A Phase 2 Clinical Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of Different Prime-Boost Vaccination Schedules of 2013 and 2017 A(H7N9) Inactivated Influenza Virus Vaccines Administered With and Without AS03 Adjuvant in Healthy US Adults.

INTRODUCTION: A surge of human influenza A(H7N9) cases began in 2016 in China from an antigenically distinct lineage. Data are needed about the safety and immunogenicity of 2013 and 2017 A(H7N9) inactivated influenza vaccines (IIVs) and the effects of AS03 adjuvant, prime-boost interval, and priming effects of 2013 and 2017 A(H7N9) IIVs. METHODS: Healthy adults (n = 180), ages 19-50 years, were enrolled into this partially blinded, randomized, multicenter phase 2 clinical trial. Participants were randomly assigned to 1 of 6 vaccination groups evaluating homologous versus heterologous prime-boost strategies with 2 different boost intervals (21 vs 120 days) and 2 dosages (3.75 or 15 µg of hemagglutinin) administered with or without AS03 adjuvant. Reactogenicity, safety, and immunogenicity measured by hemagglutination inhibition and neutralizing antibody titers were assessed. RESULTS: Two doses of A(H7N9) IIV were well tolerated, and no safety issues were identified. Although most participants had injection site and systemic reactogenicity, these symptoms were mostly mild to moderate in severity; injection site reactogenicity was greater in vaccination groups receiving adjuvant. Immune responses were greater after an adjuvanted second dose, and with a longer interval between prime and boost. The highest hemagglutination inhibition geometric mean titer (95% confidence interval) observed against the 2017 A(H7N9) strain was 133.4 (83.6-212.6) among participants who received homologous, adjuvanted 3.75 µg + AS03/2017 doses with delayed boost interval. CONCLUSIONS: Administering AS03 adjuvant with the second H7N9 IIV dose and extending the boost interval to 4 months resulted in higher peak antibody responses. These observations can broadly inform strategic approaches for pandemic preparedness. Clinical Trials Registration. NCT03589807.

Reassessment of the risk of narcolepsy in children in England 8 years after receipt of the AS03-adjuvanted H1N1 pandemic vaccine: A case-coverage study.

BACKGROUND: Early studies of narcolepsy after AS03-adjuvanted pandemic A/H1N12009 vaccine (Pandemrix) could not define the duration of elevated risk post-vaccination nor the risk in children aged under 5 years who may not present until much older. METHODS/FINDINGS: Clinical information and sleep test results, extracted from hospital notes at 3 large pediatric sleep centers in England between September 2017 and June 2018 for narcolepsy cases aged 4-19 years with symptom onset since January 2009, were reviewed by an expert panel to confirm the diagnosis. Vaccination histories were independently obtained from general practitioners (GPs). The odds of vaccination in narcolepsy cases compared with the age-matched English population was calculated after adjustment for clinical conditions that were indications for vaccination. GP questionnaires were returned for 242 of the 244 children with confirmed narcolepsy. Of these 5 were under 5 years, 118 were 5-11 years, and 119 were 12-19 years old at diagnosis; 39 were vaccinated with Pandemrix before onset. The odds ratio (OR) for onset at any time after vaccination was 1.94 (95% confidence interval [CI] 1.30-2.89), The elevated risk period was restricted to onsets within 12 months of vaccination (OR 6.65 [3.44-12.85]) and was highest within the first 6 months. After one year, ORs were not significantly different from 1 up to 8 years after vaccination. The ORs were similar in under five-year-olds and older ages. The estimated attributable risk was 1 in 34,500 doses. Our study is limited by including cases from only 3 sleep centers, who may differ from cases diagnosed in nonparticipating centers, and by imprecision in defining the centers' catchment population. The potential for biased recall of onset shortly after vaccination in cases aware of the association cannot be excluded. CONCLUSIONS: In this study, we found that vaccine-attributable cases have onset of narcolepsy within 12 months of Pandemrix vaccination. The attributable risk is higher than previously estimated in England because of identification of vaccine-attributable cases with late diagnoses. Absence of a compensatory drop in risk 1-8 years after vaccination suggests that Pandemrix does not trigger onsets in those in whom narcolepsy would have occurred later.

Drugs for preventing lung cancer in healthy people.

