Aliskiren: new drug. Arterial hypertension: no evidence of clinical efficacy

(1) Pharmacological management of arterial hypertension is based on antihypertensive drugs with proven efficacy on morbidity and/or mortality endpoints. (2) Aliskiren is the first renin inhibitor to reach the market. (3) There are no published trials of aliskiren with clinical endpoints. Five double-blind short-term (8 weeks) placebo-controlled trials showed a moderate effect on blood pressure. This effect was not superior to that of other antihypertensive drugs with which aliskiren was compared: hydrochlorothiazide, amlodipine, irbesartan, losartan, valsartan, lisinopril and rampiril. (4) When added to another antihypertensive drug, aliskiren had little or no additional effect on blood pressure. In particular, there is no firm evidence that adding aliskiren to amlodipine 5 mg/day is any more effective than doubling the dose of amlodipine. (5) Aliskiren has not been tested in patients with renovascular hypertension or severe hypertension, but pharmacological data suggest that aliskiren might be less effective in these individuals. (6) Overall, the adverse effect profile of aliskiren does not seem to be any better than that of other antihypertensive drugs. Aliskiren contributes to the onset of angioedema, cough, diarrhea and abdominal pain, hyperuricaemia, gout attacks, kidney stones and skin rash. Pharmacovigilance should focus specifically on certain adverse effects that are known to occur with other drugs acting on renin-angiotensin axis, such as angioedema, muscle disorders and anaemia, even though few such cases were observed with aliskiren during clinical trials. (7) Aliskiren is contraindicated during pregnancy, as are other antihypertensive drugs acting on the renin-angiotensin axis. (8) In practice, it is better not to use aliskiren to treat hypertensive patients because better-assessed antihypertensive drugs with longer follow-up are available.     

Hydralazine and prazosin in the treatment of hypertension.

We report the results of an observer blind crossover trial in 31 patients with essential hypertension comparing the hypotensive effect of four doses of prazosin and of hydralazine used as the third step of triple therapy and additional data on the efficacy of low dose combinations of these two drugs. Both drugs had an appreciable antihypertensive effect, 1 mg of prazosin being equivalent to 12.5 mg of hydralazine. Increasing the dose of prazosin from 4 to 8 mg twice daily and hydralazine from 50 to 100 mg twice daily did not consistently reduce blood pressure. The combination of the two drugs at low doses resulted in the blood pressure of more patients being controlled (diastolic blood pressure 90 mm Hg or below) than when either drug was used alone at high dose. The symptoms reported by patients were similar for both drugs. The combination did not lead to an increased reporting frequency. The trial demonstrates one of the problems of a crossover study, namely a treatment/period interaction.     

Pharmacoeconomics of hypertension management: the place of combination therapy

Pharmacological treatment of hypertension has been shown to reduce the risk of stroke, coronary events, heart failure and progression of renal disease. However, rates of successful blood pressure control remain low among treated patients while antihypertensive medication represents a large and increasing proportion of healthcare expenditure in many countries. Several influential pharmacoeconomic analyses have confirmed the cost effectiveness of conventional antihypertensive treatments, usually involving monotherapy with diuretics or beta-blockers, compared with alternative strategies. Recent research has shown that a considerable proportion of the total cost of antihypertensive treatment in general practice is due to factors such as inadequate blood pressure control, poor compliance with therapy, discontinuation and switching between therapies. These factors operate to a much lesser extent in well-conducted clinical trials, and have not been fully incorporated into most economic studies. Some novel strategies, particularly low dose combinations of antihypertensive agents, may offer advantages in terms of efficacy, reduced adverse effects and improved compliance with treatment. There is therefore a need for comprehensive pharmacoeconomic analyses of novel strategies, taking these additional factors into account. Until such studies are available, the wider use of low dose combination therapy and other novel strategies should not be held back on the basis of earlier economic studies that have not included all relevant considerations.     

Fixed-dose combinations in the first line of antihypertensive therapy

Several clinical studies confirm that fixed low-dose combinations have a number of advantages in the therapy of hypertension. The components with different mode of action provide additive therapeutic effects, resulting in higher blood pressure reduction and greater proportion of responders, moreover the use of low dose antihypertensive agents decreases the frequency of adverse effects. Due to single drug regimen and better tolerance improved compliance is expected. In addition fixed-dose combinations offer cost-containment from the perspective of the patient and the health care service.     

