Nebivolol in the management of essential hypertension: a review

Nebivolol is a lipophilic beta1-blocker. It is devoid of intrinsic sympathomimetic or membrane stabilising activity but appears to have nitric oxide-mediated vasodilatory effects. Nebivolol is administered as a racemic mixture of equal proportions of d- and l-enantiomers. The drug does not significantly influence glucose or plasma lipid metabolism and appears to have a protective effect on left ventricular function. At the recommended dosage (5 mg once daily) nebivolol reduces resting diastolic blood pressure as effectively as standard therapeutic dosages of atenolol, metoprolol, lisinopril and nifedipine, as shown in comparative trials. Nebivolol reduced blood pressure significantly more than enalapril 10 mg daily in the short but not the long term, although the enalapril dose may not have been optimal. Nebivolol has an additive effect in combination with hydrochlorothiazide. Standing blood pressure and/or mean 24-hour ambulatory blood pressure is significantly and similarly reduced with nebivolol, atenolol or nifedipine. Nebivolol tended to prevent increases in early morning blood pressure better than nifedipine. Overall response rates to nebivolol therapy (a decrease in sitting/supine diastolic blood pressure to < or = 90 mm Hg or a 10% or > or = 10 mm Hg fall in diastolic blood pressure) ranged from 58 to 81% after 4 to 52 weeks' treatment. In comparative studies, response rates were greater in nebivolol than in enalapril or metoprolol recipients, but not significantly different from those in atenolol or nifedipine recipients. Nebivolol 5 mg once daily is well tolerated in patients with hypertension. Adverse events are infrequent, transient and mild to moderate. Those reported most often include headache, fatigue, paraesthesias and dizziness. Several studies reported no signs of orthostatic hypotension with nebivolol. Comparative trials revealed no significant differences between the frequency and severity of adverse events in patients receiving nebivolol, atenolol, enalapril or placebo; however, the overall incidence of adverse events was greater with nifedipine or metoprolol. Some atenolol or enalapril, but not nebivolol, recipients reported impotence or decreased libido during therapy. CONCLUSION: Current evidence indicates that nebivolol 5 mg once daily is a well tolerated beta-blocker, which is as effective as once daily atenolol and other classes of antihypertensive agents. It may therefore be recommended as a useful alternative first-line treatment option for the management of patients with mild to moderate uncomplicated essential hypertension.     

Antihypertensive effect of a new formulation of slow release oxprenolol in essential hypertension

To test whether a new formulation of a slow release oxprenolol (SLOx) can produce a steady 24-h antihypertensive effect, we recorded 24-h intraarterial blood pressure (Oxford technique) in eight ambulant inpatients (age 44.5 +/- 3.0 years, mean +/- SE) with a mild or moderate hypertension who were untreated since three weeks. The study was started seven days after hospitalization and was conducted according to a randomized doubleblind cross-over design. Blood pressure recordings were made after (a) a 7-day administration of SLOx in a single evening dose, and (b) a 7-day administration of placebo. This design allowed to determine the effect of SLOx without interference from nonspecific blood pressure lowering factors. Blood pressure effects of handgrip, submaximal cyclette exercise, and cold pressor test 20-24 h after the administration of SLOx and placebo were also evaluated. The blood pressure tracing was analyzed beat-to-beat by a computer which provided also the analysis of the heart rate data. The 24-h mean systolic and diastolic blood pressure measured during placebo were 144.6 +/- 6.4 and 81.1 +/- 3.9 mm Hg, the corresponding heart rate being 76.9 +/- 3.5 beats/min. SLOx reduced these values by 6.2, 10.6, and 4.8%, respectively, all effects being similarly evident throughout the blood pressure recording. The pressor responses to handgrip, cyclette exercise, and cold pressor test were not affected by SLOx. By contrast, the small tachycardic response to handgrip and the large tachycardic response to submaximal cyclette exercise were significantly reduced by the drug.(ABSTRACT TRUNCATED AT 250 WORDS)     

Trandolapril/verapamil sustained release: a review of its use in the treatment of essential hypertension