BACKGROUND: This is the second update of this Cochrane Review. Some studies have suggested a protective effect of antioxidant nutrients and higher dietary levels of fruits and vegetables on lung cancer. OBJECTIVES: To determine whether vitamins and minerals and other potential agents, alone or in combination, reduce lung cancer incidence and lung cancer mortality in healthy populations. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase from 1974 to May 2019 and screened references included in published studies and reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing vitamins or mineral supplements with placebo, administered to healthy people with the aim of preventing lung cancer. DATA COLLECTION AND ANALYSIS: Four review authors independently selected the trials to be included in the review, assessed their methodological quality and extracted data. For dichotomous outcomes we calculated risk ratios (RRs) and 95% confidence intervals (CIs) and pooled results using the random-effects model. We assessed the risk of bias using Cochrane's 'Risk of bias' assessment tool and certainty of evidence using the GRADE approach. MAIN RESULTS: In this update, we identified three new trials for a total of 12 studies. Six analysed vitamin A, three vitamin C, three combined vitamin D3 + calcium, four vitamin E combined with other products, one selenium supplements and nine studied combinations of two or more products. Four studies included only men and five only women. Vitamin A results in little to no difference in lung cancer incidence (RR 1.09, 95% CI 1.00 to 1.19; 5 RCTs, 212314 participants; high-certainty evidence) and lung cancer mortality (RR 1.06, 95% CI 0.81 to 1.38; 3 RCTs, 190118 participants; high-certainty evidence). But in smokers or asbestos workers vitamin A increases the risk of lung cancer incidence (RR 1.10, 95% CI 1.01 to 1.20; 3 RCTs, 43995 participants; high-certainty evidence), lung cancer mortality (RR 1.18, 95% CI 1.01 to 1.38; 2 RCTs, 29426 participants; high-certainty evidence) and all-cause mortality (RR 1.09, 95% CI 1.05 to 1.13; 2 RCTs, 32883 participants; high-certainty evidence). Vitamin A increases the risk of minor side effects, such as yellowing of the skin and minor gastrointestinal symptoms (high-certainty evidence). Vitamin C likely results in little to no difference in lung cancer incidence (RR 1.29, 95% CI 0.67 to 2.49; 2 RCTs, 14953 participants; moderate-certainty evidence). In women, vitamin C increases the risk of lung cancer incidence (RR 1.84, 95% CI 1.14 to 2.95; 1 RCT, 7627 participants; high-certainty evidence). In men, vitamin C results in little to no difference in mortality for lung cancer (RR 0.81, 95% CI 0.53 to 1.23; 1 RCT, 7326 participants; high-certainty evidence). Vitamin D + calcium may result in little to no difference in lung cancer incidence in postmenopausal women (RR 0.90, 95% CI 0.39 to 2.08; 3 RCTs, 37601 women; low-certainty evidence). Vitamin E results in little to no difference in lung cancer incidence (RR 1.01, 95% CI 0.90 to 1.14; 3 RCTs, 36841 participants; high-certainty evidence) or to lung cancer mortality (RR 0.96, 95% CI 0.77 to 1.18; 2 RCTs, 29214 participants; high-certainty evidence), but increases the risk of haemorrhagic strokes (hazard ratio (HR), 1.74, 95% CI 1.04 to 2.91; 1 RCT, 14641 participants; high-certainty evidence). Calcium results in little to no difference in lung cancer incidence in postmenopausal women (RR 0.65, 95% CI 0.13 to 3.18; 1 RCT, 733 participants) or in risk of renal calculi (RR 1.94, 95% CI 0.20 to 18.57; 1 RCT, 733 participants; low-certainty evidence). Selenium in men results in little to no difference in lung cancer incidence (RR 1.11, 95% CI 0.80 to 1.54; 1 RCT, 17448 participants; high-certainty evidence) and lung cancer mortality (RR 1.09, 95% CI 0.72 to 1.66; 1 RCT, 17448 participants; high-certainty evidence) and increases the risk for grade 1 to 2 dermatitis (RR 1.16, 95% CI 1.04 to 1.31; 1 RCT, 17448 participants; high-certainty evidence) and for alopecia (RR 1.28, 95% CI 1.07 to 1.53; 1 RCT, 17448 participants; high-certainty evidence). The combination of vitamins A, C, E + selenium + zinc results in little to no difference in lung cancer incidence (RR 0.64, 95% CI 0.28 to 1.48; 1 RCT, 12741 participants; high-certainty evidence). AUTHORS' CONCLUSIONS: Well-designed RCTs have shown no beneficial effect of supplements for the prevention of lung cancer and lung cancer mortality in healthy people. Vitamin A supplements increase lung cancer incidence and mortality in smokers or persons exposed to asbestos. Vitamin C increases lung cancer incidence in women. Vitamin E increases the risk of haemorrhagic strokes.

Perinatal α-tocopherol overload programs alterations in kidney development and renal angiotensin II signaling pathways at birth and at juvenile age: Mechanisms underlying the development of elevated blood pressure.

