Nebivolol/hydrochlorothiazide (HCTZ) combination in patients with essential hypertension: a pooled analysis from five non-interventional studies with a focus on diabetic and elderly patients.

BACKGROUND AND OBJECTIVES: Nebivolol is a third-generation beta-blocker, characterized by unique pharmacological properties. The combination of nebivolol and hydrochlorothiazide (HCTZ) has been evaluated in large-scale clinical trials. This post-marketing surveillance analysis evaluated the effectiveness of the nebivolol/HCTZ combination in a "real-life" setting that included diabetic and elderly patients. PATIENTS AND METHODS: The analysis was based on data from five non-interventional studies conducted in Germany, which lasted up to 12 weeks. Data from patients treated with nebivolol/HCTZ 5/12.5 mg/day in combination were pooled. The following parameters were calculated at the final visit, in the whole population and in elderly (>70 years) and diabetic subgroups: (1) difference from baseline in diastolic blood pressure (DBP) and in systolic blood pressure (SBP); (2) percentage of responder patients (reduction in DBP or SBP of 10 or 20 mmHg, respectively). Alterations in laboratory parameters were also monitored. RESULTS: In total, 86 patients (mean age 58.9 +/- 10.8 years) were included in the analysis. Nebivolol/HCTZ significantly reduced both DBP (-11.8 +/- 7.9 mmHg; p<0.0001 vs baseline) and SBP (-22.5 +/- 13.5 mmHg; p<0.0001 vs baseline). In total, 81.4% of patients were responders (75% and 83.3% in elderly and diabetic patients, respectively). No clinically significant alterations in laboratory parameters were observed. DISCUSSION: This study confirms that nebivolol/HCTZ is an effective and well tolerated therapeutic strategy in a real-life setting as well as in clinical trials. Therefore, this combination may represent a first-choice therapy in the management of hypertension.

Comparison of benazepril-amlodipine and captopril-thiazide combinations in the management of mild-to-moderate hypertension.

OBJECTIVE: To compare the efficacy and tolerability of benazepril 10 mg + amlodipine 5 mg combination (BZ+AM) versus captopril 50 mg + hydrochlorothiazide 25 mg (CP+HT) combination. MATERIAL: 405 outpatients with mild-to-moderate arterial hypertension not adequately controlled by a monotherapy with ACE inhibitors or calcium channel blockers or diuretics entered this multicenter, double-blind, randomized, parallel-group study. METHOD: After a 2-week placebo run-in, 397 patients with sitting diastolic (D) blood pressure (BP) > 95 mmHg and/or sitting systolic (S) BP > 160 mmHg were randomized to receive either BZ+AM (201 patients) or CP+HT (196 patients) once daily for 12 weeks. Main outcome measure was sitting DBP and SBP values at the end of active treatment. The response rate was defined as the proportion of patients with either a final sitting DBP < 90 mmHg or decreased by at least 10 mmHg or a sitting SBP < 150 mmHg or decreased by at least 20 mmHg from baseline. RESULTS: The DBP and SBP values obtained with BZ+AM were, respectively, 2.7 and 3.7 mmHg lower than those obtained with CP+HT (both p < 0.001 vs. CP+HT). The response rate in the BZ+AM group (94.8%) was better than that observed in the CP+HT group (86.0%, p = 0.004). The incidence of adverse events was similar with the 2 treatment regimens (17.9% for both). CONCLUSIONS: These data suggest a higher antihypertensive efficacy of the fixed combination BZ 10 mg+AM 5 mg as compared with CP 50 mg+HT 25 mg.

A multicenter, randomized double-blind study of valsartan/hydrochlorothiazide combination versus amlodipine in patients with mild to moderate hypertension.

