Long-term safety and efficacy of anacetrapib in patients with atherosclerotic vascular disease.

AIMS: REVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major coronary events. We now report results from extended follow-up beyond the scheduled study treatment period. METHODS AND RESULTS: A total of 30 449 adults with prior atherosclerotic vascular disease were randomly allocated to anacetrapib 100 mg daily or matching placebo, in addition to open-label atorvastatin therapy. After stopping the randomly allocated treatment, 26 129 survivors entered a post-trial follow-up period, blind to their original treatment allocation. The primary outcome was first post-randomization major coronary event (i.e. coronary death, myocardial infarction, or coronary revascularization) during the in-trial and post-trial treatment periods, with analysis by intention-to-treat. Allocation to anacetrapib conferred a 9% [95% confidence interval (CI) 3-15%; P = 0.004] proportional reduction in the incidence of major coronary events during the study treatment period (median 4.1 years). During extended follow-up (median 2.2 years), there was a further 20% (95% CI 10-29%; P < 0.001) reduction. Overall, there was a 12% (95% CI 7-17%, P < 0.001) proportional reduction in major coronary events during the overall follow-up period (median 6.3 years), corresponding to a 1.8% (95% CI 1.0-2.6%) absolute reduction. There were no significant effects on non-vascular mortality, site-specific cancer, or other serious adverse events. Morbidity follow-up was obtained for 25 784 (99%) participants. CONCLUSION: The beneficial effects of anacetrapib on major coronary events increased with longer follow-up, and no adverse effects emerged on non-vascular mortality or morbidity. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomized trials of lipid-modifying agents to assess their full benefits and potential harms. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN) 48678192; ClinicalTrials.gov No. NCT01252953; EudraCT No. 2010-023467-18.

Clinical Performance of Complete-Arch Implant- Supported Rehabilitations Using Monolithic Lithium Disilicate Restorations Bonded to CAD/CAM Titanium and Zirconia Frameworks up to 5 Years.

This clinical study evaluated the survival of monolithic lithium disilicate (ML) (IPS Emax, Ivoclar Vivadent) restorations bonded to complete-arch CAD/CAM made titanium or zirconia frameworks. Between August 2007 and December 2009, 15 patients (7 female, 8 male; mean age: 56.8 years old) received 30 implant-supported screw-retained rehabilitations with ML restorations cemented to CAD/CAM made titanium (T) (n=6) or zirconia (Z) frameworks (n=24) adhesively (Multilink Automix, RelyX Unicem) and followed up until December 2015. The evaluation protocol involved technical failures (chipping, debonding or fracture of crown/framework, screw loosening), Californian Dental Association (CDA) quality criteria (Romeo: Excellent; Sierra: Acceptable; Tango: Retrievable; Victor: Not acceptable) and biological failures (mucositis, peri-implantitis). Mean observation time was 60.3 months. No implants were lost, and all the prostheses were in situ. Four mechanical failures occurred in the form of minor chipping (n=3 in ML-Z, n=1 in ML-T) and major fracture in ML crown (n=1 in ML-Z). Romeo scores (N=370) decreased until final observation (N=347) and 23 Sierra scores were given to the restorations. Mucositis was observed in 3 patients and peri-implantitis in one patient. Complete-arch implant-borne FDPs made of monolithic lithium disilicate bonded to titanium or zirconia frameworks could be a promising alternative.

Liver stiffness reduction and serum fibrosis score improvement in HIV/hepatitis C virus-coinfected patients treated with direct-acting antivirals.