Trandolapril/verapamil sustained release (SR) [Tarka] is an oral, fixed-dose combination of the ACE inhibitor trandolapril and the SR formulation of the phenylalkylamine calcium channel antagonist verapamil. It is indicated for the treatment of hypertension in patients who require more than one agent to achieve blood pressure (BP) targets. In the large, randomised, multicentre INVEST (INternational VErapamil SR/trandolapril STudy), a verapamil SR-based treatment strategy that included trandolapril in most patients was as effective as an atenolol-based treatment strategy in reducing the risk of the primary outcome (first occurrence of death [all-cause], nonfatal myocardial infarction [MI] or nonfatal stroke) in patients with hypertension and coronary artery disease (CAD) and was as well tolerated. Trandolapril/verapamil SR is generally more effective at controlling hypertension than either component as monotherapy, and is as effective as a number of other fixed-dose combination therapies. The combination is as well tolerated as trandolapril monotherapy and is at least as well tolerated as verapamil SR monotherapy. In hypertensive patients with type 2 diabetes mellitus in the BENEDICT (BErgamo NEphrologic DIabetes Complications Trial), trandolapril/verapamil SR prolonged the time to the onset of persistent microalbuminuria compared with placebo, as did trandolapril monotherapy. Thus, trandolapril/verapamil SR is an effective option for the treatment of essential hypertension in patients requiring more than one agent to achieve BP targets, including those with compelling indications, such as CAD or type 2 diabetes.     

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

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

Felodipine. A review of the pharmacology and therapeutic use of the extended release formulation in older patients.

Felodipine is a dihydropyridine calcium antagonist which may be administered once daily in an extended release (ER) formulation. As monotherapy in older patients with mild to moderate essential hypertension, felodipine ER once daily provides effective control of blood pressure (BP). The drug has also been effective, either as monotherapy or in combination with other antihypertensive medications, in comparisons with other antihypertensive agents, and does not adversely affect lipid profiles or, in patients with diabetes mellitus, glycaemic control. Results in patients with angina pectoris and congestive heart failure indicate a potential role for felodipine ER in these indications and data also suggest the drug reduces left ventricular hypertrophy. In addition, felodipine ER appears suitable for use in patients with concomitant respiratory disease, renal or hepatic dysfunction, cerebrovascular or peripheral ischaemic disease, or gout, making it particularly useful in the elderly who often have more than one significant clinical condition. Felodipine ER has generally been well tolerated by older patients in clinical trials, although further confirmation in the long term is desirable. Thus, felodipine ER effectively lowers BP in older patients with essential hypertension with the added convenience of once daily administration. It may be used as monotherapy or in combination with other antihypertensive agents and is a practical advance in the treatment of hypertension in the elderly.     

Felodipine. A review of the pharmacology and therapeutic use of the extended release formulation in cardiovascular disorders.

Felodipine is a vascular-selective, dihydropyridine calcium antagonist previously investigated as a conventional tablet formulation administered twice daily. More recently considerable experience has been gained with an extended release (ER) formulation which has the convenience of once daily administration. Felodipine ER has been well studied in patients with essential hypertension. As monotherapy in mild to moderate essential hypertension, felodipine ER is at least as effective in reducing blood pressure as other calcium antagonists, beta-blockers, diuretics and ACE inhibitors, with some results favouring felodipine ER at a statistically significant level at the dosages used. It is also effective combined with controlled release metoprolol or enalapril in patients with mild to moderate essential hypertension. In patients with more severe forms of essential hypertension uncontrolled by beta-blocker and/or diuretic therapy, felodipine ER was effective as an 'add-on' therapy in placebo-controlled trials, and, at the dosages used, more effective than either sustained release nifedipine or nitrendipine. Felodipine produces effective control of blood pressure without negative effects on cardiac performance. In addition to its antihypertensive action, results suggest that felodipine therapy is associated with significant regression of left ventricular hypertrophy. Furthermore, it appears suitable for use in patients with concomitant diabetes, renal dysfunction or asthma, and is also being investigated for use in patients with congestive heart failure or angina pectoris. Felodipine ER is an effective drug for the treatment of all grades of essential hypertension, and can be used both as monotherapy and in combination with other antihypertensive agents. Further clinical experience should fully establish the long term tolerability of felodipine ER and consequently its place in therapy relative to other accepted antihypertensive drugs. However, with the convenience of once daily administration, felodipine ER is a worthwhile innovation in the treatment of hypertension.     