OBJECTIVE: To compare the antihypertensive efficacy and tolerability of a once-daily fixed valsartan/hydrochlorothiazide (HCTZ) combination and amlodipine in subjects with mild-to-moderate hypertension. SUBJECTS AND SETTING: In this multicentre, double-blind, randomized, comparative trial, 690 patients with sitting systolic blood pressure (BP) > or = 160 mmHg and sitting diastolic BP > or = 95 mmHg at the end of a 2-week placebo wash-out period were randomized to valsartan-based treatment (n = 342) or amlodipine (n = 348). METHODS: The patients received valsartan 80 mg o.d. or amlodipine 5 mg o.d for 4 weeks; in the case of an unsatisfactory blood pressure response, the treatments could be respectively changed to the fixed combination of valsartan 80 mg + HCTZ 12.5 mg o.d. or amlodipine 10 mg o.d. for a further 8 weeks. RESULTS: Both treatment approaches decreased systolic blood pressure and diastolic blood pressure to the same extent. The rate of responders to treatment at the end of fourth week (before up-titration) was 57.4% among the valsartan-treated patients and 61.9% among the amlodipine-treated patients (ns). At the end of the study, the rate of responders was not significantly different between the two groups (74.9 versus 72.1%). Valsartan-based treatment had a slightly lower incidence of adverse events (1.5 versus 5.5%; P = 0.006). CONCLUSIONS: The results of this trial demonstrate that the valsartan/hydrochlorothiazide combination and amlodipine are equally effective in lowering BP, and that the combination is better tolerated.

[Evaluation of the efficacy and tolerance of doxazosin vs. enalapril inaged patients with light to moderate arterial hypertension]. / Valutazione dell'efficacia e della tollerabilità del doxazosin vs enalapril in pazienti anziani affetti da ipertensione arteriosa lieve-moderata.

The above study was performed as a single blind trial in 70 elderly patients (average age 66 years) who were randomized into two groups of 36 and 34 subjects respectively. After clinical and laboratory evaluation without treatment for at least two weeks, the two groups were treated with enalapril 5-10 or 20 mg daily plus doxazosin at the dosage of 1-2-4- or 8 mg daily; they were observed for 24 weeks. During the trial, pressure values, both systolic and diastolic, were seen to diminish significantly in both groups. This effect was accompanied by minor, usually transient side effects. At echocardiography at the end of the treatment period, doxazosin was found to reduce some volumetric cardiac parameters, thus showing to be apt to counteract left ventricular hypertrophy. These findings go to counteract left ventricular hypertrophy. These findings go to show that alpha-1 inhibitors are a valid alternative in the "first step" of antihypertensive therapy, especially in patients at risk for cardiovascular complications.

Systolic hypertension in the elderly: long-term lacidipine treatment. Objective, protocol, and organization. SHELL Study Group.

Isolated systolic hypertension (ISH) is a definite risk factor for cardiovascular complications (i.e., cardiac failure, coronary artery disease, and stroke) independent of diastolic elevation. The prevalence of ISH is estimated to be approximately 15-20% in the population above the age of 60 years, and increases with advancing age. The Systolic Hypertension in the Elderly (SHELL) study is planned to evaluate the efficacy and tolerability of lacidipine, matched with the diuretic chlorthalidone, in treatment of ISH in elderly hypertensive patients (EHP). One hundred fifteen Italian centers will participate in the study. Fifty centers are associated with the Società Italiana di Geriatria Ospedaliera and 65 centers are departments of internal medicine or outpatient clinics for management of hypertension. A total of 4,800 patients will be enrolled in the trial. Two subprojects will consist of periodical echocardiographic evaluation and 24-h ambulatory blood pressure monitoring. The primary end point of the SHELL study is the incidence of cardiovascular and cerebrovascular events in EHP with ISH, treated with either lacidipine or chlorthalidone. In particular, the SHELL trial is intended to determine whether lacidipine treatment will significantly reduce fatal myocardial events and total cardiovascular mortality.

Evening vs morning isradipine sustained release in essential hypertension: a double-blind study with 24 h ambulatory monitoring.