OBJECTIVES: Only a few studies have addressed liver stiffness dynamics after hepatitis C virus (HCV) treatment in patients with HIV/HCV coinfection. The aim was to evaluate the variation in liver stiffness and in serum liver fibrosis scores in HIV/HCV-coinfected patients before and after treatment with direct-acting antivirals (DAAs). METHODS: Liver stiffness measured using transient elastography as well as serum liver fibrosis scores [fibrosis-4 (FIB-4) score and the aspartate aminotransferase to platelet ratio index (APRI)] were evaluated before and at 6-12 months after DAA treatment. Variation in the outcome variables was evaluated using the Wilcoxon nonparametric test. Univariate analysis and multivariate regression models were used. RESULTS: A total of 78 HIV/HCV-coinfected subjects were included in the study. Median values of hepatic stiffness significantly decreased after DAA treatment compared with baseline [16.8 (interquartile range (IQR) 10.2-27.0) kPa at baseline vs. 9.4 (IQR 6.7-15.0) kPa after DAA treatment; P < 0.01). Further, a decrease in median FIB-4 score [2.8 (IQR 1.5-4.8) vs. 2.0 (IQR 1.3-3.2), respectively; P < 0.01] and APRI [0.9 (IQR 0.5-2.2) vs. 0.4 (IQR 0.2-0.7), respectively; P < 0.01] was found. In univariate analysis, liver stiffness decrease was associated with increasing age, 'other' HCV genotype (vs. G1), the presence of cirrhosis, higher pre-DAA liver stiffness, sofosbuvir-based regimens and longer DAA treatment (all P < 0.05). Multivariate regression confirmed the significance of the association only with higher baseline liver stiffness (P < 0.01). Greater FIB-4 and APRI reductions were associated with higher respective baseline values, while the presence of hepatic steatosis correlated with lower score reduction after DAA. CONCLUSIONS: A reduction in liver stiffness and an improvement in fibrosis scores were observed in HIV/HCV-coinfected patients soon after DAA treatment. The clinical implications of these observations need to be evaluated in larger populations with longer follow-up.

Prognostic significance of serum uric acid in outpatients with chronic heart failure is complex and related to body mass index: data from the IN-CHF Registry.

BACKGROUND AND AIMS: In the field of cardiovascular diseases, elevated levels of serum uric acid (UA) reflect a marked activation of the xanthine oxidase pathway with increase in free radicals production; it is often associated with an inflammatory state, oxygen consumption and endothelial dysfunction. All these associations have been also confirmed in heart failure (HF) but the pathophysiological role of UA in this setting is not well understood. The aim of this study was to evaluate the prognostic role of UA in outpatients enrolled in the Italian Registry of Congestive Heart Failure (IN-CHF). METHODS AND RESULTS: All patients met the European Society of Cardiology (ESC) criteria for diagnosis of HF. We considered patients with complete clinical data and UA level available at the baseline and at 1-year follow-up. The study population was composed of 877 patients aged 63 ± 12 years. One-year mortality was 10.8% and dead patients had a higher level of UA than survivors (7.1 mg dl⁻¹ vs 6.6 mg dl⁻¹, p < 0.0207). In multivariable full model of analysis, UA did not result in an independent predictor of death in overall population, but only in patients with low body mass index (BMI) (≤22 kg m⁻²) (hazard ratio (HR): 2.38, 95% confidence interval (CI) 1.36-4.18). In this subgroup, a statistically significant gradual relationship between UA and survival was detected starting from values higher than 8 mg dl⁻¹. CONCLUSION: Elevated level of UA is not an independent predictor of mortality in chronic HF, but it markedly worsens outcome if associated with low level of BMI. This association is likely an indicator of chronic inflammatory and catabolic state.

Determinants of surgical delay for hip fracture.

