EFFICACY AND TOLERABILITY OF NEBIVOLOL COMPARED WITH OTHER ANTIHYPERTENSIVE DRUGS: A META-ANALYSIS

Aim: Lowering BP to normal levels without quality of life deterioration is the most important means of reducing cardiovascular risk. Recent studies have challenged the position of beta-adrenoreceptor antagonists (beta-blockers) as first-line antihypertensive drugs. Nebivolol is a third-generation, highly selective beta (1)-blocker that causes vasodilation through nitric oxide (NO) release. This meta-analysis investigates the efficacy and tolerability of nebivolol compared with other antihypertensive drugs and placebo in patients with hypertension. Methods: Twelve randomized controlled studies were included, in which nebivolol 5 mg once daily was compared with the recommended clinical doses of other antihypertensive drugs (n=9), placebo (n=2), and both (n=1). The clinical studies were selected after a MEDLINE search up to 2007, using the key words “nebivolol” and “hypertension”. Results: Antihypertensive response rates (the percentage of patients achieving target BP levels or a defined DBP reduction) were higher with nebivolol than with ACE inhibitors (odds ratio [OR] 1,92; p=0,001) and all antihypertensive drugs combined (OR 1,41; p=0,001) and similar to beta-blockers, calcium channel antagonists (CCAs) and the angiotensin receptor antagonist (ARA) losartan. Moreover, a higher percentage of patients receiving nebivolol achieved target BP levels compared with patients treated with losartan (OR 1,98; p=0,004), CCAs (OR 1,44; p=0,024), and all antihypertensive drugs combined (OR 1,35; p=0,012). The percentage of patients experiencing adverse events did not differ between nebivolol and placebo; adverse event rates were significantly lower with nebivolol than losartan (OR 0,52; p=0,016), other beta-blockers (OR 0,56; p=0,007), nifedipine (OR 0,49; p<0,001), and all antihypertensive drugs combined (OR 0,59; p><0,001). Conclusion: Results of previous pharmacokinetic studies suggest that nebivolol 5 mg may not conform completely to the definition of a classic beta-blocker, demonstrating additional antihypertensive effect due to endothelial NO release-mediated vasodilation. This meta-analysis showed that nebivolol 5 mg achieved similar or better rates of treatment response and BP normalization than other drug classes and other antihypertensive drugs combined, with similar tolerability to placebo and significantly better tolerability than losartan, CCAs, other beta-blockers, and all antihypertensive drugs combined. Although not definitive, this meta-analysis suggests that nebivolol 5 mg is likely to have advantages over existing antihypertensives and may have a role in the first-line treatment of hypertension.> <0,001), and all antihypertensive drugs combined (OR 0,59; p <0,001). Conclusion: Results of previous pharmacokinetic studies suggest that nebivolol 5 mg may not conform completely to the definition of a classic beta-blocker, demonstrating additional antihypertensive effect due to endothelial NO release-mediated vasodilation. This meta-analysis showed that nebivolol 5 mg achieved similar or better rates of treatment response and BP normalization than other drug classes and other antihypertensive drugs combined, with similar tolerability to placebo and significantly better tolerability than losartan, CCAs, other beta-blockers, and all antihypertensive drugs combined. Although not definitive, this meta-analysis suggests that nebivolol 5 mg is likely to have advantages over existing antihypertensives and may have a role in the first-line treatment of hypertension

Histone Hyperacetylation Is Associated with Amelioration of Experimental Colitis in Mice

Abstract Inhibitors of histone deacetylases (HDAC) are being studied for their antiproliferative effects in preclinical cancer trials. Recent studies suggest an anti-inflammatory role for this class of compounds. Because inflammatory bowel disease is associated with an increased risk of malignancies, agents with antiproliferative and anti-inflammatory properties would be of therapeutic interest. HDAC inhibitors from various classes were selected and evaluated for their in vitro capacity to suppress cytokine production and to induce apoptosis and histone acetylation. Valproic acid (VPA) and suberyolanilide hydroxamic acid (SAHA) were chosen for further studies in dextran sulfate sodium- and trinitrobenzene sulfonic acid-induced colitis in mice. In vitro, inhibition of HDAC resulted in a dose-dependent suppression of cytokine synthesis and apoptosis induction requiring higher concentrations of HDAC inhibitors for apoptosis induction compared with cytokine inhibition. Oral administration of either VPA or SAHA reduced disease severity in dextran sulfate sodium-induced colitis. The macroscopic and histologic reduction of disease severity was associated with a marked suppression of colonic proinflammatory cytokines. In parallel to the beneficial effect observed, a dose-dependent increase in histone 3 acetylation at the site of inflammation was shown under VPA treatment. Furthermore, SAHA as well as VPA treatment resulted in amelioration of trinitrobenzene sulfonic acid-induced colitis, which was associated with an increase of apoptosis of lamina propria lymphocytes. Inhibitors of HDAC reveal strong protective effects in different models of experimental colitis by inducing apoptosis and suppressing proinflammatory cytokines, thereby representing a promising class of compounds for clinical studies in human inflammatory bowel disease

Preventive administration of Mycobacterium tuberculosis 10-kDa heat shock protein (hsp10) suppresses adjuvant arthritis in Lewis rats