A randomized, double-blind, placebo controlled study evaluated the effects on 24 h ambulatory blood pressure (ABP) of isradipine sustained release (I-SRO) administered once daily, in the morning (AM) or in the evening (PM). Eighteen uncomplicated essential hypertensives (10 men, mean age 55 +/- 6 years) with casual sitting DBP 96-110 mm Hg received, according to a triple-way crossover design, I-SRO 5 mg AM, or 5 mg PM, or placebo for 4 weeks. A 24 h ABP monitoring (Spacelabs 90207) was carried out at the end of each treatment. Twenty-four hour BP was 145.3/89.8 mm Hg after randomized placebo. AM and PM I-SRO significantly reduced 24 h BP, by 13.7/8.7 and 12.9/8.2 mm Hg respectively. Daytime (07.00 h-23.00 h) BP significantly decreased by 15.0/9.7 mm Hg with AM and 13.2/8.7 mm Hg with PM regimen; night-time BP (23.00 h-07.00 h) significantly decreased by 11.6/7.1 and 12.3/7.4 mm Hg, respectively. Nocturnal nadir BP values were 132.6/78.1 after randomized placebo, 120.9/71.4 after AM I-SRO and 121.0/72.4 mm Hg after PM I-SRO. Morning peak BP values were 154.6/96.9, 139.5/87.6 and 137.5/85.5 mm Hg, respectively. Mean BP values in the early morning hours (i.e. between 03.00 h and 08.00 h) were significantly decreased by 12.1/7.3 mm Hg after AM and 14.3/7.9 mm Hg after PM intake. No significant differences were detected in the BP lowering effect of the two I-SRO regimens.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of a vasodilating beta-blocker and a cardioselective beta-blocker in long-term treatment of hypertension: a European multicentre study.

The therapeutic effectiveness and safety of indenolol, a vasodilating beta-blocker with beta 2-agonism, was compared with that of atenolol, a cardioselective beta-blocker, in a 1-year double-blind trial. A total of 143 hypertensive patients (diastolic blood pressure 95-115 mmHg after 1 month of placebo) were randomly allocated to either atenolol, 50 mg/day, or indenolol, 60 mg/day. If the target diastolic blood pressure (less than or equal to 90 mmHg) was not reached after 1 month, the beta-blocker was doubled. If the target was still not reached, a diuretic was added after 2 months and doubled after 4 months. There was a higher overall responsiveness and monotherapy was more effective in the atenolol group, but at the lower dose indenolol was more effective than atenolol; however, no differences between drugs were significant. Although the drop-out rate was higher with indenolol, withdrawals due to side effects were similar in both groups. Indenolol was as effective and safe as atenolol in long-term antihypertensive therapy.

[Captopril and hydrochlorothiazide combined in the treatment of mild-to-moderate hypertension. Evaluation of sugar and lipid metabolism in a long-term study]. / Captopril e idroclorotiazide associati nel trattamento della ipertensione lieve-moderata. Valutazione del metabolismo glucidico e lipidico in uno studio a lungo termine.

Ten hypertensive patients (I-IIWHO) were treated for a period of three months with captopril 50 mg + hydrochlorothiazide 25 mg once or twice daily, with the aim of evaluating the antihypertensive effectiveness of this association and the lack of influences on lipid and mainly glucose metabolism. Blood pressure and heart rate were evaluated every month, while chemical tests were performed at the beginning and at the end of the trial. Besides before and after treatment were studied blood glucose and insulin levels during oral glucose tolerance test, at times 0, 15', 30', 60', 90', 120', 180'. Our data show that captopril combined with hydrochlorothiazide has a good antihypertensive action, and doesn't alter lipid and glucose metabolism either after oral glucose tolerance test.

[Problems in the treatment of the hypertensive diabetic patient]. / Problemi di trattamento del paziente iperteso diabetico.

Hypertension is much more common among diabetics than non-diabetics and particular care must be taken in treating both chronic pathologies. It is in fact vital to consider the effect antihypertensive drugs may have on diabetes and its complications. Hence the choice of anti-hypertensive drug for a patient with diabetes mellitus must be preceded by a careful study of the metabolic effects of that drug. An attempt is made to assess the interference by antihypertensive agents with glucose metabolism and to identify an appropriate treatment protocol for the patient with both arterial hypertension and diabetes mellitus.

