randomly assigned to either C 25/HCTZ 12.5 twice daily during the first 6 weeks and C 50/HCTZ 25 once daily during the second 6 weeks or C 50/HCTZ 25 once daily followed by C 25/HCTZ 12.5 twice daily. Both regimens showed comparable efficacy on office diastolic BP (91.6 vs 91.3 mm Hg). Systolic BP was slightly but significantly higher (P = 0.02) with the once daily formulation (141.2 vs 139.1 mm Hg). Fixed combinations once daily and twice daily resulted in identical working ambulatory BP (133.7 +/- 13/83.6 +/- 8 mm Hg vs 132.4 +/- 11/83.3 +/- 7 mm Hg) without affecting heart rate. Adverse events were reported by 16% of patients and cough was the most common occurring in 7%. In conclusion, these results indicate that the fixed combination of C 50/HCTZ 25 given once daily controls office and working BP as well as the fixed combination C 25/HCTZ 12.5 given twice daily in patients with mild to moderate hypertension.     

Effect of three months’ treatment with irbesartan on blood and pulse pressure of hypertensive type 2 diabetic patients: open,observational study in 31 793 patients

ABSTRACT

Objectives: In hypertensive diabetics the cardiovascular risk is substantially increased. Therefore, an effective reduction of both blood pressure and pulse pressure is of particular importance for these patients. The aim of the prospective observational study in hypertensive type 2 diabetics was to assess the effect of a switch from the previous antihypertensive therapy to the angiotensin-II-receptor antagonist irbesartan (alone or in combination with HCTZ) on the reduction of blood pressure and pulse pressure, the reduction of diabetic nephropathy (microalbuminuria), and tolerability.

Methods: 8714 general practitioners included 31?793 type 2 diabetics aged at least 18 years in an open observational study. After inclusion in to the study the patients received irbesartan 300?mg as monotherapy or in combination with hydrochlorothiazide 12.5?mg (HCTZ). Main outcome measures for efficacy were the reduction of systolic (SBP) and diastolic (DBP) blood pressures, reduction of pulse pressure, and blood pressure responder (reduction in DBP ≥ 10 mmHg or diastolic < 90 mmHg), diastolic normalization (DBP < 90 mmHg) and overall normalization rates (SBP < 140 mmHg and DBP < 90 mmHg) after 3 months. Further outcome measures included the reduction of microalbuminuria or proteinuria, and adverse events (AEs) as a measure of tolerability.

Results: Thirty-eight per cent of patients received irbesartan 300?mg and 61% irbesartan in combination with HCTZ. Mean systolic blood pressure was reduced by 22.5?mmHg, diastolic blood pressure by 10.7?mmHg (baseline values: 160.2 and 93.2?mmHg). Pulse pressure fell on average by 11.6?mmHg. 83.4% of the patients were responders, with an overall normalization rate of 42.7% (SBP < 140?mmHg and DBP < 90?mmHg), respectively 73.8% (DBP < 90?mmHg). The antihypertensive benefit was achieved irrespective of the previous medication. Mean albuminuria decreased by about 27.7?mg/L. Only 0.3% of patients experienced adverse events.

Conclusions: In type 2 diabetics with hypertension and either uncontrolled or no previous antihypertensive therapy a change to treatment with irbesartan or irbesartan/HCTZ for 3 months resulted in a distinct reduction of systolic and diastolic blood pressures, with concomitant effective reductions of pulse pressure and microalbuminuria.     

Efficacy and tolerability of candesartan cilexetil/hydrochlorothiazide and amlodipine in patients with poorly controlled mild-to-moderate essential hypertension.

The antihypertensive efficacy and tolerability of combination therapy with candesartan cilexetil, 16 mg plus hydrochlorothiazide (CC/HCTZ), 12.5 mg was compared with that of amlodipine, in a multicentre, double-blind, randomised, parallel-group study in patients with mild-to-moderate essential hypertension inadequately controlled by monotherapy. After a two week run-in period on existing therapy, patients with a sitting diastolic blood pressure (DBP) of 90-110 mmHg and a sitting systolic blood pressure (SBP) 相似文献   

Use of a sustained-release formulation of oxprenolol and cyclopenthiazide (‘Trasidrex’) in the management of hypertension: A general practice study

Summary

An open study was carried out in general practice on 678 hypertensive patients being treated with a beta-blocker but who still had resting diastolic blood pressures greater than 100 mmHg. Previous treatment was stopped and substituted with I or 2 tablets daily of a fixed combination product containing 160?mg oxprenolol hydrochloride in a sustained-release formulation plus 0.25?mg cyclopenthiazide per tablet. After 4-weeks treatment on this regimen, blood pressure levels fell significantly, from 179/108 mmHg to 155/93 mmHg, without any increase in the reporting of unpleasant side-effects.     