The role of olmesartan medoxomil in the management of hypertension

Intensive blood pressure control is a desirable and obtainable goal in patients with hypertension, according to the most recent treatment guidelines from Europe and the US. Achieving target blood pressure depends on the efficacy of antihypertensive treatment and patient compliance. Olmesartan medoxomil, a non-peptidergic angiotensin AT1 receptor antagonist, has been shown to be effective and well tolerated. Continuation of initial treatment is higher with AT1 receptor antagonists than for any other class of antihypertensive drugs. Olmesartan medoxomil may also have end-organ protective effects that provide additional clinical benefit. Optimal blood pressure control may be achieved faster if initial treatment contains the most efficacious and well tolerated antihypertensive drug or drugs. The ongoing European study, known as OLMEBEST (Efficacy and safety of OLMEsartan: reduction of Blood pressure in the treatment of patients suffering from mild to moderate ESsenTial hypertension), will provide important information on the use of olmesartan medoxomil as an initial treatment for hypertension.     

福辛普利治疗轻、中度原发性高血压疗效和安全性的系统评价

目的:系统评价福辛普利治疗轻、中度原发性高血压的疗效和安全性,以为临床提供循证参考。方法:计算机检索中国期刊全文数据库、万方数据库、中文科技期刊全文数据库(维普资讯)、PubMed、Cochrane Library、EMBase(Ovid)、Medline(Ovid)、Medline In-Process,收集福辛普利治疗轻、中度原发性高血压的随机对照试验(RCT),提取资料后采用Cochrane协作网专用的Rev Man 5.2统计软件进行Meta分析。结果:纳入18项RCT,合计1 511例患者。Meta分析结果表明,福辛普利可以显著降低轻、中度原发性高血压患者的收缩压(SBP)和舒张压(DBP),其降压效果与钙离子拮抗剂比较差异无统计学意义,但显著优于部分利尿药;福辛普利与氢氯噻嗪合用可显著降低患者SBP,对DBP的降低作用与其他药物比较差异无统计学意义;与中药相比,福辛普利的降压作用主要表现为降低患者SBP,对DBP的降低作用与中药比较差异无统计学意义;福辛普利治疗轻、中度原发性高血压的不良反应发生率与其他药物比较差异无统计学意义。结论:福辛普利治疗轻、中度原发性高血压的疗效与钙离子拮抗剂相当,优于其他类型的抗高血压药物,安全性亦较好。由于纳入研究数量较少、质量偏低,该结论有待高质量、大样本的RCT进一步证实。     

Determination of the optimal dose of the antihypertensive drug cicletanine hydrochloride in man

The optimal antihypertensive dose of cicletanine (BN 1270) was investigated in 3 short-term and 3 long-term therapeutic trials using doses of 12.5 to 200 mg. There was a dose-response effect such that in double-blind studies of 1 month's duration, 50 mg/d was the minimum effective dose in mild to moderate hypertensive patients, while a higher dose, 200 mg/d, was more effective in patients with severe hypertension. Despite a quicker reduction in blood pressure by 100 mg cicletanine compared with 50 mg, a similar antihypertensive effect resulted after 3 months' treatment. In patients with mild to moderate hypertension the average decrease in blood pressure over this period was 43.7/38.0 mmHg. A daily dose of 50 mg, which may be increased, particularly at the beginning of treatment, is therefore the optimal recommended dose for these patients. Furthermore, the similar efficacy of the 50 mg and 100 mg doses was confirmed in the long-term trial in the elderly. In all studies, at all doses, cicletanine had a gradual antihypertensive effect, avoiding the risks associated with a sudden fall in blood pressure. The different rates of effect of the 50 mg and 100 mg doses are thought to be due to different mechanisms of action: since 50 mg has no natriuretic effect and 100 mg has a slight natriuretic effect, which is even more pronounced at higher doses.     

