Hypertension in women: the role of progesterone and aldosterone.

The age-related course of blood pressure and its gender-related difference, as well as the incidence of hypertension, have been the subject of multiple experimental, clinical and epidemiological studies over the past decades. The role of the sex hormones estradiol and testosterone within this gender dimorphism has been investigated without conclusive results. In this review, we provide background information on the gender difference in blood pressure, describe the impact of progesterone and aldosterone, and discuss the pathophysiology of aldosteronism as well as the potential role of drospirenone as a gender-specific agent for the prevention and treatment of hypertension and for cardiovascular protection.

A new oscillometric method for pulse wave analysis: comparison with a common tonometric method.

In the European Society of Cardiology-European Society of Hypertension guidelines of the year 2007, the consequences of arterial stiffness and wave reflection on cardiovascular mortality have a major role. But the investigators claimed the poor availability of devices/methods providing easy and widely suitable measuring of arterial wall stiffness or their surrogates like augmentation index (AIx) or aortic systolic blood pressure (aSBP). The aim of this study was the validation of a novel method determining AIx and aSBP based on an oscillometric method using a common cuff (ARCSolver) against a validated tonometric system (SphygmoCor). aSBP and AIx measured with the SphygmoCor and ARCSolver method were compared for 302 subjects. The mean age was 56 years with an s.d. of 20 years. At least two iterations were performed in each session. This resulted in 749 measurements. For aSBP the mean difference was -0.1 mm Hg with an s.d. of 3.1 mm Hg. The mean difference for AIx was 1.2% with an s.d. of 7.9%. There was no significant difference in reproducibility of AIx for both methods. The variation estimate of inter- and intraobserver measurements was 6.3% for ARCSolver and 7.5% for SphygmoCor. The ARCSolver method is a novel method determining AIx and aSBP based on an oscillometric system with a cuff. The results agree with common accepted tonometric measurements. Its application is easy and for widespread use.

[Arteriell wall-stiffness: a new important cardiovascular risk factor]. / Arterielle Wandsteifigkeit: ein neuer bedeutender kardiovaskulärer Risikofaktor.

In addition to blood pressure (BP), Augmentation index (AIx) and pulse wave velocity (PWV) are two further parameters to assess arterial function. Even so these functions are partly interdependent, each of them is a strong and independent predictor of vascular risk and end organ damage. In consideration of the high general interest in cardiovascular disease, the diagnostic improvement in assessing abnormal vascular function by these new techniques should be promptly put into practice. The earlier the recognition of vascular dysfunction, the better the chance to prevent vascular or end organ damage by treatment. As dysfunction is directly derived from the vessels where damage should be prevented, AIx and PWV are closer to the object of interest than risk scores, containing predominantly variables which are independent of the vascular tree. Furthermore, they should become abnormal prior to anatomic alteration such as plaques and thus are preferable in early risk diagnostics. As long as BP is the only vascular function diagnosed, its value is similar to that of high cholesterol or waist circumference. But in joining AIx and PWV, these parameters present information on vessel wall function, such as elasticity and on unfavourable hemodynamic flow conditions. An advantage of AIx and PWV over BP-recording is their lower variability as shown in a comparison in 97 hypertensive patients. The standard deviation (SD) of three consecutive blood pressure recordings was systolic/diastolic: 8.7/6.0 mmHg, the SD of three consecutive HR-recording 3.2 beats/min, the SD of three AIx-recordings: 3.9% (TensioClinicgerät) and SD of three PWV-recordings: 1.6 m/sec (TensioClinicgerät).

Blood pressure characteristics of hypertensive patients in Austria as determined by self-monitoring (SCREEN-II).

This is the first large-scale, countrywide study evaluating blood pressure levels in treated hypertensive patients based on home blood pressure monitoring. The study was conducted all over Austria by 166 physicians enrolling a total of 1303 patients each taking at least 30 home blood pressure readings (a total of 39,000 readings). Stratification of patients into groups with normotension, mild hypertension or severe hypertension followed the recommendations of the Austrian Hypertension League (normotension defined as no more than seven readings higher than 135/85 mmHg, according to a blood pressure load of no more than 25%). The data collected show that these patients are inadequately treated, with only 17% being normotensive. Treatment results are no better than in patients with blood pressure measured in an office setting: the number of those achieving normotension is 17% vs 16%, although the self-measuring patients obviously receive better treatment with more patients being prescribed combination therapy.