BACKGROUND AND OBJECTIVE: Recent guidelines recommend early surgical treatment of hip fractures in the elderly. The aim of the present study is to analyse the factors delaying surgical treatment of hip fractures in elderly patients by more than 2 days and to investigate whether these factors are consistent between a teaching and a community hospital. DESIGN: Retrospective cohort study using hospital discharge records and patients' charts. SETTING: Orthopaedics and traumatology departments of a teaching hospital and a small town hospital in Northern Italy. PARTICIPANTS: 1768 consecutive patients aged 65 years or more who underwent surgery for hip fractures between 2004 and 2007. INTERVENTIONS: Surgery for hip fracture. MAIN OUTCOME MEASURE(S): Surgery within two days from admission. RESULTS: 938 (53.1%) patients were operated within 2 days of admission to the hospital. Logistic regression models were used to examine potential predictors of surgery delay including gender, age, hospital, comorbidity, type of intervention (partial or total hip replacement, reduction and internal fixation), International Normalized Ratio (INR), Haemoglobin (Hb), American Society of Anaesthesiologists (ASA) score, and day of admission (categorized as Monday to Wednesday, Thursday-Friday, Saturday-Sunday). Age, type of intervention (partial or total hip replacement), INR score > 1.5 and an ASA score of 4 compared to 1-2, admission on Thursday-Friday or Saturday-Sunday and the interaction hospital × arrhythmia significantly predicted a surgery delay of more than 2 days. CONCLUSIONS: Both organization and medical problems accounted for delays of surgical treatment of hip fractures. Established protocols aimed to optimize the patient flow logistics and to manage comorbidities are crucial to make hospitals more patient-centred and to improve patient outcomes.

The Morfeo Study: A 1-year follow-up of complications of vegetative state in a dedicated facility.

OBJECTIVES: Vegetative State (VS) implies significant issues. The aim of the MORFEO study is to identify the most relevant complications in VS patients and to supply clinicians and policy-makers with data derived from the analysis of a cohort of patients treated in a dedicated long-term facility setting. METHODS: A cohort of 22 VS patients treated between 2003 and 2007 were enrolled and followed up for 1 year. The information recorded were: Disability Rating Scale (DRS), Levels of Cognitive Functioning (LCF), pressure sores, nutritional status, neurological complications, articular complications (passive range of motion-ROM), deep-vein thrombosis and infections. The Kolmogorov-Smirnov test was used to verify the normal distribution of the variables. The indicators of complications were analysed with the Friedman test (continuous variables) and with the Cochran Q test (dichotomous variables). RESULTS: DRS and LCF values showed no significant variation. The number of pressure sores decreased. The nutritional status remained satisfying. The ROM worsened in lower limb joints; a trend (p = ns) towards an improved range was observed in shoulders and elbows. Fifteen infections were recorded. CONCLUSIONS: The data that proved significant suggest a minimum set of quality-of-care indicators in VS patients: pressure sores follow-up, nutritional status, ROM and incidence of infections.

Immediate loading of 4 implants. A case report.

Despite the obvious benefits of two-stage implants, patients do experience discomfort as they have to continue wearing non-fixed total dentures whilst postoperative healing takes place. These patients would be more comfortable if a functional and esthetically pleasing solution could be arrived at in a shorter time. In an effort to achieve this, the scientific community has researched and fitted ''immediate load'' implants. The current literature states that this procedure, when fitting 4 or more interforaminal implants, is both predictable and reliable. The procedure increases neither the number of implant failures nor the amount of bone lost. In the case reported, 4 implants were inserted and a bar constructed. The practicality of this procedure is seen in reduced time and costs. An initial total denture was used at the start, first as a surgery guide, then as an individual tray for impression, and eventually as final total denture. Fixing the initial total denture to the implant, considerably reduced the time taken in the whole implant procedure and provided the patient with a more comfortable, pleasing solution. The use of the bar prevented the denture from moving, guaranteed full support from the implants, and reduced or prevented the bone loss seen in patients where non-implant supported total dentures have been used. This procedure had the additional benefit of versatility - as it could have been used as an intermediate stage towards providing a more complex prosthesis, such as a Toronto prosthesis.

Endogenous dopamine (DA) and DA2 receptors: a mechanism limiting excessive sympathetic-adrenal discharge in humans.