Transdermal clonidine. A preliminary review of its pharmacodynamic properties and therapeutic efficacy

The clonidine transdermal therapeutic system (TTS) is a cutaneous delivery device which provides therapeutically effective doses of clonidine at a constant rate over 7 days. In clinical trials it reduces blood pressure in patients with mild to moderate hypertension as effectively as oral clonidine but with greater stability of blood pressure control. Most patients find the transdermal system more convenient than oral treatments, and compliance may be improved. The side effects known to occur with orally administered clonidine, dry mouth and sedation in particular, are also produced with transdermal administration, but possibly at a lower incidence than during oral treatment. A proportion of patients experience adverse skin reactions with the transdermal system. At this stage of its development, transdermal clonidine has not been adequately compared with other 'standard' antihypertensive treatments such as diuretics or beta-adrenoceptor blocking drugs. However, despite the lack of such comparative studies, transdermal clonidine represents a worthwhile new approach to antihypertensive therapy, particularly in terms of patient convenience.     

Haemodynamic changes in peripheral arterial circulation during antihypertensive treatment with captopril, methyldopa and indapamide

Structural changes in resistance vessels of the lower limbs have been detected in early stages of arterial hypertension. In these patients it might be important to reduce blood pressure by drugs which do not impair peripheral blood flow. Twenty-four patients with arterial hypertension, without target organ damage were randomly given a placebo, 50 mg captopril, 500 mg methyldopa or 2.5 mg indapamide and their blood pressure, arterial blood flow and peripheral resistance were measured at baseline and at the peak action of the antihypertensive treatment. Significant decreases in blood pressure and peripheral resistance have been induced by a single oral dose of captopril and methyldopa: a concomitant significant increase in peripheral blood flow to the lower limbs was also observed during methyldopa treatment. No acute effect was observed on the placebo or on indapamide: the latter induced a decrease in blood pressure and in peripheral resistance along with an increase in arterial blood flow during long-term treatment after four weeks of therapy. Our observations seem to support the usefulness in hypertensive patients with concomitant lesions in the peripheral arterial tree of antihypertensive agents such as methyldopa and indapamide which increase blood flow and reduce peripheral resistance while lowering high blood pressure.     

Guanfacine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of hypertension

Guanfacine, a phenylacetyl-guanidine derivative, is a centrally acting alpha-adrenoceptor agonist, with a mechanism of antihypertensive action similar to that of clonidine. It reduces blood pressure in patients with essential hypertension at least as effectively as clonidine or methyldopa. Like lower doses of clonidine, guanfacine can be given once daily due to its relatively long elimination half-life. Although dry mouth and sedation occur frequently with higher doses of guanfacine, their incidence is lower than with other centrally acting antihypertensives; in addition, other troublesome side effects such as orthostatic hypotension or sexual dysfunction also occur much less with guanfacine than with other centrally acting antihypertensive agents. While a withdrawal syndrome may occur on abruptly discontinuing guanfacine administration, the symptoms are generally mild, and the incidence of withdrawal symptoms appears lower than occurs with abrupt withdrawal of clonidine. Thus, guanfacine is an effective and well tolerated alternative to other centrally acting antihypertensive drugs. Whether its final place in therapy will be as an alternative 'second-line' drug, or as initial monotherapy in patients with mild to moderate hypertension, remains to be clarified in comparative studies with diuretics, calcium antagonists, and beta-adrenoceptor blocking drugs.     

Trends in pharmacogenomics of drugs acting on hypertension.

With the recent rapid increase in scientific understanding of the human genome it is becoming possible to identify the extent to which genetic variations influence drug response. The emergence of pharmacogenetics heralds a new era in which drug therapies will be selected on the basis of differences in individuals' genotypes, enhancing drug safety and efficacy. The major focus of this review is pharmacogenetics of antihypertensive drugs. Genetics can influence the pharmacokinetics and pharmacodynamics of such drugs at different levels. The presently available applications of genetic concepts to some drugs commonly used in the treatment of hypertension (ACE-inhibitors, diuretics, beta-blockers...) will be summarized. Also sensitivity to salt intake will be considered as an example of pharmacogenetics. The identification of genetic markers of drug response will help to achieve a better control of blood pressure in the population, by allowing a better tailor of antihypertensive therapy to individual patients.     