[Hypertension therapy in the elderly. Our experience with converting enzyme inhibitors]. / La terapia dell'ipertensione nell'anziano. Esperienza con gli inibitori dell'enzima di conversione.

Arterial hypertension shows, in the elderly, particular features and special problems connected with its pharmacological treatment. In our work ten patients, aged between 65-75, suffering from essential hypertension, were examined for eight weeks. At the end of this period, we observed a significant reduction of systolic and diastolic pressure, heart rate being unchanged. We didn't observe any significant change in the metabolic parameters considered (uricemia, creatininemia, triglycerides and cholesterol). No patient had to interrupt the treatment as a consequence of side effects. According to our data, we can affirm that Captopril reduces arterial pressure gradually and doesn't cause orthostatic hypotension, being thus very useful in the elderly.

Acute and long-term haemodynamic effects of propranolol and indenolol in hypertension.

The haemodynamic effect of indenolol, a beta-adrenoceptor blocker with intrinsic sympathomimetic activity (ISA) in animals, has been evaluated in a double-blind cross-over randomized trial after acute (3 days) and long-term treatment (28 days), in 12 hypertensive patients in comparison with that of propranolol. Patients were evaluated at rest and during isometric exercise (hand grip). The overall acute effect of both beta-adrenoceptor blocking drugs was to decrease mean blood pressure, heart rate and cardiac output, while total peripheral resistance increased. In the long-term studies the haemodynamic effect of propranolol was still characterized by cardiodepression and unchanged peripheral resistance. Patients on the long-term treatment with indenolol showed normal cardiac output and reduced total peripheral resistance. The data are compatible with a relatively strong ISA of indenolol, which would be responsible for the haemodynamic pattern observed during chronic treatment.

Evidence for a role of a serum factor stimulated by metoclopramide in regulating aldosterone secretion.

The stimulatory effect of metoclopramide upon aldosterone secretion is independent of the known aldosterone-regulating mechanisms (renin, potassium, adrenocorticotropic hormone), is unrelated to its effect on prolactin and is absent when metoclopramide is directly added to isolated adrenal zona glomerulosa cells. To examine the possibility of a "humoral" mediation of aldosterone stimulation by metoclopramide, we evaluated the effect of serum of 10 normal subjects injected with metoclopramide (10 mg i.v.) on aldosterone production by collagenase-dispersed calf adrenal zona glomerulosa cells. Whereas no effect was observed with serum collected before the injection, serum collected from 5 to 30 min after the injection stimulated aldosterone production. The effect was seen 2.5 min after the injection, was significant at 5 min (P 0.05), 10, 15, 20 and 30 min (P 0.01). The effect disappeared 40 min after the injection, when plasma aldosterone in subjects was still elevated (P 0.01). The biological half-life of the factor (t1/2) is about 12.5 min. A significant correlation was found between the maximal aldosterone response to metoclopramide in vivo and the maximal effect of serum in vitro (r2=0.69;P 0.01). We suggest that metoclopramide stimulates aldosterone production in vivo by the increase in serum of a factor which, in turn, stimulates aldosterone and whose physiological significance remains to be evaluated.

In vitro steroidogenic properties of FK 33 824, a stable analog of methionine-enkephalin. Opiate-dopamine interaction in the control of aldosterone production.

The steroidogenic properties of a stable analog of the endogenous opioid methionine-enkephalin, FK 33 824, were studied with calf adrenal glomerulosa cells and its effects were compared to those of angiotensin II (A II) and metoclopramide. Metoclopramide, A II, and FK 33 824 induced dose-related increases in aldosterone production. The order of potency in stimulating aldosterone was A II, FK 33 824, metoclopramide. Metoclopramide and FK 33 824 did not increase cortisol production. The response to A II but not to FK 33 824 was inhibited by equimolar concentrations of (Sar1 Ala8) antagonist analog of AII (saralasin acetate). By contrast in the presence of equimolar concentrations of naloxone, an opioid receptor antagonist, FK 33 824-induced aldosterone production was markedly inhibited while the response to A II was unchanged. Increases in cAMP accompanied the steroidogenic response to ACTH but not to A II or FK 33 824. Dopamine at physiological concentrations (10(-10) M) inhibited FK 33 824-induced aldosterone production. These results suggest that FK 33 824 is an aldosterone secretagogue and that it initiates steroidogenesis by mechanisms similar to those of A II. However the inability to block its effect with a specific antagonist of A II provides evidence for its action on a separate site.

