Oxidative Stress and Respiratory System: Pharmacological and Clinical Reappraisal of N-Acetylcysteine

The large surface area for gas exchange makes the respiratory system particularly susceptible to oxidative stress-mediated injury. Both endogenous and exogenous pro-oxidants (e.g. cigarette smoke) trigger activation of leukocytes and host defenses. These mechanisms interact in a “multilevel cycle” responsible for the control of the oxidant/antioxidant homeostasis. Several studies have demonstrated the presence of increased oxidative stress and decreased antioxidants (e.g. reduced glutathione [GSH]) in subjects with chronic obstructive pulmonary disease (COPD), but the contribution of oxidative stress to the pathophysiology of COPD is generally only minimally discussed. The aim of this review was to provide a comprehensive overview of the role of oxidative stress in the pathogenesis of respiratory diseases, particularly COPD, and to examine the available clinical and experimental evidence on the use of the antioxidant N-acetylcysteine (NAC), a precursor of GSH, as an adjunct to standard therapy for the treatment of COPD. The proposed concept of “multilevel cycle” helps understand the relationship between respiratory diseases and oxidative stress, thus clarifying the rationale for using NAC in COPD. Until recently, antioxidant drugs such as NAC have been regarded only as mucolytic agents. Nevertheless, several clinical trials indicate that NAC may reduce the rate of COPD exacerbations and improve small airways function. The most plausible explanation for the beneficial effects observed in patients with COPD treated with NAC lies in the mucolytic and antioxidant effects of this drug. Modulation of bronchial inflammation by NAC may further account for these favorable clinical results.     

Major bleeding in patients undergoing PCI and triple or dual antithrombotic therapy: a parallel-cohort study

The combination of oral anticoagulants with dual antiplatelet therapy (DAT) in patients undergoing percutaneous coronary intervention with stent implantation (PCI-stenting) is subject to controversy due to the high risk of bleeding. In this multicenter retrospective parallel-group study, we compared the rate of adverse events in chronically anticoagulated patients who underwent PCI-stenting and were discharged on aspirin, clopidogrel and warfarin (triple antithrombotic therapy [TT] group) and were followed in Italian anticoagulation centers, with a parallel cohort of patients who underwent PCI-stenting and were discharged on DAT group. The primary endpoint was the incidence of major bleeding while the patients were in TT and DAT. A secondary endpoint was the occurrence of major ischemic adverse events (MACEs). The final cohort consisted of 229 TT patients and 231 DAT patients followed up for 6 and 7 months, respectively. There were 11 (4.8 %; 9.1 % patient/years) major bleeding events in the TT group (1 was fatal) as compared to 1 (0.4 %; 0.7 % patient/years) event in the DAT group (p = 0.003). Of the 28 (6.1 %) MACE recorded during the follow-up, 12 (5.2 %) occurred in the TT group and 16 (6.9 %) in the DAT group. In conclusion, despite close monitoring of anticoagulated patients in dedicated centers, the major bleeding incidence remains high among unselected patients undergoing PCI-stenting and treated with TT. Any efforts to minimize these events should be pursued.     

Comparison of in vitro and in vivo biological effects of trabectedin,lurbinectedin (PM01183) and Zalypsis® (PM00104)

This study: (i) investigated the in vitro cytotoxicity and mode of action of lurbinectedin (PM01183) and Zalypsis® (PM00104) compared with trabectedin in cell lines deficient in specific mechanisms of repair, (ii) evaluated their in vivo antitumor activity against a series of murine tumors and human xenografts. The antiproliferative activity, the DNA damage and the cell cycle perturbations induced by the three compounds on tumor lines were very similar. Nucleotide Excision Repair (NER) deficient cells were approximately fourfold more resistant to trabectedin, lurbinectedin and Zalypsis®. Cells deficient in non‐homologous end joining (NHEJ), MRN complex and translesion synthesis (TLS) were slightly more sensitive to the three compounds (approximately fivefold) while cells deficient in homologous recombination (HR) were markedly more sensitive (150–200‐fold). All three compounds showed a good antitumor activity in several in vivo models. Lurbinectedin and trabectedin had a similar pattern of antitumor activity in murine tumors and in xenografts, whereas Zalypsis® appeared to have a distinct spectrum of activity. The fact that no relationship whatsoever was found between the in vitro cytotoxic potency and the in vivo antitumor activity, suggests that in addition to direct cytotoxic mechanisms other host‐mediated effects are involved in the in vivo pharmacological effects.     

Different effect of statins on platelet oxidized-LDL receptor (CD36 and LOX-1) expression in hypercholesterolemic subjects.