Efficacy of very low dose perindopril 2 mg/indapamide 0.625 mg combination on left ventricular hypertrophy in hypertensive patients: the P.I.C.X.E.L. study rationale and design.

The PICXEL study is designed to evaluate the effects of long-term administration of very low-dose combination perindopril 2 mg/indapamide 0.625 mg (Per/Ind) vs enalapril in reducing left ventricular hypertrophy (LVH) in hypertensive patients. This multicentre, controlled, randomised, double-blind, parallel group study is carried-out to assess the variation of left ventricular mass index (LVMI) after treatment, using a centralised control of M-mode echocardiography determinations, and a dedicated software for semi-automatic measurement. Following a 4-week placebo run-in period, hypertensive outpatients aged >/=18 years, with LVH (LVMI >120 and 100 g/m(2) for men and women, respectively), are randomised to receive once daily, over 52 weeks, either Per/Ind or enalapril. According to blood pressure levels, the dose may be adjusted. In addition to clinical examinations, ECG, blood pressure, heart rate and laboratory assessments echocardiographic determinations are performed for selection, at baseline, after 24 weeks and at the end of the study. The main outcome criteria is the change from baseline in LVMI which is considered the primary efficacy criterion; changes in blood pressure and echo-Doppler parameters constitute secondary criteria. Two-sided Student's t-test for independent samples will be used to differentiate the effects of the treatment between groups with alpha = 5%, and the inter-group difference of LVMI variation will be analysed with a power of 90%. A sample size of 500 patients is required making it necessary to randomise at least 550 patients, based on a 10% proportion of potentially non-assessable patients. The results of this study, obtained after applying strict methodological procedures and requirements, are expected to provide valuable and reliable information on the effects of long-term administration of Per/Ind on LVH, and on its potential superiority over enalapril.

[Angiotensin receptor blockers--significance for the therapy of hypertension]. / Angiotensin-Rezeptor-Blocker--Bedeutung für die Hochdrucktherapie.

Angiotensin receptor antagonists (ARB) are equally effective but better tolerated than all the other blood pressure lowering agents. The reason, why they are not subscribed as first line drugs for uncomplicated hypertension, is the higher price for these products. What the real difference in costs is, remains unclear because calculations are missing to what extent lesser controls of therapy would shift the balance in favour of the ARBs. For other indications than hypertension, but often associated with that condition, be it per se or as a consequence of it, the effects of the ARBs are studied in large trials these days. For some of them the benefit, which has been proven for ACE inhibitors, is not yet established for the ARBs, but evidence emerges that they are also useful in the treatment of cardiac failure, left ventricular hypertrophy and diabetic and other kinds of nephropathy. A large percentage of hypertensive patients can be treated effectively with ARBs without considerable side effects, thus increasing adherence and minimizing the necessity of safety controls.

Intestinal elimination of hydroxyethyl starch?