氯沙坦和贝那普利治疗原发性高血压对照试验

目的：探讨氯沙坦治疗轻、中度原发性高血压的临床疗效。方法：81例原发性高血压病患者随机分成两组。氯沙坦组（治疗组）：41例,（50－100）mg/d,口服;贝那普利组（对照组）：40例,（10－20）mg/d,口服：疗程均8周。治疗前后做动态血压,肝、肾功能,血糖等检查。结果：治疗组降压总有效率92．7％,对照组90．0％,两组疗效相似,但氯沙坦24h血压控制优于贝那普利,不良反应前者少于后者。结论：氯沙坦是一种安全、作用持续稳定、耐受性良好、不良反应轻微的治疗轻、中度原发性高血压的新型降压药物之一,值得临床推广应用。     

Terazosin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in essential hypertension

Terazosin is a post-synaptic alpha 1-adrenoceptor antagonist with a similar pharmacodynamic profile to prazosin. It differs from prazosin in having a longer duration of action, with an elimination half-life some 2 to 3 times that of prazosin, allowing the convenience of once daily administration. Moreover, its absorption from the gastrointestinal tract is more complete and predictable than that of prazosin which may facilitate dose titration. Terazosin therapy results in a significant reduction in blood pressure in patients with mild to moderate essential hypertension, with little influence on heart rate. The drug is an effective antihypertensive when administered as monotherapy or in combination with a range of antihypertensive agents including beta-blockers, diuretics and combinations of the two. In the few patients with congestive heart failure studied, terazosin produced an increase in cardiac output with a reduction in ventricular filling pressure and systemic vascular resistance, but no studies have been performed to assess the therapeutic potential of terazosin in this indication. Reductions in total plasma cholesterol and low density plus very low density lipoprotein cholesterol fractions have been reported after terazosin therapy, while high density lipoprotein cholesterol concentrations have tended to increase. Should such beneficial changes be confirmed in long term clinical studies they would suggest a therapeutic advantage of terazosin over some other antihypertensive drugs, particularly diuretics, which have been reported to adversely affect the plasma lipid profile. The most common side effects associated with terazosin treatment are dizziness, headache, asthenia and nasal congestion, but these are usually mild and do not require treatment discontinuation. Terazosin is normally administered once daily, starting at a dose of 1 mg/day and gradually titrating upwards as the blood pressure stabilises at each new dose, until blood pressure is adequately controlled or to a maximum dose of 20mg daily. First-dose syncope occurs rarely after terazosin, and can largely be avoided by giving the first dose at bedtime. Thus, terazosin offers a useful alternative to the drugs currently available for the management of mild to moderate essential hypertension either as monotherapy or in combination with other antihypertensive drugs.     

肾交感神经射频消融术治疗顽固性高血压的研究进展

原发性高血压是以体循环动脉压增高为主要表现的临床综合征,长期高血压可影响重要脏器尤其是心、肺、肾的功能,最终导致脏器功能衰竭。顽固性高血压也称为难治性高血压,定义为在改善生活方式的基础上,应用足够剂量且合理的3种或以上降压药物(包括利尿剂)之后血压仍未达标。此类患者易发生多种危重并发症如心脑血管意外(如脑卒中、心力衰竭、心肌梗死等)、肾功能衰竭,甚至猝死。因此,应积极调整不当生活方式、采用合理药物治疗以最大程度降低血压,若血压仍控制不佳的高危患者可考虑肾交感神经射频消融术。     