α-Tocopherol (α-Toc) overload increases the risk of dying in humans (E.R. Miller III et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality Ann Int Med. 142 (2005) 37-46), and overload during early development leads to elevation of blood pressure at adult life, but the mechanism(s) remains unknown. We hypothesized that α-Toc overload during organogenesis affects the renal renin angiotensin system (RAS) components and renal Na+ handling, culminating with late elevated blood pressure. Pregnant Wistar rats received α-Toc or the superoxide dismutase mimetic tempol throughout pregnancy. We evaluated components of the intrarenal renin angiotensin system in neonate and juvenile offspring: Ang II-positive cells, Ang II receptors (AT1 and AT2), linked protein kinases, O2- production, NADPH oxidase abundance, lipid peroxidation and activity of Na+-transporting ATPases. In juvenile offspring we followed the evolution of arterial blood pressure. Neonates from α-Toc and tempol mothers presented with accentuated retardment in tubular development, pronounced decrease in glomerular Ang II-positive cells and AT1/AT2 ratio, intense production of O2- and upregulation of the α, ε and λ PKC isoforms. α-Toc decreased or augmented the abundance of renal (Na++K+)ATPase depending on the age and α-Toc dose. In juvenile rats the number of Ang II-positive cells returned to control values as well as PKCα, but co-existing with marked upregulation in the activity of (Na++K+) and Na+-ATPase and elevated arterial pressure at 30 days. We conclude that the mechanisms of these alterations rely on selective targeting of renal RAS components through genic and pro-oxidant effects of the vitamin.

Vitamin E for Alzheimer's dementia and mild cognitive impairment.

BACKGROUND: Vitamin E occurs naturally in the diet. It has several biological activities, including functioning as an antioxidant to scavenge toxic free radicals. Evidence that free radicals may contribute to the pathological processes behind cognitive impairment has led to interest in the use of vitamin E supplements to treat mild cognitive impairment (MCI) and Alzheimer's disease (AD). This is an update of a Cochrane Review first published in 2000, and previously updated in 2006 and 2012. OBJECTIVES: To assess the efficacy of vitamin E in the treatment of MCI and dementia due to AD. SEARCH METHODS: We searched the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (ALOIS), the Cochrane Library, MEDLINE, Embase, PsycINFO, CINAHL, LILACS as well as many trials databases and grey literature sources on 22 April 2016 using the terms: "Vitamin E", vitamin-E, alpha-tocopherol. SELECTION CRITERIA: We included all double-blind, randomised trials in which treatment with any dose of vitamin E was compared with placebo in people with AD or MCI. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures according to the Cochrane Handbook for Systematic Reviews of Interventions. We rated the quality of the evidence using the GRADE approach. Where appropriate we attempted to contact authors to obtain missing information. MAIN RESULTS: Four trials met the inclusion criteria, but we could only extract outcome data in accordance with our protocol from two trials, one in an AD population (n = 304) and one in an MCI population (n = 516). Both trials had an overall low to unclear risk of bias. It was not possible to pool data across studies owing to a lack of comparable outcome measures.In people with AD, we found no evidence of any clinically important effect of vitamin E on cognition, measured with change from baseline in the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog) over six to 48 months (mean difference (MD) -1.81, 95% confidence interval (CI) -3.75 to 0.13, P = 0.07, 1 study, n = 272; moderate quality evidence). There was no evidence of a difference between vitamin E and placebo groups in the risk of experiencing at least one serious adverse event over six to 48 months (risk ratio (RR) 0.86, 95% CI 0.71 to 1.05, P = 0.13, 1 study, n = 304; moderate quality evidence), or in the risk of death (RR 0.84, 95% CI 0.52 to 1.34, P = 0.46, 1 study, n = 304; moderate quality evidence). People with AD receiving vitamin E showed less functional decline on the Alzheimer's Disease Cooperative Study/Activities of Daily Living Inventory than people receiving placebo at six to 48 months (mean difference (MD) 3.15, 95% CI 0.07 to 6.23, P = 0.04, 1 study, n = 280; moderate quality evidence). There was no evidence of any clinically important effect on neuropsychiatric symptoms measured with the Neuropsychiatric Inventory (MD -1.47, 95% CI -4.26 to 1.32, P = 0.30, 1 study, n = 280; moderate quality evidence).We found no evidence that vitamin E affected the probability of progression from MCI to probable dementia due to AD over 36 months (RR 1.03, 95% CI 0.79 to 1.35, P = 0.81, 1 study, n = 516; moderate quality evidence). Five deaths occurred in each of the vitamin E and placebo groups over the 36 months (RR 1.01, 95% CI 0.30 to 3.44, P = 0.99, 1 study, n = 516; moderate quality evidence). We were unable to extract data in accordance with the review protocol for other outcomes. However, the study authors found no evidence that vitamin E differed from placebo in its effect on cognitive function, global severity or activities of daily living . There was also no evidence of a difference between groups in the more commonly reported adverse events. AUTHORS' CONCLUSIONS: We found no evidence that the alpha-tocopherol form of vitamin E given to people with MCI prevents progression to dementia, or that it improves cognitive function in people with MCI or dementia due to AD. However, there is moderate quality evidence from a single study that it may slow functional decline in AD. Vitamin E was not associated with an increased risk of serious adverse events or mortality in the trials in this review. These conclusions have changed since the previous update, however they are still based on small numbers of trials and participants and further research is quite likely to affect the results.