OBJECTIVE: Hydroxyethyl starch (HES) is mainly eliminated via the kidneys. Any information about extrarenal elimination obtained so far has been either incomplete or contradictory. The objective of this study was to quantify the intestinal excretion of infused HES with a mean molecular weight of 200,000 and a molar substitution of 0.5 (HES 200/0.5) and to compare the reappearance/recovery rate in urine and plasma. DESIGN: Prospective clinical study without control group. SETTING: The study was conducted at the Institute of Hypertension of the Society of Clinical Pharmacology, Vienna, Austria, which is an establishment for research in volunteers. PARTICIPANTS: The results of six out of seven healthy male volunteers were appropriate for analysis. One trial subject had to be excluded from the study because of severe protocol violation (mixing of stool and urine samples). INTERVENTIONS AND METHODS: Each volunteer was administered 500 ml of 10% HES 200/0.5 in a 0.9% NaCl solution intravenously within 1 h. A gut lavage with 6 l of a polysaccharide free solution was continuously administered from 3 h prior to until 2 h after the HES infusion to facilitate the collection of the samples and to exclude any source of error at analysis. HES was quantified with the hexokinase method. MEASUREMENTS AND RESULTS: Right from the beginning of the infusion until 10 h after its completion, the cumulative HES excretion with feces (principle parameter) and urine as well as selective plasma volume and HES plasma level were measured. Six and 14 h after the infusion had been completed, the recovery rates of HES in urine were about 30% and 40%, respectively, and in plasma about 23% and 8%, respectively. By contrast, not more than a kind of "background noise amount" of HES (about 0.2 %) could be recovered in feces ( mean value in % of the infused amount of the substance). Six and 14 h after the infusion had been completed, the total recovery rates of HES were 53% and 49%, respectively. CONCLUSION: In a physiologically unimpaired gut HES 200/0.5 is not, or only to an infinitesimal extent, eliminated via the intestine. The question if there is any alternative path to renal excretion for HES still remains to be answered. As the calculated reappearance/recovery rate of HES is only about 50 % of the administered dose, further investigations as to the final fate of HES appear necessary.

Felodipine-metoprolol combination tablet: a valuable option to initiate antihypertensive therapy?

The aim of the present study was to assess the efficacy and tolerability of a calcium antagonist/beta-blocker fixed combination tablet used as first-line antihypertesnive therapy in comparison with an angiotensin converting enzyme inhibitor and placebo. Patients with uncomplicated essential hypertension (diastolic blood pressure between 95 and 110 mm Hg at the end of a 4-week run-in period) were randomly allocated to a double-blind, 12-week treatment with either a combination tablet of felodipine and metoprolol (Logimax), 5/50 mg daily (n = 321), enalapril, 10 mg daily (n = 321), or placebo (n = 304), with the possibility of doubling the dose after 4 or 8 weeks of treatment if needed (diastolic blood pressure remaining >90 mm Hg). The combined felodipine-metoprolol treatment controlled blood pressure (diastolic < or =90 mm Hg 24 h after dose) in 72% of patients after 12 weeks, as compared with 49% for enalapril and 30% for placebo. A dose adjustment was required in 38% of patients receiving the combination, in 63% of patients allocated to placebo, and 61% of enalapril-treated patients. The overall incidence of adverse events was 54.5% during felodipine-metoprolol treatment; the corresponding values for enalapril and placebo were 51.7% and 47.4%, respectively. Withdrawal of treatment due to adverse events occurred in 18 patients treated with the combination, in 10 patients on enalapril, and 12 patients on placebo. No significant change in patients' well-being was observed in either of the three study groups. These results show that a fixed combination tablet of felodipine and metoprolol allows to normalize blood pressure in a substantially larger fraction of patients than enalapril given alone. This improved efficacy is obtained without impairing the tolerability. The fixed-dose combination of felodipine and metoprolol, therefore, may become a valuable option to initiate antihypertensive treatment.

[How reproducible is blood pressure measurement? Intra- and interindividual blood pressure variability in routine practice]. / Wie reproduzierbar ist die Blutdruckmessung? Intra- und interindividuelle Blutdruckvariabilität im Alltag.

Considering the reproducibility of blood pressure readings the epidemiologist and the physician in his clinical work take two different points of view. Studying drug effects the epidemiologist is interested in significant differences of blood pressures in a study population. The physician however, who estimates the effect of his prescription given to an individual patient has to compare single blood pressure readings in single individuals. In a pharmacological study we accept without any doubt the need of certain numbers of investigations to define a difference of 10 mm Hg as significant. In clinical routine however we behave quite differently and judge single readings intuitively as equal or different, independent of any statistical considerations. Not only the doctor but also the scientific societies with the highest reputation share the same point of view. In their recommendations they accept an arithmetic mean of two blood pressure readings as sufficient to judge blood pressures in individuals. In order to discuss this topic primarily from the doctors point, we analysed repeated blood pressure readings of 21 volunteers who tested 20 different blood pressure devices. We conclude, that the ongoing practice of judging the blood pressures of the patients meets only the needs of the epidemiologist. Reproducibility of single readings or mean values of two readings however are insufficient to draw satisfactory conclusions from the distributions of blood pressure in single individuals. Due to the short and long term blood pressure variability increasing the numbers of readings within a single day does not improve reproducibility sufficiently. It seems that the amount of blood pressure readings which are necessary to improve reproducibility of "the patients blood pressures" should be increased and taken over several days. If this is true, daily self-recordings should be the most promising approach.