Effects of sibutramine plus verapamil sustained release/trandolapril combination on blood pressure and metabolic variables in obese hypertensive patients

Objective: The management of obese hypertensive subjects may require the administration of anti-obesity and antihypertensive drugs. Sibutramine use has raised concerns regarding a potential increase in subjects' blood pressure and heart rate. The primary end-points of this study were an evaluation of the effect of sibutramine together with a verapamil sustained release/trandolapril combination tablet versus verapamil sustained release/trandolapril alone on the blood pressure and heart rate in obese hypertensive patients. Research design/methods: Patients received a low-fat low-calorie diet and were randomly allocated to open-label verapamil sustained release/trandolapril 180/2 mg (n = 26) or sibutramine 10 mg together with verapamil sustained release/trandolapril 180/2 mg (n = 28) daily for 6 months. Results: Significant reductions in the subjects' systolic blood pressure and diastolic blood pressure were observed in both groups (p < 0.01 versus baseline). At 6 months a greater fall in blood pressure was observed in the sibutramine/verapamil sustained release/trandolapril group compared with the verapamil sustained release/trandolapril group (systolic blood pressure 21.9 ± 8.1 versus 15.9 ± 12.3 mmHg and diastolic blood pressure 15.7 ± 8.1 versus 9.1 ± 9.9 mmHg) but this was only significant (p = 0.03) for diastolic blood pressure. The subjects' heart rate did not change significantly in any group. No significant sibutramine-associated attenuation of blood pressure reduction was observed during the study. The sibutramine/verapamil sustained release/trandolapril treatment resulted in significantly greater improvement in the subjects' anthropometric variables, homeostasis model assessment and lipid profiles compared with verapamil sustained release/trandolapril administration. The subjects' small dense low-density lipoprotein cholesterol, high-sensitivity C-reactive protein and visfatin plasma levels were only measured in the sibutramine/verapamil sustained release/trandolapril group (all decreased by p < 0.05 versus baseline). Conclusions: The sibutramine/verapamil sustained release/trandolapril combination in obese hypertensive patients significantly reduced their blood pressure and improved their anthropometric and metabolic variables without affecting the heart rate.     

Antihypertensive effect of indapamide given in conjunction with captopril in severe hypertension

The efficacy of captopril alone or in combination with indapamide was evaluated in 17 patients with severe hypertension (diastolic greater than 120 mmHg) previously treated with triple antihypertensive therapy, i.e. diuretic, beta-blocker and a vasodilator. After a wash-out period of 1 week, captopril was given initially as 75 mg/day for 2 weeks; at the end of this period, the dosage was doubled to 150 mg/day and continued at this level for a further 2 weeks. Indapamide (2.5 mg/day) was then added to the regimen and administered for 1 month. The results showed that captopril alone lowered, but did not normalize the blood pressure. The mean diastolic pressure was reduced to 117 and 103.8 mmHg after dosages of captopril of 75 mg and 150 mg, respectively. On the addition of indapamide, the blood pressure was normalized to 93.82 mmHg mean diastolic pressure. Systolic readings were similarly reduced. Two patients developed skin rashes while on captopril alone: no other treatment-related side-effects were reported once indapamide therapy had commenced.     

Pharmacokinetic and pharmacodynamic interaction between irbesartan and hydrochlorothiazide in renal hypertensive dogs

Combined irbesartan/hydrochlorothiazide (HCTZ) formulations are often used clinically. Pharmacokinetic-pharmacodynamic (PK/PD) modeling was applied to investigate the pharmacokinetic and pharmacodynamic interaction between irbesartan and HCTZ in renal hypertensive dogs at non-steady-state and steady-state. The renal hypertensive dogs were treated with oral irbesartan alone, or HCTZ alone, or the combination of irbesartan and HCTZ for 8 days. Blood pressure and plasma concentrations were measured and pharmacokinetic-pharmacodynamic parameters were analyzed. Irbesartan showed a two-compartment model pharmacokinetic profile. The concentration-time course of irbesartan was not changed by HCTZ, but irbesartan increased the peak plasma concentration and area under the curve of HCTZ at steady-state. HCTZ had no blood pressure lowering effect at non-steady-state. Irbesartan plus HCTZ had greater blood pressure lowering action than irbesartan alone. HCTZ increased actions of irbesartan. Hysteresis loops were found between effect and plasma concentrations of irbesartan after a single dose. However, hysteresis loops disappeared at steady state with more rapid realization of maximum concentration and effects. The relationship between effects and effect-compartment concentrations of the drugs was represented by a sigmoid Emax model. The results suggest synergistic pharmacodynamic interaction between irbesartan and HCTZ in renal hypertensive dogs and some differences of pharmacokinetic-pharmacodynamic properties between irbesartan and irbesartan/HCTZ combinations at non-steady-state and steady state.