Chlorpropamide-alcohol flushing in non insulin-dependent diabetes: prevalence of small and large vessel disease and or risk factors for angiopathy.

One hundred and eight non insulin-dependent diabetics were tested for alcohol flushing after chlorpropamide administration (CPAF test). The overall prevalence of patients who flushed at the first challenge was 32%. However, nearly half of them still flushed after alcohol administration, when placebo was given instead of chlorpropamide, so that the prevalence of 'true' flushers was only 17%. Even though the distribution of retinal lesions was similar in 'true' flushers and in non flushers, severe loss of visual acuity was confined to the non flushers and aspecific flushers. The frequency of pathological ECG findings and of peripheral pulse reduction or abolition was significantly higher in the non flushers and aspecific flushers. Blood pressure, serum lipids and hemostatic parameters were similar in the two groups, and therefore do not explain the differences in prevalence of lesions. This study confirms the previous findings of a lower prevalence of large vessel lesions in flushers; however, the prevalence of 'true' CPAF phenomenon in our out-patient population appears to be much lower than previously reported.

[Acute and chronic cardiac decompensation: is vasodilator therapy useful?]. / Scompenso cardiaco acuto e cronico: è utile la terapia con vasodilatatori?

Systemic vasodilators represent a new approach in the treatment of the acute and chronic heart failure, as they reduce the afterload acting on the aortic impedance and/or the venous return to the heart. Vasodilators have been classified as venodilators (nitrates), which reduce left ventricular filling pressure and relieve pulmonary congestion; arteriolar dilators (hydralazine, phentolamine) which enhance cardiac output; and balanced vasodilator (nitroprusside, prazosin), which dilate both resistance and capacitance vessels. While nitroprusside and phentolamine are used in the treatment of the acute myocardial infarction, nitrates, hydralazine and prazosin are used in the long term treatment of the chronic congestive heart failure. Presumably, the renin-angiotensin system plays an important role in increasing peripheric vascular resistance in congestive heart failure. For this reason the inhibitors of the angiotensin-converting enzyme, such as captopril and teprotide, are also used. The treatment with vasodilators, recommended to patients with severe heart failure, is not an alternative to that with digitalis and diuretics: such a combination may in fact result as a very useful one.

[Antigens and antibodies in acute viral hepatitis caused by the B virus. Clinical significance]. / Antigeni ed anticorpi dell'epatite acuta virale da virus B. Significato clinico.

Three antigen-antibody systems are so far known to be related to viral hepatitis type B. Tests for evidencing HBsAg and antiHBs are easily performed and important for the diagnosis, prevention and study of hepatitis B. The tests for evidencing HBcAg and HBc are still the subject of study and research. The presence of HBsAg in a subject shows he is hosting hepatitis B virus. It may also be present without hepatopathy or it may be associated with acute or chronic hepatitis B. At the present time there is no feasible way of eliminating the chronic carrier condition. The problem represented by healthy carriers as infection risks is currently under study.

[Prognosis of acute hepatitis B]. / Prognosi dell'epatite acuta di tipo B.

The clinical course, persistance of HBs antigen, and the liver biopsy morphological picture were evaluated in 40 patients with acute viral hepatitis, type B. In 34 cases, the disease ran a satisfactory course and clinical cure was corroborated histologically. In 4 cases, onset was particularly severe and the disease ran a long course. Here the immunological test for HBs antigen was still positive 8 weeks after the disease began, while a biopsy at 4 months showed a morphological picture similar to that of acute hepatitis. Lastly, two cases with a protracted clinical course displayed persistent HBs antigen positivity one year after the acute episode, with a histological finding of persistent hepatitis and cirrhosis of the liver respectively.