Hydroxymethyl-glutaryl-CoA-reductase inhibitors (statins) reduce cardiovascular mortality by decreasing cholesterol as well as by non-lipid-related actions. Oxidized low-density lipoproteins (ox-LDL) are pro-atherogenic molecules and potent platelet agonists. CD36 and lectin-like ox-LDL receptor-1 (LOX-1) are specific ox-LDL receptors also expressed in platelets. This study was planned to address whether treatment with atorvastatin 10 mg/day, pravastatin 40 mg/day or simvastatin 20 mg/day could affect platelet CD36 and LOX-1 expression. Twenty-four patients for each treatment were evaluated after 3, 6, and 9 days and at 6 weeks for complete lipid profile (chromogenic), ox-LDL (ELISA), platelet P-selectin (P-sel), CD36, LOX-1 (FACS), and intracellular citrullin recovery (iCit) (HPLC). Data show hyperactivated platelets (P-sel absolute values, percent variation in activated cells, all p < 0.001), and CD36 and LOX-1 overexpression (all p < 0.001) in patients at baseline. P-sel, CD36, and LOX-1 were significantly decreased by atorvastatin and simvastatin (all p < 0.01) and related with iCit increase (r = 0.58, p < 0.001) and platelet-associated ox-LDL (r = 0.51, p < 0.01) at 9 days. Pravastatin reduced LOX-1 and P-sel (p < 0.05) at 6 weeks in relation with decreased LDL and ox-LDL (r = 0.39, p < 0.01 and r = 0.37, p < 0.01, respectively). These data suggest that atorvastatin and simvastatin reduce platelet activity by exposure of CD36 and LOX-1 before significant LDL reduction, whereas pravastatin action is detected later and in relation with LDL and ox-LDL lowering. Rapid and consistent reduction of CD36 and LOX-1 could be considered a direct anti-atherothrombotic mechanism related to the role of ox-LDL in platelet activation, platelet-endothelium interactions, and NO synthase activity.     

A Randomized Comparison of Alternative Techniques to Achieve Coronary Sinus Cannulation During Biventricular Implantation Procedures

INTRODUCTION: Biventricular pacing system implantation is a time-consuming and challenging procedure. A critical step in biventricular pacemaker implantation is coronary sinus (CS) cannulation. CS cannulation can be achieved either using dedicated guiding catheters (guiding catheter alone positioning strategy, GCA) or with the aid of an electrophysiology catheter advanced inside the guiding catheter (electrophysiology catheter aided positioning strategy, EPA). AIM OF THE STUDY: To evaluate whether the EPA technique is useful for reducing CS cannulation time compared to a conventional GCA technique. METHODS: Thirty-four consecutive patients were randomly assigned to the GCA (18 patients) or EPA (16 patients) CS cannulation strategy. RESULTS: Time to successful catheterization of CS was 5.0 +/- 2.4 min in the EPA group versus 10.1 +/- 5.4 min in the GCA group p = 0.004. Fluoroscopy time was 4.6 +/- 2.3 min in the EPA group versus 9.2 +/- 4.9 min in the GCA group p = 0.004. Total contrast dye volume to search and engage the CS ostium was 0.0 ml in the EPA group versus 14.3 +/- 3.4 ml in the GCA group p < 0.001. CONCLUSIONS: Cannulation of CS with the adjunct of an electrophysiology catheter to dedicated delivery systems significantly reduces procedural time, fluoroscopy time and contrast dye volume compared to a conventional strategy.     

Effectiveness of alendronate treatment in postmenopausal women with osteoporosis: relationship with BsmI vitamin D receptor genotypes

OBJECTIVE: To assess whether there is a relationship between the effectiveness of alendronate treatment in postmenopausal women with osteoporosis and BsmI vitamin D receptor (VDR) genotypes. DESIGN: Prospective baseline-controlled clinical trial. PATIENTS: Sixty-eight Italian osteoporotic women were enrolled and treated with alendronate at a dose of 10 mg/day for 12 months. MEASUREMENTS: At entry and after treatment, lumbar bone mineral density (BMD) and serum osteocalcin (OC) and urinary deoxypyridinoline/creatinine ratio (DPD-Cr) levels were evaluated. DNA was extracted from blood and analysed for the BsmI polymorphism of the VDR gene. RESULTS: The mean percentage (% +/- SD) change from baseline in lumbar BMD was significantly higher (P < 0.01) in bb than in BB BsmI VDR genotypes (7.92 +/- 4.31 vs. 3.40 +/- 1.81). No significant difference in lumbar BMD was observed in Bb VDR patients (6.01 +/- 3.89) in comparison with other groups. The mean percentage of change in serum OC and urinary DPD-Cr levels was significantly (P < 0.01) lower in individuals with bb than in those with BB BsmI VDR genotypes (-14.34 +/- 2.87 vs.-10.39 +/- 1.43 and -9.61 +/- 5.56 vs.-4.61 +/- 2.31). No significant difference in serum OC and urinary DPD-Cr levels was observed in Bb VDR patients (-12.31 +/- 2.11 and -6.52 +/- 2.65) in comparison with other groups. CONCLUSION: The different BsmI vitamin D receptor genotypes modify the pharmacological response to alendronate treatment in postmenopausal women with osteoporosis.