Amlodipine/benazepril: fixed dose combination therapy for hypertension

Myocardial infarction, stroke, heart failure and end-stage renal disease have all been linked to inadequate control of blood pressure. Despite overwhelming evidence that uncontrolled hypertension is responsible for a sizeable number of adverse health-related outcomes, control of the disease remains considerably suboptimal. Available data demonstrate that in order to achieve adequate blood pressure control, a large number of patients require therapy with more than one medication. Fixed dose combination antihypertensive therapy has many advantages over other treatment options. Positive effects on blood pressure control, rates of adherence, adverse effects and cost have been identified. Amlodipine/benazepril (Lotrel^®, Novartis) is a fixed dose combination product indicated for the treatment of hypertension. Although not currently recommended as first-line therapy, studies confirm that this combination of a long-acting calcium antagonist and an angiotensin-converting enzyme (ACE) inhibitor possesses substantial blood pressure lowering capabilities. Whereas adverse events tend to become more frequent with increasing doses of antihypertensive monotherapy, the rate of adverse events attributed to amlodipine/benazepril in clinical trials often correlates with rates ascribed to placebo. Amlodipine/benazepril is capable of sustaining blood pressure control over a 24 h period and appears to be minimally affected by an occasional dose omission. Unlike the older calcium antagonists, amlodipine is unlikely to cause alterations in myocardial contractility. Additionally, the amlodipine/benazepril combination product costs less than the same therapy administered as the individual components. It is, therefore, reasonable to consider therapy with amlodipine/benazepril in appropriate patients after an adequate trial of antihypertensive monotherapy.     

Amlodipine/benazepril: fixed dose combination therapy for hypertension

Myocardial infarction, stroke, heart failure and end-stage renal disease have all been linked to inadequate control of blood pressure. Despite overwhelming evidence that uncontrolled hypertension is responsible for a sizeable number of adverse health-related outcomes, control of the disease remains considerably suboptimal. Available data demonstrate that in order to achieve adequate blood pressure control, a large number of patients require therapy with more than one medication. Fixed dose combination antihypertensive therapy has many advantages over other treatment options. Positive effects on blood pressure control, rates of adherence, adverse effects and cost have been identified. Amlodipine/benazepril (Lotrel), Novartis) is a fixed dose combination product indicated for the treatment of hypertension. Although not currently recommended as first-line therapy, studies confirm that this combination of a long-acting calcium antagonist and an angiotensin-converting enzyme (ACE) inhibitor possesses substantial blood pressure lowering capabilities. Whereas adverse events tend to become more frequent with increasing doses of antihypertensive monotherapy, the rate of adverse events attributed to amlodipine/benazepril in clinical trials often correlates with rates ascribed to placebo. Amlodipine/benazepril is capable of sustaining blood pressure control over a 24 h period and appears to be minimally affected by an occasional dose omission. Unlike the older calcium antagonists, amlodipine is unlikely to cause alterations in myocardial contractility. Additionally, the amlodipine/benazepril combination product costs less than the same therapy administered as the individual components. It is, therefore, reasonable to consider therapy with amlodipine/benazepril in appropriate patients after an adequate trial of antihypertensive monotherapy.     

替米沙坦与非洛地平对原发性高血压纤溶系统的影响

目的 比较替米沙坦和非洛地平对原发性高血压患者纤溶系统的影响.方法 60例原发性高血压患者随机均分为替米沙坦组和非洛地平组,观察治疗后血压、血浆组织型纤溶酶原激活物(tPA)及其抑制物(PAI-1)含量、D-二聚体(D-D)和血管性血友病因子(vWF)水平的变化.结果 两组患者治疗后血压均显著下降(P<0.01),PAI-1、vWF和D-D水平均显著性下降(P<0.05),tPA和tPA/PAI-1比值明显升高(P<0.05).组间D-D和vWF水平无显著差异,替米沙坦组PAI-1含量减少更明显、tPA和tPA/PAI-1比值增加更显著.结论 替米沙坦和非洛地平缓释片均能有效改善原发性高血压的纤溶障碍,但替米沙坦优于非洛地平.     

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

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

Labetalol in the treatment of essential hypertension: a single-blind dose ranging study

The hypotensive efficacy of labetalol was evaluated in 29 patients with essential hypertension in a single-blind dose ranging study. After a two-week period of placebo treatment, labetalol was given in oral doses of 0.6 g/d, 0.8 g/d, and 0.8 g/d combined with 25-50 mg/d of hydrochlorothiazide. Each regimen lasted four weeks. The decrease in blood pressure was dose dependent: 90% of patients showed a significant reduction in diastolic blood pressure and 75% showed a significant reduction in systolic blood pressure. In 69% of the patients, side effects of the drug were noted, and in five patients (17%), treatment was discontinued because of the side effects. Seven patients received labetalol intravenously before the oral treatment. Their heart rate and blood pressure reductions were similar to those found in patients only taking the medication orally. We conclude that labetalol is an efficient and safe antihypertensive agent in both oral and intravenous administration. However, the high incidence of side effects makes labetalol a drug of second choice in uncomplicated hypertensive patients.     

