Follow-up of Antihypertensive Therapy Improves Blood Pressure Control: Results of HYT (HYperTension survey) Follow-up.

INTRODUCTION: Although improved during the past few years, blood pressure control remains sub optimal. AIM: The impact of follow-up assessment on blood pressure control was evaluated in a group of patients of the HYT (HYperTension survey), treated with a combination of different dihydropyridine calcium-channel blockers (CCBs regimen) and inhibitors of renin-angiotensin-aldosterone system (RAAS) and with uncontrolled blood pressure. This was obtained assessing (a) the rate of blood pressure control at 3 and 6 months of follow-up in the whole group of patients, (b) the rate of blood pressure control and the average blood pressure values in subjects treated with different DHP-CCBs regimen. METHODS: From the 4993 patients with uncontrolled blood pressure, (BP ≥ 140/90 or ≥140/85 in patients with diabetes), 3729 (mean age 61.2 ± 11.5 years), maintained CCBs regimen combined wih RAAS blockers and were evaluated at 3 and 6 months follow-up. At each visit BP (semiautomatic device, Omron-M6, 3 measurements), heart rate, adverse events and treatment persistence were collected. RESULTS: At 1st and 2nd follow-up the rate of controlled BP was 63.5 and 72.8% respectively (p < 0.05 vs 35.3% at baseline), whereas in diabetes was 32.5 and 37.9% respectively (p < 0.05 vs 20% at baseline). No differences in heart rate were observed. No differences in control rate were observed between the different CCBs regimen. The incidence of drugs related adverse events was 3.6%. CONCLUSIONS: These findings provide evidence that: (a) the follow-up of hypertensive patients under therapy increase the rate of blood pressure control; (b) there is no significant difference in the antihypertensive effect between different CCBs regimen;

Treatment and control of hypertension in Turkish population: a survey on high blood pressure in primary care (the TURKSAHA study).

Although the management and the control rates of hypertension are generally low throughout the world, there are substantial differences between the countries. The aim of this study was to determine the control rate of blood pressure and the characteristics of the patients who have been admitted to primary care units in Turkey. Our study included 16,270 patients aged above 18 years who were diagnosed as hypertensive in representative nationwide sample of 1,000 primary care units in Turkey. The mean age of the patients was 60+/-11 years (60.1% women). Of 16,270 patients, 15 187 (93.3%) were on an antihypertensive treatment, whereas 1,083 (6.7%) were receiving no treatment. The patients who were women, diabetic, smoker, obese, and those who had a concomitant cardiovascular disease (CVD) had a higher rate of antihypertensive treatment. Of 15,187 treated patients, 4,912 (30.2%) had a controlled systolic blood pressure, 7,063 (43.4%) a controlled diastolic blood pressure, and in 3,931 (24.2%), both were under control. A logistic regression analysis demonstrated that age (OR 1.33), diabetes (OR 4.96), body mass index (OR 1.41) and the presence of a CVD (OR 1.19) were predictors for blood pressure being under control. The blood pressure control rates ranged between 16.6 and 30.5% among seven geographical regions. In the primary care units in Turkey, the blood pressure control rate is consistently low in treated hypertensive patients. In addition, there are differences between the geographical regions in both the proportion of those receiving medications and the blood pressure control rates.

Genetic polymorphisms and endothelial dysfunction in patients with essential hypertension: a cross-sectional case-control study.

BACKGROUND: Both in animal models and humans an association between endothelial constitutive nitric oxide synthase (ecNOS) gene polymorphism and the development of hypertension has been found. However, the relation between ecNOS polymorphism and endothelial function in patients with hypertension has not been systematically studied. Genes of the renin-angiotensin system include the angiotensin-converting enzyme (ACE) gene, and the angiotensin II type 1 receptor (ATIR) gene, and have been associated with essential hypertension. However, no consistent data are available about the relation between polymorphisms of these genes and the presence of endothelial dysfunction in such patients. OBJECTIVES: To assess the presence of genetic polymorphisms and of endothelial dysfunction in patients with essential hypertension. To determine the effects of gene polymorphisms on endothelial dysfunction in these subjects. METHODS: In 129 patients with essential hypertension and the same number of age-matched controls polymorphisms of the ecNOS gene, ACE gene, and AT1R gene were analysed by polymerase chain reactions. Endothelial function was assessed by maximal endothelial dependent vasodilation in response to reactive hyperaemia using high resolution ultrasound examinations of the brachial arteries. To assess correlation between genetic markers, endothelial function, and the presence of hypertension both univariate and multivariate analyses were used including Pearson's and Spearman's correlation coefficients, and multiple logistic regressions. RESULTS: The size of endothelium-dependent vasodilation between patients and controls differed by 16% (p<0.02). However, the presence of genetic polymorphisms of the ecNOS, ACE, and AT1R genes did not significantly differ between patients and controls. Neither were there any statistically significant differences in endothelial function between various genotypes of the three genes. This was so for both the patients and the controls, although in all of these comparisons the controls overall displayed a slightly better endothelial function than the patients did. Multiple regression analysis with endothelial dysfunction as dependent and the presence of gene polymorphisms as independent variables did not reveal any significant correlation either. CONCLUSION: A significant relation between endothelial dysfunction and essential hypertension was demonstrated. However, no relations between genetic markers and the presence of essential hypertension or between endothelial dysfunction and genetic markers were established. The failure of our study to demonstrate the latter may be due to confounders. Also, other genes may be more important in the pathogenesis of endothelial dysfunction and essential hypertension. The current study underscores that endothelial dysfunction and hypertension are not simple genetic disorders, and that they are, essentially, multicausal.