We studied the effects of presynaptic dopamine (DA) 2 receptor blockade on the sympathetic-adrenal response to graded exercise in seven normal men. DA2 receptor blockade was achieved by means of domperidone (DMP) administration. The exercise consisted of progressive cycling activity, from 30-80% of the predetermined maximal oxygen consumption for each man. Systolic, diastolic, and mean arterial pressures; heart rate; and plasma norepinephrine (NE), epinephrine (E), PRL, glucose, lactate, FFA, sodium, potassium, cortisol, and PRA were measured at rest, during exercise, and during recovery after placebo or DMP administration. Graded exercise caused significant increases in systolic and mean arterial pressures and plasma NE, E, lactate, sodium, potassium, FFA, cortisol, and PRA. DMP administration before exercise caused a significant increase in plasma PRL (P = 0.0009), a greater increase in plasma NE at the end of the exercise (P = 0.002), and an overall increase in plasma E (P = 0.02) and FFA (P = 0.02) concentrations. These results strongly suggest that endogenous DA limits catecholamine release during sympathetic-adrenal stimulation by activating DA2 receptors.

Influence of lipophilicity on the biological activity of cyclic pseudopeptide NK-2 receptor antagonists.

A series of cyclic pseudopeptides of the formula cyclo(Leu psi[CH2NH]Xaa-Gln-Trp-Phe-beta Ala), where Xaa represents the residue of an alpha-amino acid, has been synthesized in order to establish the role of the Xaa side chain for tachykinin NK-2 receptor antagonist activity. Syntheses have been carried out in solid phase with either Fmoc or Boc strategy. The antagonist potency on NK-2 receptors in the hamster isolated trachea (HT) and the rabbit isolated pulmonary artery (RPA) bioassays increases with Xaa lipophilicity; cyclo(Leu psi[CH2NH]Cha-Gln-Trp-Phe-beta Ala) and cyclo(Leu psi[CH2NH]Asp(NHBzl)-Gln-Trp-Phe-beta Ala) resulted in being the two most active antagonists (pA2 = 9.06 and 9.26 on HT, respectively). A significant linear correlation was found between pA2 values determined in HT and RPA bioassays and capacity factors measured in reversed phase HPLC. The comparison between the biological activities of cyclic hexapeptides containing or not containing the aminomethylene moiety proved the crucial role of the pseudopeptide bond for determining high antagonist potency at the NK-2 receptor.

Supratentorial atrophy in spinocerebellar ataxia type 2: MRI study of 20 patients.

There have been only few studies of brain magnetic resonance imaging (MRI) in spinocerebellar ataxia (SCA) type 2. We investigated 20 SCA2 patients, from 11 Sicilian families, and 20 age-matched control subjects using MRI. Our data confirm that olivopontocerebellar atrophy (OPCA) is the typical pattern in SCA2. We found no significant correlation between infratentorial atrophy, disease duration, or the number of CAG repeats in our SCA2 patients, but there was supratentorial atrophy in 12 patients, with a significant correlation between supratentorial atrophy and disease duration. OPCA appears to represent the "core" of the SCA2: however, central nervous system involvement is not limited to pontocerebellar structures. We therefore consider central nervous system degeneration in SCA2 as a widespread atrophy. MRI is helpful in diagnosing SCA, but it is not diagnostic in the absence of clinical and molecular studies. We suggest that serial MRI may play a role in evaluating "in vivo" the progressive steps of neurodegeneration in SCA2, for a better comprehension of the pathophysiology of this disorder.

Evidence of luteinizing hormone secretion in hypothalamic amenorrhea associated with weight loss.

