Omalizumab decreases exacerbation frequency, oral intake of corticosteroids and peripheral blood eosinophils in atopic patients with uncontrolled asthma.

Omalizumab is a humanized monoclonal anti-IgE antibody approved in 2005 by the European Medicine Agency (EMA) for the treatment of severe persistent allergic asthma, which remains inadequately controlled despite optimal therapy with high doses of inhaled corticosteroids and long-acting β2-adrenergic agonists. Within this context, the present observational study refers to 16 patients currently treated with omalizumab at the Respiratory Unit of "Magna Græcia" University Hospital located in Catanzaro, Italy, whose anti- IgE therapy was started in the period included between March 2007 and February 2010, thus lasting at least 10 months. After 40 weeks of add-on treatment with omalizumab, very relevant decreases were detected, in comparison with pre-treatment mean (± standard deviation) values, in monthly exacerbation numbers (from 1.1 ± 0.6 to 0.2 ± 0.4; p < 0.01) and oral corticosteroid consumption (from 22.6 ± 5.0 to 1.2 ± 2.9 mg/day of prednisone; p < 0.01). These changes were associated with stable improvements in lung function, expressed as increases of both FEV1 (from 53.6 ± 14.6% to 77.0 ± 14.9% of predicted values; p < 0.01) and FEV1/FVC ratio (from 56.3 ± 9.5% to 65.8 ± 9.2%; p < 0.01). Moreover, in 5 patients who persistently had increased numbers of eosinophils (mean ± SD: 15.9 ± 8.0% of total WBC count; absolute number: 1,588.0 ± 956.9/μl) despite a long-lasting therapy with inhaled and systemic corticosteroids, the peripheral counts of these cells decreased down to near normal levels (mean ± SD: 6.3 ± 2.3% of total WBC count; absolute number: 462.0 ± 262.3/μl) after 16 weeks of treatment with omalizumab. Therefore, this descriptive evaluation confirms the efficacy of add-on omalizumab therapy in selected patients with exacerbation-prone, chronic allergic uncontrolled asthma, requiring a continuous intake of oral corticosteroids

Update on optimal use of omalizumab in management of asthma

Omalizumab is a humanized monoclonal anti-IgE antibody recently approved for the treatment of severe allergic asthma. This drug inhibits allergic responses by binding to serum IgE, thus preventing interaction with cellular IgE receptors. Omalizumab is also capable of downregulating the expression of high affinity IgE receptors on inflammatory cells, as well as the numbers of eosinophils in both blood and induced sputum. The clinical effects of omalizumab include improvements in respiratory symptoms and quality of life, paralleled by a reduction of asthma exacerbations, emergency room visits, and use of systemic corticosteroids and rescue bronchodilators. Omalizumab is relatively well-tolerated, and only rarely induces anaphylactic reactions. Therefore, this drug represents a valid option as add-on therapy for patients with severe persistent allergic asthma inadequately controlled by high doses of standard inhaled treatments

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P &lt; 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P &lt; 0.001), sNox2-dp (r(s), -0.57; P &lt; 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P &lt; 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation

Acute rhabdomyolysis during treatment with amisulpride and metformin

International audienc

Comparison of the bronchodilating effects of inhaled formoterol, salmeterol and salbutamol in asthmatic patients.

Ten subjects with various degrees of asthma severity underwent a three-day trial, with the aim of evaluating the bronchodilating effect of inhaled formoterol (12 mg), in comparison with salbutamol (200 mg) and salmeterol (50 mg). The bronchodilation afforded by formoterol paralleled that of salbutamol in rapidity (mean percentage increases in functional measurements (FEV1) vs. baseline recorded 5 min after drug administration: 7.7%, 9.3%, and 0.3% for salbutamol, formoterol and salmeterol, respectively) and that of salmeterol in duration (mean percentage increases in FEV1 vs. baseline recorded 12 h after drug administration: 16.8% and 15.9% for formoterol and salmeterol, respectively). Moreover, the maximal effect of formoterol resulted to be slightly higher in comparison with salbutamol (P50.001) and salmeterol (P50.05); in this regard, the mean percentage increases in FEV1 vs. baseline recorded 2 h after salbutamol and formoterol, and 4 h after salmeterol were 22.3%, 29.5%, and 24.6%, respectively. Therefore, these results suggest that formoterol can be used, in addition to its utilization as long-acting bronchodilator, also as an effective rescue medication for the immediate relief of asthma symptoms

Potential role of potassium channel openers in the treatment of asthma and chronic obstructive pulmonary disease.