N-3-substituted pyrimidinones as potent, orally active, AT1 selective angiotensin II receptor antagonists.

A novel series of nonpeptide angiotensin II (A II) antagonists containing a pyrimidinone ring which carries a C-linked biphenyltetrazole moiety and a carboxyheteroaryl group on the 3-position have been prepared. Their affinity for the AT1 receptor was determined in a binding assay on rat adrenal cortical membranes. The in vivo antihypertensive properties were tested by evaluating the inhibition of the pressor response to A II followed by iv and id administration. Extensive molecular modeling studies, including comparison of molecular electrostatic potential distributions, conformational analysis, and overlays on a computational pharmacophore model of A II, were used to evaluate structural parameters of the new compounds, in comparison to other known A II antagonists (e.g., DUP-753 and SK&F 108566). According to the modeling studies, the introduction of a (carboxyheteroaryl)methyl moiety at the 3-position of the pyrimidinone ring led to derivatives with increased potency. Methyl 2-[[4-butyl-2-methyl-6-oxo-5-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl ]- 4-yl]methyl]-1-(6H)-pyrimidinyl]methyl]-3-thiophenecarboxylate (3k, LR-B/081), one of the most potent compounds in the series (Ki = 1.4 nM), exhibited a marked antihypertensive activity on oral administration to conscious renal hypertensive rats, with long duration of action. It was selected for clinical evaluation in the treatment of hypertension in man.

Bioequivalence assessment of two different tablet formulations of diltiazem after single and repeated doses in healthy subjects.

The study was performed on 14 healthy volunteers in order to compare the pharmacokinetics and hence assess the bioequivalence of two different tablet formulations of diltiazem administered orally. The study was carried out after single doses (60 mg) and repeated doses (60 mg three times a day for six days and 60 mg on the seventh day) according to a randomised, cross-over, open design. The pharmacokinetic parameters AUC0-infinity (ng h/ml), Tmax(h) and Cmax (ng/ml) were calculated for the two formulations after a single dose, while AUCt1-t2 (= AUC for a repetitive dose interval or dosing cycle, ng h/ml) and PTF (peak trough fluctuation) were calculated after repeated doses. The bioequivalence assessment was the shortest 90% confidence interval for the ratio (difference) of expected medians in the respective bioequivalence range (0.80-1.20). The results of this study show that, after either a single dose or repeated doses of test or reference formulations of diltiazem, the pharmacokinetics of the two formulations are similar. The ratios of AUC on day 1 (for single-dose treatment) and on day 7 (for repeated-dose treatment), and the corresponding 90% confidence intervals demonstrate bioequivalence between the two formulations of diltiazem within the accepted range of 0.80-1.20 (80-120%).

Nebivolol and airway responsiveness in the rabbit.

Beta-adrenergic receptor antagonists are currently used as first-line therapy in the treatment of hypertension and angina pectoris, but are contraindicated or used with caution in patients with bronchospastic syndromes. In this study we evaluated in vivo the effects of nebivolol on airway responsiveness compared to atenolol, pindolol, and propranolol. In New Zealand white rabbits total lung resistance (R(L)) and dynamic compliance (Cdyn) were calculated. In acute protocol, the animals were intravenously injected with the beta-blockers at different doses while in the chronic protocol, animals were daily injected for 30 days. Furthermore, the changes induced by beta-blockers (higher doses) in R(L) and Cdyn after a treatment with salbutamol were calculated. In acute treatment, airway responsiveness to histamine was not modified by nebivolol at any dosage, but increased significantly following the exposure to the higher doses of the other beta-blockers. In chronic treatment, the thirty-day exposure to nebivolol, did not modify the airway responsiveness to histamine, whereas the other beta-blockers significantly increased airway responsiveness. Moreover, nebivolol affected the salbutamol-induced relaxation less markedly than other beta-blockers do. These data demonstrate that nebivolol respect the other beta-blockers used in this study, does not significantly affect the airway responsiveness, therefore it could be used in patients with both cardiovascular and bronchial diseases more safely than other beta-blockers drugs.