The lack of plasma luteinizing hormone (LH) pulsatile pattern or episodic LH secretory bursts during night have been demonstrated in hypothalamic amenorrhea. The availability of both sensitive and specific immunofluorimetric assay and algorithm for pulse detection enabled us to reanalyze the question of whether or not patients with hypothalamic amenorrhea secrete LH in a pulsatile fashion. Seven women with secondary amenorrhea associated with weight loss and four normally cycling women were studied, sampling every 5 minutes for 8 hours. Control subjects were studied during four different phases of the menstrual cycle. In all amenorrheic patients, a frequent LH pulsatile secretion, with pulses of low amplitude, was found (10.7 +/- 1.4 peaks/8 h; mean +/- SEM). The pulse frequency was significantly higher (P less than 0.05) than any phases of the control group (early follicular: 7 +/- 0.4 peaks/8 h; late follicular: 6.8 +/- 0.6 peaks/8 h; early luteal: 4.3 +/- 0.4 peaks/8 h; late luteal: 7 +/- 0.3 peaks/8 h). The LH pulsatile release in amenorrheic patients showed a mean pulse duration and amplitude shorter than in any phase of the menstrual cycle of the controls. In conclusion, in weight-loss-related-amenorrhea, the major change was not the absence of the LH pulsatile release but its increased frequency with reduced pulse amplitude.

Reduced spinal bone density in young women with amenorrhoea.

To assess the influence of diminished oestrogen production on bone density, we studied 23 amenorrhoeic women and 20 controls (age range 16-29 years) divided into four groups: group 1: 6 patients with idopathic hypogonadotrophic hypogonadism with primary amenorrhoea (IHH); group 2: 5 patients with delayed puberty owing to thalassaemia major (TM); group 3: 12 patients with secondary hypothalamic amenorrhoea (HA); group 4: 20 women with normal menses (controls). Secondary sexual characteristics had developed in all except the women with TM. Groups 1 and 2 had never menstruated and group 3 had been amenorrhoeic for 6 months to 3 years. The control group was studied during the follicular phase of the cycle. None of the patients were taking oestrogens at the time of observation. Plasma concentrations were determined for 17 beta-oestradiol (E2), deidroepiandrosterone sulphate (DHEA-S), cortisol (F), prolactin (PRL), thyroid hormones (T3 and T4), and gonadotrophins (LH and FSH). Spinal bone mineral density (BMD g/cm2) was assessed by dual photon absorbiometry. BMD (mean +/- 1SD) was reduced in the patients (group 2: 0.920 +/- 0.95; group 1: 0.980 +/- 0.94; and group 3: 1.037 +/- 0.75) as compared with the controls (1.290 +/- 0.95) (P less than 0.01). In the three groups of patients, plasma E2 levels were lower than 50 pg/ml and were positively correlated with the BMD. As expected, plasma gonadotrophin levels were highly and significantly reduced (P less than 0.01) in the patients, compared with that of the controls. These results suggest that reduced spinal BMD in hypogonadic women may be related to the lack of oestrogenic influence on bone metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Bis-arenoxypropanolamines as potential beta-adrenolytics: a reinvestigation.

A number of symmetrical as well as asymmetrical bis-arenoxypropanolamines have been synthesized and evaluated for their beta-adrenolytic properties. The pharmacological characterization of these compounds was performed in vitro by direct studies (3H-dihydroalprenolol was used as the specific ligand for beta-receptors), and by determining the beta-blocking capacity on isoproterenol (ISO)-induced increased heart rate (isolated guinea-pig atrium); and in vivo by evaluating the antagonism on ISO-induced hypotension and tachycardia, as well as the intrinsic sympathomimetic activity (ISA) on reserpinized and vagotomized rats. The best result was observed with the simplest derivative, i.e. the bis-phenoxypropanolamine compound, which shows in vitro and in vivo potencies almost comparable to propranolol and, moreover, significant bronchodilating activity.

A linear propagation model adapted to the study of fast perturbations in arterial hemodynamics.