Treatment of left ventricular hypertrophy in hypertensive patients with a combination of verapamil and captopril--a multicenter study.

UNLABELLED: The regression of left ventricular hypertrophy in hypertensive patients was evaluated in a multicenter study with a combination therapy of verapamil 120 mg and captopril 25 mg given once or twice daily. The degree of left ventricular hypertrophy was assessed using echocardiography, while hypertension was evaluated by means of twice daily blood pressure self-measurements and ambulatory blood pressure monitoring. RESULTS: An overall of 61 patients was evaluated. Left ventricular mass had decreased by 13.5% during the 6-month treatment period. This reduction neither correlated with the baseline left ventricular mass nor with the extent of blood pressure decrease. CONCLUSION: The combination therapy-verapamil 120 mg plus captopril 25 mg--is well tolerated by hypertensive patients with left ventricular hypertrophy and produced a decrease of left ventricular mass that is independent of the extent of blood pressure decrease.

[Compliance of the hypertensive patient in medical practice--analysis of an observation study. 2]. / Die Compliance des Hypertonikers in der ärztlichen Praxis--Analyse einer Anwendungsbeobachtung. 2. Teil.

In a subgroup of 301 hypertensive patients out of the user--observation study ("Anwendungsbeobachtung") with Renitec und CO-Renitec we studied which compliance-improving methods are effective. We tested the effects of blood pressure self-measurement and of an exclusive conversation with the patients. It could be shown, at least in our approach, that the conversation with the patient resulted in a lighter efficacy than blood pressure self-measurement: > 80% compliance was found in 80% of the patients, compared with only 40% of the patients with standard care.

[Therapy of hypertension in general practice with Renitec and Co-Renitec--analysis of an administration study]. / Die Therapie des Hochdrucks in der ärztlichen Praxis mit Renitec und Co-Renitec--Analyse einer Anwendungsbeobachtung.

In a user-observation study ("Anwendungsbeobachtung") it could be demonstrated that Renitec and Co-Renitec lowered elevated blood pressure but not sufficiently according to the WHO-criteria. It seems that the necessary dose titrations are not carried out in a daily routine. Furthermore it has to be stated that even widespread observation studies are not able to differentiate the properties of a drug. It remains to be considered whether more requirements on observation studies are necessary (regarding exact criteria for their design and increased monitoring) and should be implemented to improve the quality of data, although this would mean more time for the physician. Only under such conditions statements about rare side effects, influences of concomitant diseases and their treatments will be possible.

A comparative bioavailability study on two new sustained-release formulations of disodiummonofluorophosphate versus a nonsustained-release formulation in healthy volunteers.

In 12 healthy volunteers the pharmacokinetic parameters of two new sustained-release formulations of disodiummonofluorophosphate (MFP) (B and C) were compared with those of a nonsustained-release reference preparation (A). This randomized study had a single-dose, triple-cross over design and consisted of 3 trial days separated by a 1-week washout period. Serial blood samples were obtained over a period of 24 hours and 24-hour urine was collected. Serum and urine fluoride concentrations were determined using an ion-sensitive electrode (Orion Research). The results of this study showed a significant reduction of the area under the serum concentration versus time curve (AUC) for the sustained-release formulations (AUC B: 1487 +/- 354 ng/ml x hour, AUC C: 1369 +/- 384 ng/ml x hour) compared with the reference preparation (AUC A: 2374 +/- 652 ng/ml x hour) (B/A: 63%, C/A: 58%) (P < 0.001). Furthermore, the peak serum concentrations of fluoride (Cmax) for B and C (CmaxB: 166 +/- 42 ng/ml, CmaxC: 110 +/- 48 ng/ml) were significantly lower than for A (CmaxA: 380 +/- 77 ng/ml) (P < 0.001). The 24-hour urine fluoride recovery rates were 5.6 +/- 0.7 mg fluoride for A, 3.6 +/- 0.8 mg for B, and 3.2 +/- 1.1 mg for C and corresponded well to the relative fluoride bioavailability, as concluded from the serum fluoride concentration. In conclusion, the sustained-release preparations of MFP led to a decrease of fluoride bioavailability and avoided high peak serum concentrations.