Antihypertensive combination therapy

The rationale behind employing combination antihypertensive therapy stems from growing evidence that there is a greater need for more aggressive control of systemic arterial pressure to levels below what we have traditionally accepted (140/90 mmHg), and that we have had historically poor control rates with existing approaches to antihypertensive therapeutics. Single agent therapeutic approaches result in only a 40-50% control rate after 6 months of therapy, illustrating that there is a dramatically high rate of discontinuation of antihypertensive drugs in clinical practice. These poor results suggest that there are issues about inadequate education, insufficient efficacy or poor tolerability for which we need to be concerned. Consequently, efforts are under way to reapproach antihypertensive care by focusing on the need for improved education, as well as to reevaluate the traditional teaching of starting with one drug and titrating it upward until an adequate clinical response is achieved. The problem with the latter approach is that it frequently results in an increased incidence of adverse events which interfere with patient tolerability and compliance. Utilization of lower doses of two or more agents may provide satisfactory reduction of blood pressure without the increased risk of adverse events with higher doses of the individual monotherapies. Moreover, there may be complimentary, additive, or even synergistic effects of two drugs working together by different mechanisms. Therefore, a low-dose therapeutic combination may represent an optimal approach, not only for patients unresponsive to higher doses of individual monotherapies, but perhaps also to initiate treatment.     

两种降压联合用药方案对高血压合并糖尿病患者血压变异性影响的比较

目的比较两种降压联合用药方案对高血压合并糖尿病患者血压变异性影响。方法 68例高血压合并2型糖尿病患者分为2组,分别使用缬沙坦胶囊联合吲达帕胺片及依那普利胶囊联合硝苯地平缓释片降压治疗,治疗前及治疗3个月后分别进行24h动态血压监测,观察血压控制情况,比较两组降压联合用药方案治疗前后血压变异性指标。结果使用两种降压联合用药方案均显著降低血压,均可降低血压变异性,但服用缬沙坦胶囊联合吲达帕胺片治疗的患者血压变异性指标优于服用依那普利胶囊联合硝苯地平缓释片的患者。结论两种降压联合用药方案对高血压合并2型糖尿病患者均能有效降压,但考虑降低血压变异性,缬沙坦胶囊联合吲达帕胺片优于依那普利胶囊联合硝苯地平缓释片。     

高龄老年高血压患者降压治疗的临床研究

目的 研究高龄老年高血压患者降压治疗的效果。方法 检测350例高龄患者在降压治疗后舒张压（DBP）≥90mmHg时,70mmHg≤DBP〈90mmHg及DBP〈70mmHg时的血压情况、肾功能损伤情况以及心室射血分数（LEVF）。结果 高龄高血压患者进行降压治疗使舒张压达到70～90mmHg时患者血压稳定、肾损伤减少、LEVF升高（P〈0.05）,优于其他两组患者。结论 高龄高血压患者降血压治疗后使舒张压维持在70～90mmHg之间对患者最有利,符合J形曲线标准。     

贝那普利与卡托普利降压效果的对比研究

目的 对比观察贝那普利与卡托普利治疗轻、中度高血压患者的临床疗效与安全性.方法 将120例高血压患者随机平分为两组,分别给予贝那普利和卡托普利治疗,均加用小剂量氢氯噻嗪, 治疗8周, 于治疗前及治疗8周末行血压监测, 评定各组降压效果.结果 贝那普利组患者降压有效率高于卡托普利组,组间比较差异有统计学意义(P<0.05);不良反应发生率两组间差异无统计学意义(P>0.05).结论 贝那普利对轻、中度原发性高血压病有较好的降压效果,联合应用小剂量利尿剂可提高疗效.     

What can be learned from the experience with the fixed low-dose combination of perindopril/indapamide in the treatment of hypertension?

The association of low doses of perindopril and indapamide in a single pill has been developed to meet the criteria required for a fixed-dose combination to be used as first-line therapy. The experience accumulated so far has demonstrated a greater antihypertensive efficacy of this preparation compared with various monotherapies, but not at the expense of a worsening of tolerability. The perindopril/indapamide combination is particularly effective in lowering systolic and pulse blood pressure. Starting treatment with this fixed-dose combination improves arterial stiffness and allows a better regression of cardiac hypertrophy than angiotensin-converting enzyme-inhibition or beta-adrenoceptor blockade alone. In hypertensive patients with Type 2 diabetes, a greater reduction of urinary albumin excretion can be obtained with the perindopril/indapamide association compared with an angiotensin-converting enzyme inhibitor administered as monotherapy. There is evidence that a first-line management of hypertension based on a low-dose perindopril/indapamide combination can provide a better efficacy/safety ratio than other well-established therapeutic strategies.