The hemodynamic effect of rapid body accelerations is studied in this work using two different models of wave propagation in blood vessels. Simulation curves have been obtained with both models and compared with those measured in vivo on a dog's carotid artery. Results of the first model demonstrate that classic linear theories, based on linearization of the Navier-Stokes and continuity equations, provide a good explanation of the initial effect of body acceleration on pressure. However, the same models significantly underestimate the subsequent pressure perturbation damping. Modified empirical expressions for wave propagation, able to furnish a more accurate description of pressure energy losses occurring during fast hemodynamic phenomena, are thus utilized in the second model and their biophysical significance discussed.

Synthesis of a series of Homopterocarpane derivatives with potential antitumor and anti-AIDS activity.

The synthesis of a series of derivatives related to (+/-) cis 6a, 12a-dihydro-6H,7H-[1]-benzopyrano-[4,3-b]-[1]-benzopyran (Homopterocarpane) is described. The synthesized derivatives have been tested at National Cancer Institute in its in vitro anti-cancer and anti-AIDS screening programs. The synthesized compounds are inactive in anti-HIV assay, while some show a GI50 < 100 microM (and < 50 microM in several cell lines) in NCI antitumor screening.

[The effects of the acute administration of atrial natriuretic peptide on the mechanisms regulating diuresis and natriuresis in the essential hypertension patient]. / Effetti della somministrazione acuta di peptide atriale natriuretico su alcuni meccanismi di regolazione della diuresi e della natriuresi nell'iperteso essenziale.

The authors investigated the role of atrial natriuretic peptide (alpha-hANP 99-126) in essential hypertension by evaluating some hemodynamic and renal effects of acute peptide infusion (1 micrograms/kg for 1 min + 50 ng/kg for the following 20 min) in fourteen subjects: eight mild to moderate, untreated, essential hypertensives (EH) and six normotensive (N) controls, during 2 hour-clearance periods, the 1st after ANP infusion, the 2nd during placebo (PL) administration. The double-blind study was carried out after the patients had rested and fasted overnight. It showed no significant changes in heart rate (HR); instead, compared with placebo, mean blood pressure (MBP) decreased significantly in both groups, beginning from the 3rd min after ANP infusion was begun (N: PL = 87.04 +/- 1.7 mmHg, ANP = 80.9 +/- 3.7 mmHg, p less than 0.0001; EH: PL = 102.6 +/- 3.2 mmHg, ANP = 97.7 +/- 5.9 mmHg, p less than 0.01). Among the urinary parameters we considered, cyclic GMP (cGMP) increased after ANP infusion in all subjects (N: PL = 129.1 +/- 56.3 pmol/mL, ANP = 199.2 +/- 85.4 pmol/mL; EH: PL = 106.55 +/- 56.2 pmol/mL, ANP = 220.03 +/- 92.7 pmol/mL, p less than 0.05); diuresis showed a prompt and significant increase in EH (N: PL = 837 +/- 368 mL, ANP = 1066 +/- 340 mL; EH: PL = 713 +/- 286 mL, ANP = 1043 +/- 280 mL, p less than 0.005), and so did natriuresis (N: PL = 23 +/- 14.3 mEq/L, ANP = 33 +/- 14.6 mEq/L; EH: PL = 25.6 +/- 8.9 mEq/L, ANP = 41.9 +/- 13.8 mEq/L, p less than 0.01); urinary potassium excretion was significantly reduced in EH (N: PL = 18.7 +/- 12.9 mEq/L, ANP = 14.2 +/- 6.9 mEq/L; EH: PL = 16.5 +/- 7.9 mEq/L, ANP = 10.7 +/- 4.8 mEq/L, p less than 0.005), while no changes were noted in glomerular filtration rate (GFR), estimated as creatinine clearance, urinary magnesium, albumin and aldosterone excretion. To investigate other potential mechanisms involved in renal effects of ANP, the urinary excretion of both prostaglandins 6-cheto PGF1-alpha and thromboxane B2 (TXB2), and dopamine were studied. The results showed only a significant decrease of dopamine urinary excretion in EH after ANP administration (N: PL = 50.4 +/- 28.7 micrograms/L, ANP = 45.0 +/- 29.7 micrograms/L; EH: PL = 47.3 +/- 21.5 micrograms/L, ANP = 27.1 +/- 12.7 micrograms/mL, p less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)

[BRING-UP 2: presentation of the study]. / BRING-UP 2: presentazione dello studio.