Pulmonary disposition of lomefloxacin in patients with acute exacerbation of chronic obstructive pulmonary disease. A multiple-dose study.

In this study we have measured the concentrations of lomefloxacin at steady state in serum and in the intrapulmonary region at specified intervals for 24 h following administration of the last dose of drug in patients suffering from acute exacerbation of chronic obstructive pulmonary disease (COPD). Twenty subjects were enrolled. They received lomefloxacin 400 mg orally once-daily for 5 consecutive days. All patients were divided into five groups, with 4 subjects in each group, according to sampling times (2, 4, 8, 12, and 24 h after the last dose). At bronchoscopy, bronchial biopsies and bronchoalveolar lavage (BAL) were performed. At 12 h after the last dose, serum concentration of lomefloxacin was >1.0 microg/mL and at 24 h it was still detectable, but, at all times, the concentrations in bronchial secretion, bronchial mucosa, and epithelial lining fluid (ELF) were greater than the concentrations in serum [bronchial secretions (pg/mL) = 2.5+/-1.2; 2.2+/-1.0: 2.0+/-1.1; 1.8+/-1.1; 0.6+/-0.3. bronchial mucosa (microg/g) = 5.9+/-2.1; 6.2+/-1.8; 2.6+/-2.2; 1.9+/-1.5; 1.0+/-0.9. ELF (microg/mL) = 6.9+/-2.8; 5.9+/-2.6; 3.1+/-1.9; 2.2+/-1.0; 0.8+/-1.3. serum (microg/mL) = 3.2+/-1.4; 2.8+/-0.9: 2.1+/-1.5; 1.2+/-1.1; 0.4+/-0.81. We must stress that we observed a large inter-individual variability in concentrations. Our data show that lomefloxacin once-daily induces high and sustained concentrations in the various potential sites of pulmonary infection and clearly indicate that the pharmacokinetic behavior of this fluoroquinolone permits once-daily administration in patients with acute exacerbations of COPD.

Glutamergic transmission and cardiovascular apparatus in normotensive rats.

The cardiovascular effects induced by L-glutamic acid (G) on the cardiovascular apparatus of normotensive ethyl urethane-anaesthetized rats have been evaluated. (a) When administered i.v. (1 to 100 mg/kg) G induced a transitory and dose-dependent increase of arterial pressure (AP) with very moderate sinus bradycardia. It was antagonized by L-glutamic acid diethyl ester (GDEE, 0.1 to 100 mg/kg i.v.). (b) The intracerebroventricular (i.c.v.) administration of G (third ventricle, right lateral ventricle, posterior hypothalamus and striatum) at a dose of 0.1 to 10 mg/an induced a transitory and dose-dependent increase of AP, abolished by i.c.v. GDEE (1 to 10 mcg/an). (c) G hypertension was reduced by several procedures, i.e. catecholamine depletion, alpha 1, alpha 1 and alpha 2 or beta adrenergic blocks, alpha 2 central adrenergic stimulation, Ca2+ transmembrane or gangliary block, surrenectomy, and spinal transection at C7. (d) Atropine, bilateral vagotomy and sinus carotidal denervation increased G hypertension. (e) Therefore the bradycardia does seem to be due to a reflex-mediated effect via sinus carotid and aortic baroreceptors. (f) These data show that glutamergic transmission also participates through a central mechanism in the regulation of cardiovascular function in rats, via an increase in central sympathetic efferent activity.

Effect of pyridoxine alpha-ketoglutarate (PAK) on ammonia and pyruvic and lactic acid blood levels in patients with cirrhosis.

Administration of PAK to patients with hepatic cirrhosis significantly reduced hyperammonaemia and plasma levels of pyruvic and lactic acid. No significant changes in glycaemia were found. PAK treatment increased plasma levels of glutamic acid and decreased plasma levels of glutamine. This double-blind placebo controlled trial showed that PAK administration has a positive effect on some metabolic disturbances in cirrhotic patients.

[The therapeutic prospects of ischemic cardiopathy]. / Prospettive terapeutiche della cardiopatia ischemica.

Having thoroughly reviewed the risk factors and pathophysiologic features of ischemic heart disease, the authors describe therapeutic protocols at present in use and take stock of the perspectives opened by new drugs with different kinetic and dynamic and more advanced properties compared to those at present in use.