[Individualized therapy of hypertension. The Austrian Professional Group of Clinical Pharmacology]. / Individuelle Hochdrucktherapie.

The Austrian Working Group on "Individualization of Antihypertensive Therapy" (IHT) published guidelines for the treatment of hypertensive patients with additional risk factors, diseases and other circumstances leading to a modification of the standard therapy. According to the number of prescribeable drugs the quantity of different recommendations is difficult to be followed without assistance. To support the performance of the guidelines, the Austrian Working Group IHT offers instructions (folder) and PC-Software.

[Patient compliance of hypertensive patients in the physician's practice]. / Compliance von Hypertonikern in der ärztlichen Praxis.

Compliance of hypertensive patients is primarily estimated in participating patients in clinical trials. Although compliance is overestimated by pill-counting, this technique is most frequently used. 389 Austrian general practitioners studied compliance in 945 hypertensives, using the Medication Event Monitoring System. The patients were asked to take the ACE-inhibitor Cilacapril once a day between 7.00 a.m. and 9.00 a.m. Each package opening was registered by a microprocessor located in the cover of the drug vial. In this study it turned out that only 1.3% of the patients did open their vials between 7.00 a.m. and 9.00 a.m. 2 thirds of the patients actually took less than 80% and 36% less than half of the prescribed medication. There was no correlation between compliance and sex, age, smoking habits, tolerance or duration of hypertension. Even fall in blood pressure was the same in compliant and non compliant patients. The conclusion is that compliance is bad in a general practitioner setting and further more that casual readings as performed in this study are an insufficient tool to judge efficacy.

[New aspects in evaluating the hypertensive patient: measuring blood pressure in the physician's office--ambulatory blood pressure monitoring--blood pressure self-measurement]. / Neue Aspekte bei der Bewertung von Hypertonikern: Blutdruckmessung in der Arztpraxis--Ambulantes Blutdruckmonitoring--Blutdruck-Selbstmessung.

The "average" blood pressure of hypertensives, which is held responsible for the adverse effects of hypertension is poorly reflected by causal readings (CR), which are taken as a surrogate. CR do not only differ from average blood pressures, but also fail to give information on blood pressure variability. According to white coat effect and blood pressure variability a satisfying classification of severity and consecutively of prognosis cannot be done in an individual. Furthermore CR fail to inform us sufficiently about therapeutic effects in single patients. To improve we have to change to blood pressure judgements which are based on many instead of occasional readings. Ambulatory blood pressure monitoring (ABM) is a possibility to overcome this weakness. Compared to casual readings the average of the ambulatory readings is higher reproducible and does not depend on placebo treatment. In spite of this advantage a general substitution of CR by ABM is impossible because the number of equipment available is too small, nobody wants to cover the costs, the procedure is inconvenient, and up till now we miss guidelines how to proceed in the daily routine. Blood pressure self-monitoring is an additional way to improve the weakness of CR. The amount of blood pressure readings needed for a satisfying judgement of blood pressure are taken and registered by the patients. The self recorded data can be used as a valuable data base to calculate average blood pressure and blood pressure variability and drug effects. Mean values of twice daily recordings of a month are highly reproducible and do highly correlate to average ABM recordings of the day.

A multicenter study using causal readings, self-recordings, and ambulatory blood pressure monitoring to assess isradipine effects. AMICUS Study Group.