Airway smooth muscle (ASM) cells express various types of potassium (K 1) channels which play a key role in determining the resting membrane potential, a relative electrical stability and the responsiveness to both contractile and relaxant agents. In addition, K 1 channels are also involved in modulation of neurotransmitter release from airway nerves. The most important K 1 channels identified in airways include large and small Ca2 1-activated, delayed-rectifier, and ATP-sensitive channels. These K 1 channels are structurally and functionally different, thus playing distinct roles in airway electrophysiology and pharmacology. Many in vitro and in vivo studies, performed in both animals and humans, have shown that K 1 channel openers are able to induce hyperpolarization of ASM cells, bronchodilation, suppression of airway hyperresponsiveness (AHR), and inhibition of neural reflexes. Therefore, airway K 1 channels represent a suitable pharmacological target for the development of new effective therapeutic options in the treatment of asthma and chronic obstructive pulmonary disease (COPD)

A single-blind, partial crossover clinical trial of the effects of inhaled fluticasone propionate and nedocromil sodium on airway hyperresponsiveness to methacholine

Background: Airway inflammation plays a central role in the pathogenesis of asthma, even in the mildest forms and at the earliest stages. Therapeutic strategies now aim to relieve bronchoconstriction as well as focus primarily on controlling the underlying inflammatory process. Clinical trials of children and adults with asthma have demonstrated that inhaled corticosteroids and cromones (such as nedocromil sodium [NS]) improve symptoms and lung function, as well as decrease nonspecific bronchial hyperresponsiveness. Objective: The aim of this study was to compare the effects of various antiinflammatory therapeutic regimens using inhaled fluticasone propionate (FP) and/or NS on airway hyperresponsiveness to methacholine. Methods: Patients with mild, persistent asthma., who tested positive to a Dermatophagoides pteronyssinus skin prick test, were randomly assigned to 1 of 4 treatment groups: (1) FP for 16 weeks; (2) FP for 8 weeks, followed by NS for 8 weeks; (3) NS for 8 weeks, followed by FP for 8 weeks, or (4) NS for 16 weeks. Each patient was evaluated every 4 weeks. Results: Thirty-two patients with asthma (16 men and 16 women; age range, 18-48 years) were included in the study; 8 patients were randomly assigned to each of the 4 treatment groups. During treatment with FP alone, the provocative dose of methacholine required to induce a 20% decrease in forced expiratory volume in 1 second (PD20) was significantly higher than that recorded during treatment with NS alone (P < 0.05 at weeks 12 and 16). However, both drugs induced progressive increases in PD20 versus baseline values throughout the study. Moreover, when FP was administered as the second drug (after NS), a further increase in PD20 compared with the values at week 8 occurred at both week 12 (P < 0.01) and week 16 (P < 0.001). In contrast, when NS was administered after 8 weeks of treatment with FP, methacholine PD20 decreased significantly compared with week 8 (P < 0.001 and P < 0.01 at weeks 12 and 16, respectively). Conclusions: Our results suggest that, in this limited population of asthmatic patients who were treated for 16 weeks, FP was effective in increasing the PD20 and that NS exerted an effective, progressive protective action against bronchial hyperresponsiveness to methacholine, thereby partially limiting the negative consequences of FP withdrawal on airway inflammation

Effects of transforming growth factor-[beta] and budesonide on mitogen-activated protein kinase activation and apoptosis in airway epithelial cells.

Airway epithelial cells play a central role in the inflammatory, apoptotic, and remodeling processes associated with asthma. Within this context, a key function is exerted by transforming growth factor-beta (TGF-beta), whose biological effects are mediated at least in part by mitogen-activated protein kinases (MAPKs). The aim of our study was to investigate, in primary cultures of human bronchial epithelial cells (HBEC), the effects of TGF-beta (10 ng/ml) on both MAPK activation and apoptosis, in the presence or absence of a pretreatment with budesonide (10-8 M). MAPK activation was detected by Western blotting, using anti-phospho-MAPK monoclonal antibodies, which specifically recognize the phosphorylated, active forms of these enzymes. Apoptosis was assayed by caspase-3 activation and fluorescence microscopy, using annexin-V (An-V) and propidium iodide (PI) as markers of cell death. Our results show that TGF-beta induced a marked ( reverse similar 9-fold) increase in p38 MAPK phosphorylation, and also dramatically enhanced cell death, which was completely prevented by specific MAPK inhibitors. Both MAPK activation and apoptosis were effectively inhibited by budesonide (BUD), thereby suggesting that the powerful antiapoptotic action of inhaled glucocorticoids may be very important for their protective role against epithelial injury, which represents a key pathogenic event in asthma

Effects of glucocorticoids on activation of c-jun N-terminal, extracellular signal-regulated, and p38 MAP kinases in human pulmonary endothelial cells.

Mitogen-activated protein kinases (MAPK) play a central role in signal transduction by regulating many nuclear transcription factors involved in inflammatory, immune, and proliferative responses. The aim of this study was to investigate, in human pulmonary endothelial cells, the effects of synthetic glucocorticosteroids on activation of c-jun N-terminal kinases, extracellular signal-regulated kinases, and p38 subgroups of the MAPK family. Human microvascular endothelial cells from lung were stimulated for 2 h with either H(2)O(2) (2 mM), IL-1beta (10 ng/mL), or tumour necrosis factor-alpha (10 ng/mL). Under these conditions, a remarkable increase in the phosphorylation pattern of c-jun N-terminal kinases, extracellular signal-regulated kinases 1/2, and p38 was detected. Pretreatment for 12 h with dexamethasone (100 nM) was able to prevent phosphorylation-dependent MAPK activation in stimulated cells, without substantially affecting the expression levels of these enzymes. Our results suggest that inhibition of MAPK signaling pathways in human pulmonary endothelial cells may significantly contribute, by interfering with activation of several different transcription factors, to the antiinflammatory and immunosuppressive effects of glucocorticosteroids