Comparative study of metoprolol and alpha-methyldopa in untreated essential hypertension

Summary The hypotensive actions of metoprolol and alpha-methyldopa have been compared in 37 men with previously untreated essential hypertension; 36 belonged to stage 1 and 1 to stage 2 of the WHO classification. After four weeks of placebo treatment the patients were randomly allocated to treatment with either of the two drugs. Treatment was started with metoprolol 75 mg daily or alpha-methyldopa 375 mg and was doubled after eight weeks. Satisfactory blood pressure control was defined as systolic blood pressure below 160 mm Hg and diastolic below 95 mm Hg. The patients were examined every four weeks and in those with unsatisfactory control the dose was gradually increased up to a maximum daily dose of metoprolol 450 mg or alpha-methyldopa 2250 mg. The trial lasted for 24 weeks after randomization. Five patients dropped out of the study. After six months, satisfactory blood pressure control was recorded in 16 out of 17 patients and 14 out of 15 patients treated with metoprolol and alpha-methyldopa, respectively. The average reduction in blood pressure produced by the two drugs was comparable. One patient in the alpha-methyldopa group developed drug exanthema and two patients a positive Coombs' test. Other side effects were few and did not differ between the two compounds.     

Design of a controlled release liquid formulation of lamotrigine

BACKGROUND AND THE PURPOSE OF THE STUDY: Lamotrigine is a broad spectrum anticonvulsant drug widely used as mono- or adjunct- therapy in adults and children. The aim of this study was to develop controlled release liquid formulation of lamotrigine to improve bioavailability and compliance of pediatric and geriatric epileptic patients. METHODS: Multiple (w/o/w) emulsion was prepared using one step emulsification technique. It was evaluated for entrapment efficiency (EE), morphology, zeta potential (ZP), polydispersity index (PI), rheology, thermal property, in vitro drug release behavior and stability. In vivo studies in albino mice were carried out using maximal electroshock seizure (MES) test and strychnine induced seizure (SIS) pattern test and results were compared with marketed formulation. RESULTS: The EE of the formulations varied from 84.37% to 98.11%. The ZP and PI values of the prepared batches were in the range of +23.46 to +28.07 and 0.256 and 0.365, respectively. Microscopic observation clearly indicated the stability of the emulsions during the storage period. All batches exhibited controlled in vitro drug release up to 12 hrs. Batch C11 exhibited significantly longer duration of protection of seizure in mice against MES and exhibited comparable efficacy in SIS as compared to the marketed formulation. MAJOR CONCLUSION: Multiple emulsion of lamotrigine compared to the marketed tablet showed plasma drug concentration within therapeutic range for longer time and comparable efficacy.     

Prospective controlled trial of two nifedipine extended release formulations in the treatment of essential hypertension

The aim of this study was to assess the pharmacodynamic equivalence of two different slow-release formulations of nifedipine (CAS-21829-25-4). In a prospective, controlled, double-blind clinical trial, 42 patients with essential hypertension (sitting diastolic blood pressure (DBP) 95-114 mmHg) underwent an initial washout, drug free period of 2 weeks, after which they were randomized to receive either 30 mg of nifedipine in the test preparation "XL" (Nifecard) or 30 mg of nifedipine in a reference formulation, "LA", during six weeks. The response to treatment was assessed by measuring the blood pressure (BP) every two weeks (standard office mercury sphygmomanometry) and by 24-h ambulatory blood pressure monitoring (ABPM). Of the 42 included patients 36 (85.5%) completed the trial: 19 on "XL" and 17 on "LA". After 2 weeks of therapy the DBP decreased by about 11% (-13.4 mmHg) and 10% (-9.5%), respectively, after 4 weeks the mean decrease versus the end of the placebo period reached about 14% (-15.5 mmHg) and 11% (-13 mmHg), and at the end of the trial the DBPs were lower by about 13% (-14.5 mmHg) in both groups. In all these measurements the within group differences were significant (p < 0.001), while the between groups differences were not (p > 0.05). Quite comparable results were obtained with ABPM, e.g. in the "XL" group the systolic blood pressure at the end of the study was lower by 12.3% (-4.6 mm Hg) and in the "LA" group, by 10.6% (-9.0 mm Hg); p = 0.358. The adverse effects were similar in both groups and they required neither particular interventions nor withdrawal from the study. The drugs under study were comparably effective and well tolerated antihypertensives.     

