A weak glutathione-related enzymatic antioxidant shield is present in human atherosclerotic lesions. Although the cause of this phenomenon remains to be determined, the present data suggest that a specific antioxidant/prooxidant imbalance operative in the vascular wall may be involved in atherogenic processes in humans.

Potential antioxidant properties of therapeutically achievable concentrations of the protonated, active form of omeprazole (OM) were investigated in vitro at specific acidic pH values to mimic intragastric conditions in the clinical setting. We found that OM is a powerful scavenger of hypochlorous acid (HOCl) even at a drug concentration of 10 microM at pH 5.3 or 3.5. This effect is also evident in the presence of the physiological HOCl scavenger ascorbate. Moreover, 10 and 50 microM OM inhibit significantly both iron- and copper-driven oxidant damage at pH 5.3 and 3.5, respectively. Since oxidative stress is involved the gastric injury of peptic ulcer and gastritis, it may be hypothesized that some therapeutical effects of OM could also be related to its antioxidant properties.

Potential oxygen radical scavenging properties of the H2-receptor antagonists cimetidine, ranitidine and famotidine were investigated. These drugs, although ineffective against superoxide anion and hydrogen peroxide, can scavenge hydroxyl radical (OH.) with a very high rate constant, which is about tenfold higher than that of the specific scavenger mannitol for famotidine (1.7 x 10(10) mol-1 s-1) and cimetidine (1.6 x 10(10) mol-1 s-1), ranitidine displaying a rate constant of 7.5 x 10(9) mol-1 s-1. These OH. savenging effects are significant beginning from 10, 28 and 100 mumol l-1 concentration for famotidine, cimetidine and ranitidine, respectively, thus suggesting that the drugs may effectively act as OH. scavengers in vivo especially in the gastric lumen. Only cimetidine can apparently bind and inactivate iron, which further emphasizes its antioxidant capacity. Moreover, all drugs, even at 10 mumol l-1 concentration, show powerful scavenging effects on hypochlorous acid and monochloramine, which are cytotoxic oxidants arising from inflammatory cells, such as neutrophils. These data suggest that some therapeutical effects of H2-receptor antagonists in peptic ulcer may also be related to their antiradical-antioxidant capacity, and that these drugs could potentially be used in other disease entities characterized by free radical-mediated oxidative stress in vivo.

Gas and tar phases of commercially available filter cigarettes were tested for ferritin-iron-releasing effects and polyunsaturated-fatty-acid oxidant capacity in vitro. A vacuum pump-dependent apparatus with Cambridge filters was used to separate gas and tar; the former was directly smoked into reaction mixtures, while the latter was extracted from Cambridge filters in aqueous medium and freshly used at 40 to 80% final concentrations. Both phases induced ferritin iron release, which was not antagonized by superoxide dismutase (SOD). In specific experiments, we have also shown that gas and tar extracts could cross an organic (i.e., chloroform)-phospholipid layer before mobilizing ferritin iron. Once delocalized from ferritin, iron could trigger lipid peroxidation; however, a marked prooxidant effect (inhibited by 20 microM deferoxamine mesylate and significantly decreased by 40 microM vitamin E) was observed only with gas, whereas tar extracts showed antioxidant effects. Accordingly, tar extracts could also antagonize lipid peroxidation driven by non-chelated iron or by peroxyl radicals. In the absence of ferritin, gas-induced lipid peroxidation was very low, and tar extracts were apparently ineffective. Thus, the intrinsic lipoperoxidative capacity of cigarette smoke is low and is due to gas; however, when smoke interacts with ferritin, a marked iron-driven peroxidation becomes manifest essentially with gas, tar components acting as antioxidants. The present data suggest that cigarette-smoke-mediated iron mobilization from ferritin may represent a specific prooxidant mechanism related to cigarette smoking in vivo.

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Circadian variations in antioxidant defences and lipid peroxidation were investigated in 12 rat hearts perfused during light (i.e., at 08.00, n = 6) and dark cycle (i.e., at 19.00, n = 6). Higher levels of non proteic thiol compounds (P < 0.01), glutathione transferase activity (P < 0.05) and lipid peroxidation (P < 0.01) were detected in evening-excised hearts, associated with a lower (P < 0.05) selenium-dependent glutathione peroxidase activity; superoxide dismutase and glutathione reductase activities, as well as vitamin E content, were similar in the two groups. Moreover, a greater release of thiobarbituric acid reactive substances (P < 0.01) and proteins (P < 0.05) was detected in the myocardial effluent of another group of 5 evening-excised hearts perfused with Krebs-Henseleit buffer containing 30 microM cumene hydroperoxide, as compared to 5 light-cycle hearts. In conclusion, a higher oxidative stress seems to be operative in the rat heart during early stages of the dark phase, in spite of the increase level of non proteic thiol compounds (namely, glutathione). An imbalance of antioxidant defences, and/or higher radical generation and unsaturation degree of biomembranes lipids, may be hypothesized to favour myocardial oxidative stress at the beginning of the motor activity phase in rats.

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Background and objectives The pangenotypic single tablet regimen of NS5B inhibitor sofobuvir (SOF) and NS5A inhibitor velpatasvir (VEL) is advised for 12 weeks in HCV-infected patients including those with compensated cirrhosis. Addition of ribavirin (RBV) may be considered in genotype 3 (GT3) with compensated and is recommended in decompensated cirrhosis. Real-life results with SOF/VEL are limited. To evaluate efficacy and safety in a large real-world-cohort including patients with different GTs and various fibrosis stages. Design In total, 1429 patients were treated with SOF/VEL 400/100 mg for 12 weeks in the Puglia registry between June 2017 and May 2018. 1319 (92.3%) reached week 12 post-treatment (SVR12) at the moment. Only 41 received RBV. Diagnosis of cirrhosis was based on transient elastography and/or APRI or FIB-4 scores. Sensitivity analysis in the population including all patients except non virological failure was conducted. Primary efficacy endpoint was the percentage of patients with SVR12. Results Patients’ mean age was 63.8 years, 42.3% had GT1. The majority were naïve and 735 (55.5%) F0/F2. Of the remaining 587, 282 had cirrhosis. SVR12 was 98.5%, 98.0% in GT1, 99.4% in GT2, 97.1% in GT3, 100% in GT4. Overall, SVR12 by sensitivity analysis was 99.4%; 99.7% among F0-F1. Among 218 PWID, SVR12 was 94.5%. Discontinuation rates were 3.7% among PWID and 0.7% among non-PWID (p = 0.004). Conclusions SOF/VEL treatment of chronic HCV infection reaches very high cure rates in a variety of patients; including those with F0/F1 and PWID.