: Adjuvant arthritis (AA) can be induced in Lewis rats by immunization with Mycobacterium tuberculosis (Mt) in oil. We have investigated the modulation of AA by mycobacterial 10-kDa heat shock protein (hsp10), administered according to several protocols known to induce immune tolerance and immune deviation. Subcutaneous immunization with hsp10 in aqueous solution did not induce a cellular immune response, evaluated as delayed-type hypersensitivity (DTH) reaction, although anti-hsp10 antibodies, mainly of the IgG2a isotype, were detected in serum of treated animals. When rats were pretreated with hsp10 in aqueous solution before AA induction, no effects were seen on arthritis-induced joint swelling, although osteolysis and lymphocyte infiltration were slightly decreased. When other routes of administration were attempted, the strongest suppression was seen in the group of animals which received four intranasal (i.n.) administrations of protein and a subsequent challenge of hsp10 in incomplete Freund's adjuvant (IFA). We also found that the extent of disease suppression among the different groups of animals correlated with serum anti-hsp10 antibody levels. These antibodies mostly belonged to the IgG2a subtype, suggesting that immune deviation may play a role in the mechanism of disease suppression by hsp10

B-blockade with nebivolol for prevention of acute ischaemic events in elderly patients with heart failure

Objectives: This subanalysis of the Study of the Effects of Nebivolol Intervention on Outcomes and Hospitalisation in Seniors with Heart Failure (SENIORS) investigates whether treatment with nebivolol, a ß-blocker with nitric oxide-releasing properties, can provide additional benefits besides its effects on heart failure (HF), by reducing cardiac ischaemic events in patients with HF of ischaemic aetiology. Design: A double-blind, randomised, placebo-controlled, multicentre trial of nebivolol in 2128 elderly patients. Patients and interventions: For this analysis, data were extracted for 2128 elderly (=70 years) HF patients in whom coronary artery disease (CAD) was the underlying aetiology (68.2%; 717 placebo-treated patients and 735 assigned to nebivolol). Main outcome measures: The main endpoint was the composite of cardiac ischaemic events at 2 year follow-up: death/hospitalisation for myocardial infarction, unstable angina or sudden death, as originally identified in the case report form. Results: At follow-up, nebivolol treatment was associated with a one-third reduction in the risk of ischaemic events, the composite endpoint occurring in 15.9% of placebo and 10.7% of nebivolol-treated patients (HR 0.68; 95% CI 0.51 to 0.90; p=0.008). This effect was independent of age, gender and ejection fraction. No difference in this composite endpoint was observed in the subgroup of patients of non-ischaemic aetiology. Conclusions: Nebivolol was effective in reducing cardiac ischaemic events in patients with HF of ischaemic aetiology. The prevention of ischaemic events can be an additional beneficial effect of ß-blockade in HF patients with underlying CAD

Histone deacetylase inhibitor ITF2357 (Givinostat) reverts transformed phenotype and counteracts stemness in in vitro and in vivo models of human glioblastoma

Purpose Aberrant expression and activity of histone deacetylases (HDACs) sustain glioblastoma (GBM) onset and progression and, therefore, HDAC inhibitors (HDACi) represent a promising class of anti-tumor agents. Here we analyzed the effects of ITF2357 (givinostat), a pan-HDACi, in GBM models for its anti-neoplastic potential. Methods A set of GBM- and patient-derived GBM stem-cell lines was used and the ITF2357 effects on GBM oncophenotype were investigated in in vitro and in vivo xenograft models. Results ITF2357 inhibited HDAC activity and affected GBM cellular fate in a dose dependent manner by inducing G1/S growth arrest (1 to 2.5μM) or caspase-mediated cell death (> 2.5μM). Chronic treatment with low doses (< 1μM) induced autophagy-mediated cell death, neuronal like phenotype and the expression of differentiation markers, such as Glial Fibrillar Actin Protein (GFAP) and Neuron-specific class III beta-tubulin (Tuj-1), this reducing neurosphere formation from patient-derived GBM stem cells. Autophagy inhibition counteracted the ITF2357-induced expression of differentiation markers in p53-expressing GBM cells. Finally, in in vivo experiments, ITF2357 efficiently passed the blood–brain barrier, so rapidly reaching high concentration in the brain tissues, and significantly affected U87MG and U251MG growth in orthotopic xenotransplanted mice. Conclusions The present findings provide evidence of the key role played by HDACs in sustaining transformed and stem phenotype of GBM and strongly suggest that ITF2357 may have a clinical potential for the HDACi -based therapeutic strategies against GBM

Histone deacetylase inhibitor ITF2357 (Givinostat) reverts transformed phenotype and counteracts stemness in in vitro and in vivo models of human glioblastoma

Purpose Aberrant expression and activity of histone deacetylases (HDACs) sustain glioblastoma (GBM) onset and progression and, therefore, HDAC inhibitors (HDACi) represent a promising class of anti-tumor agents. Here we analyzed the effects of ITF2357 (givinostat), a pan-HDACi, in GBM models for its anti-neoplastic potential. Methods A set of GBM- and patient-derived GBM stem-cell lines was used and the ITF2357 effects on GBM oncophenotype were investigated in in vitro and in vivo xenograft models. Results ITF2357 inhibited HDAC activity and affected GBM cellular fate in a dose dependent manner by inducing G1/S growth arrest (1 to 2.5μM) or caspase-mediated cell death (> 2.5μM). Chronic treatment with low doses (< 1μM) induced autophagy-mediated cell death, neuronal like phenotype and the expression of differentiation markers, such as Glial Fibrillar Actin Protein (GFAP) and Neuron-specific class III beta-tubulin (Tuj-1), this reducing neurosphere formation from patient-derived GBM stem cells. Autophagy inhibition counteracted the ITF2357-induced expression of differentiation markers in p53-expressing GBM cells. Finally, in in vivo experiments, ITF2357 efficiently passed the blood–brain barrier, so rapidly reaching high concentration in the brain tissues, and significantly affected U87MG and U251MG growth in orthotopic xenotransplanted mice. Conclusions The present findings provide evidence of the key role played by HDACs in sustaining transformed and stem phenotype of GBM and strongly suggest that ITF2357 may have a clinical potential for the HDACi -based therapeutic strategies against GBM