The antihypertensive efficacy of isradipine has been widely studied. In most studies, however, blood pressure values were assessed by causal readings (CR) only. Furthermore, whether or not such blood pressure readings are sufficient proof of efficacy is still under discussion. Thus, a multicenter study was devised wherein blood pressure were recorded by CR, self-recordings, and noninvasive ambulatory monitoring (ABM). A total of 595 patients with mild-to-moderate hypertension were treated for 6 months starting with 1.25 mg of isradipine twice daily. If, after 4 weeks of treatment, CR-determined diastolic blood pressure (DBP) was still > 90 mm Hg, this dosage was doubled (n = 327) and, at week 8, pindolol at 5 mg or spirapril at 3 mg daily was added if necessary for blood pressure control. On the basis of CR, the results confirmed that low dosages of isradipine twice daily are safe and effective in the treatment of mild-to-moderate hypertension. The mean decrease in CR-determined blood pressure was 28.5/19.0 mm Hg at week 24, and the normalization rate (DBP < or = 90 mm Hg) for all patients treated was 78.2%. However, SR-determined blood pressure reduction was 20.0/13.0 mm Hg, with a normalization rate of 42%, whereas ABM-determined blood pressure reduction was 7.0/4.2 mm Hg. On the basis of ABM recordings, 66% of the patients had a DBP < 90 mm Hg on entry into the study and their blood pressures did not decrease with treatment. Thus, it appears that CR-determined blood pressures bias study results by including normotensives and thereby overestimating efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)

Preoperative assessment and prediction of postoperative results in an artificial arterial network using computer simulation.

A computer model has been developed that can be used to describe the human arterial system mathematically. It simulates the complex relationship of morphology and hydraulics in the vessel network. After entering patient data into a standard vessel model, the mean flow velocity, the flow direction, and the blood pressure at each specified point of the flow network can be calculated. The vessel picture can be altered and modified with the help of a graphic editor. Localized or diffuse stenoses, bypasses with simple or multiple anastomoses, end-to-end anastomoses, end-to-side anastomoses, etc., can be studied in terms of the hydraulic effects on the local situation or on the entire vessel system. Experimental results of ultrasonic mean flow data in vessel systems of leg and cerebral arteries of patients are compared with calculated values. The predicted and measured flow velocities show a mean difference of about 10% indicating that such a computer model may be successfully used in the optimal planning of bypass operations.

Isradipine in the treatment of mild-to-moderate hypertension. The Austrian Multicenter Isradipine cum Spirapril Study (AMICUS).

The objective of this study was to assess the safety and efficacy of 1.25 to 2.5 mg of isradipine twice daily in patients with mild-to-moderate hypertension, as seen in general practice. A total of 595 patients were treated for 6 months with an initial dose of isradipine at 1.25 mg twice daily. This dose was doubled if normotension (diastolic blood pressure [DBP] < or = 90 mm Hg) was not achieved after 4 weeks of treatment (n = 327). If, after 8 weeks, blood pressure was still not normalized, either the angiotensin-converting enzyme (ACE) inhibitor spirapril at 3 mg (n = 58) or the beta-blocker pindolol at 5 mg (n = 54) was added to the treatment. After 24 weeks, the mean blood pressure decrease with isradipine at 1.25 mg twice daily was 28.5/19.0 mm Hg for systolic blood pressure (SBP)/DBP and, with 2.5 mg isradipine twice daily, 28.4/18.5 mm Hg. There was no relevant change in heart rate. The overall normalization rate for all 595 patients was 78.2%. Side-effects that were considered related or possibly related to treatment were reported in 73 patients (12.3%). Treatment with isradipine plus either spirapril or pindolol was discontinued in 32 patients (5.4%) because of side-effects related, or possibly related, to the study treatment. Blood pressure was also self-recorded in a subgroup of 45 patients. The self-recorded values were 11/6 mm Hg (SBP/DBP) lower than the respective causal readings at the start of active treatment. However, this difference disappeared completely after 8 weeks of treatment.