The BRING-UP 2 (ANMCO) is an observational study which evaluates the applicability, safety and efficacy profiles of beta-blockers in elderly patients and in those with severe heart failure. In this last category the recommendations for beta-blockers should be expanded, but in routine conditions of care the administration of these drugs still needs careful guide and observation.

Pulmonary embolism associated with use of bone cement during hip arthroplasty.

Main circulatory (heart frequency, HF, intra-artery pressure, AP ECG) and respiratory (arterial oxyhemoglobin saturation SaO2, end-tidal CO2) arterial gas-analysis (HGA) parameters were recorded continually during cemented hip arthroplasty in 70 consecutive non-selected patients. The use of cement did not cause any change in the parameters obtained in 21 of the cases, reduction in arterial oxygen pressure (PaO2) ranging from 11% to 38% was observed in 44 cases, associated with simultaneous reduction in ETCO2 in 11 cases. The reduction in ETCO2 was an isolated finding in 5 of the patients. AP decreased by more than 10% in only 2 cases and there was arrhythmia in another 2 cases. These findings are strongly suggestive of pulmonary embolism encouraging the hypothesis of gas embolism previously suggested by other authors. In patients with little coronary or pulmonary reserve use of cement means an increased risk of severe hemodynamic complications.

[Drug therapy of arterial hypertension. Reflections and suggestions]. / Terapia farmacologica dell'ipertensione arteriosa. Riflessioni e suggerimenti.

Treatment of arterial hypertension is an important part of medical care provided in industrialized countries today. When non-drug treatment turns out to be ineffective, or when hypertension levels are higher than target values, or target organ damage is ascertained, drug therapy must be started. This rationale comes from large-scale intervention trials, which have shown that the lowering of elevated blood pressure reduces cardiovascular morbidity and mortality. A logical aim in treatment of hypertension should be both to "normalize" hypertension-induced cardiovascular abnormalities and to maintain the quality of life, without undesirable influence on other cardiovascular risks. Moreover, if we could identify the major hemodynamic impairment behind increased blood pressure and correct it by an appropriate drug therapy, then we would have a satisfactory means to perform individualized treatment. Over the past years the empirical basis for the use of antihypertensive drugs has been replaced by a step-wise approach, but few attempts have been made to provide an approach that fits pathophysiological understanding. For this reason the above-mentioned step-wise approach has been found to be an uncorrected simplification of antihypertensive care. Also, the use of more recent drugs (calcium channel blockers, ACE-inhibitors and serotonin-receptor blockers) as an alternative to beta-blockers and diuretics in first step therapy, has further contributed to the abandonment of the step-wise approach. The different groups of antihypertensive agents are examined with reference to their mechanism of action, pharmacokinetics, indications, and desirable and untoward effects. At present, indirect vasodilators, such as calcium-antagonists, ACE-inhibitors and serotonin-receptor blockers, alone or combined with diuretics, represent an intrinsic part of basic antihypertensive therapy. Beta-adrenoceptor antagonists remain the agents of choice when the principal therapeutic aim is to reduce the adrenergic drive. Both these drugs and direct vasodilators or alpha-adrenoceptor antagonists can be employed in the most severe forms of hypertension. In such cases, combined therapy (vasodilator + antiadrenergic + diuretic agents) is often used. Sublingual nifedipine and intravenous diazoxide or sodium nitroprusside are the drugs of choice for the hypertensive crisis. The use of most of the central or peripheral sympatholytic agents has generally been abandoned. Finally, beta-blockers and calcium-antagonists have been shown to have a secure place in the management of ischemic heart disease complicating arterial hypertension. In this condition captopril also appears to be useful.