Effects of treatment with nifedipine and metoprolol in essential hypertension

Summary In a double-blind trial 26 patients with essential hypertension were treated with nifedipine or placebo for 8 weeks, following a 4-week run-in place-bo period in all patients. The daily dosage of nifedipine during this phase was 10mg 3 times daily. Metoprolol was then added to the therapeutic regimen of both groups for a further 12 weeks. Both nifedipine and metoprolol used as mono-therapy caused statistically significant reductions of arterial pressure. The addition of metoprolol to nifedipine tended to reduce blood pressure further, but blood pressures were not significantly lower than during nifedipine mono-therapy. Side-effects were few and only two patients had to be withdrawn during active therapy, one for headaches during nifedipine therapy, and another for asthma during metoprolol treatment. Combined therapy with a beta-adrenoceptor blocking agent, such as metoprolol, and a calcium antagonist with vasodilating properties, such as nifedipine, offers a theoretically interesting approach in the treatment of hypertension, even though the practical outcome in the present study probably suffered from an inadequate dose of nifedipine during the period of combined therapy.     

Propranolol vs metoprolol vs labetalol: A comparative study in essential hypertension

Summary In a double blind, within patient investigation of twenty-four patients (nineteen males and five females) with a mean age of 46.3 years (SD 10.9 years) with mild to moderate essential hypertension a comparison between equipotent beta-blocking doses of propranolol, metoprolol and labetalol was carried out. Blood pressure and pulse rate were measured in lying, sitting and standing positions and before, during and after isometric and dynamic exercise. Peak expiratory flow was recorded before and during dynamic exercise. All the active treatments were better than placebo in reducing blood pressure and heart rate. Comparing the effects of treatment, labetalol lowered sitting diastolic pressure significantly more than propranolol and standing diastolic pressure than both propranolol and metoprolol. Metoprolol and propranolol were more effective in reducing heart rate. Propranolol significantly reduced peak flow rate compared to labetalol. During the exercise, both isometric and dynamic, the heart rate and the blood pressure, both systolic and diastolic, of the treated patients were lower than those on placebo. There was little difference between the drugs in the influence on blood pressure, but metoprolol and propranolol were significantly more effective than labetalol in lowering the heart rate.     

Gastrointestinal transit of a controlled release naproxen tablet formulation

The gastrointestinal transit of a controlled release naproxen tablet formulation has been measured in healthy young and old subjects using the technique of gamma scintigraphy. Gastric emptying of the tablet was affected by food (mean emptying times for fasted subjects were 0.64 h (young) and 0.86 h (old) increased to 3.0 h (young) and 3.3 h (old) following a light breakfast). The small intestinal transit times for both fed and fasted states was about 3.2 h. There were no significant differences that could be attributed to subject age for gastric emptying and small intestinal transit.     

Travoprost/timolol fixed combination in the management of open-angle glaucoma: a clinical review

INTRODUCTION: many patients with glaucoma require multiple medications for adequate disease control. This review summarizes the efficacy and safety of the travoprost/timolol fixed combination in lowering intraocular pressure in eyes with glaucoma. AREAS COVERED: phase III and IV evaluations of travoprost/timolol are reviewed, including trials comparing the fixed combination with constituents, with unfixed concomitant therapy and with other unfixed and fixed combinations of glaucoma medications. The safety of travoprost/timolol is also reviewed. EXPERT OPINION: the role of fixed-combination drugs, including travoprost/timolol, in the management of glaucoma is discussed. Unmet needs in glaucoma therapy, including long-acting drug delivery systems and therapies that treat glaucoma via mechanisms other than reduction of intraocular pressure, are also presented.     

Moxonidine: a review of its use in essential hypertension

Moxonidine (Physiotens, Moxon, Cynt) is an orally administered imidazoline compound with selective agonist activity at imidazoline I1 receptors and only minor activity at alpha2-adrenoceptors. Moxonidine acts centrally to reduce peripheral sympathetic activity, thus decreasing peripheral vascular resistance. In patients with mild to moderate hypertension, moxonidine reduces blood pressure (BP) as effectively as most first-line antihypertensives when used as monotherapy and is also an effective adjunctive therapy in combination with other antihypertensive agents. It improves the metabolic profile in patients with hypertension and diabetes mellitus or impaired glucose tolerance, is well tolerated, has a low potential for drug interactions and may be administered once daily in most patients. Thus, moxonidine is a good option in the treatment of patients with mild to moderate hypertension, particularly as adjunctive therapy in patients with the metabolic syndrome.