Immunogenicity and Safety of an EB66 Cell-Culture-Derived Influenza A/Indonesia/5/2005(H5N1) AS03-Adjuvanted Vaccine: A Phase 1 Randomized Trial.

BACKGROUND: Cell-culture-derived (CC) influenza vaccine production methods could provide benefits over classical embryonated-egg technology, including a higher production capacity and the faster creation of a supply that meets demand. METHODS: A CC-inactivated split-virus influenza A/Indonesia/5/2005(H5N1) vaccine derived from the EB66 cell line (hereafter, "CC-H5N1") was investigated in a phase 1 randomized, blinded study. Healthy adults (n = 521) received 2 vaccine doses (days 0 and 21) of either investigational CC-H5N1 vaccine (1.9 µg or 3.75 µg of hemagglutinin antigen [HA] with the AS03 adjuvant system or 15 µg of plain HA), embryonated-egg-derived vaccines (3.75 µg of HA with AS03 or 15 µg of plain HA), or placebo. Assessment of the adjuvant effect and immunogenicity was performed using Center for Biologics Evaluation and Research acceptability criteria 21 days after dose 2. Safety was assessed until month 12. RESULTS: AS03-adjuvanted CC-H5N1 elicited a homologous hemagglutination inhibition antibody response that satisfied immunogenicity criteria 21 days after dose 2 and persisted at month 12. Adjuvant effect and immune response against a drift-variant strain were demonstrated. No vaccine-related serious adverse events were reported. The immunogenicity and safety of the CC-H5N1 formulation containing 3.75 µg of HA and AS03 appeared to be similar to those for the licensed egg-derived AS03-adjuvanted control vaccine. CONCLUSIONS: The feasibility of the EB66 cell line to produce an immunogenic influenza vaccine with acceptable safety profile was demonstrated. Antigen sparing was achieved through combination with AS03 adjuvant. This CC-H5N1 might contribute to the rapid access of vaccine in the event of an influenza A(H5N1) pandemic. CLINICAL TRIALS REGISTRATION: NCT01236040.

AS03B-adjuvanted H5N1 influenza vaccine in children 6 months through 17 years of age: a phase 2/3 randomized, placebo-controlled, observer-blinded trial.

BACKGROUND: This phase 2/3, randomized, placebo-controlled, observer-blinded study assessed the immunogenicity, reactogenicity, and safety of an inactivated, split-virion H5N1 influenza vaccine (A/Indonesia/5/2005) in children aged 6 months through 17 years. METHODS: Children received 2 influenza vaccine doses 21 days apart, each containing 1.9 µg of hemagglutinin and AS03B adjuvant (5.93 mg of α-tocopherol). The randomization ratio was 8:3 for vaccine to placebo, with equal allocation between 3 age strata (6-35 months, 3-8 years, and 9-17 years). Immunogenicity against the vaccine strain was assessed 21 days after the first and second vaccine doses for all vaccinees, at day 182 for half, and at day 385 for the remaining half. Reactogenicity after each dose and safety up to 1 year after vaccination were evaluated. RESULTS: Within each age stratum, the lower limit of the 98.3% confidence interval for the day 42 seroprotection rate was ≥70%, thus fulfilling the US and European licensure criteria. The immune responses elicited by vaccine persisted well above baseline levels for 1 year. The vaccine was more reactogenic than placebo, but no major safety concerns were identified. CONCLUSIONS: AS03B-adjuvanted H5N1 influenza vaccine was immunogenic and showed an acceptable safety profile in all age groups studied. Clinical Trials Registration: NCT01310413.

A first-generation physiologically based pharmacokinetic (PBPK) model of alpha-tocopherol in human influenza vaccine adjuvant.

Alpha (α)-tocopherol is a component of a new generation of squalene-containing oil-in-water (SQ/W) emulsion adjuvants that have been licensed for use in certain influenza vaccines. Since regulatory pharmacokinetic studies are not routinely required for influenza vaccines, the in vivo fate of this vaccine constituent is largely unknown. In this study, we constructed a physiologically based pharmacokinetic (PBPK) model for emulsified α-tocopherol in human adults and infants. An independent sheep PBPK model was also developed to inform the local preferential lymphatic transfer and for the purpose of model evaluation. The PBPK model predicts that α-tocopherol will be removed from the injection site within 24h and rapidly transfer predominantly into draining lymph nodes. A much lower concentration of α-tocopherol was estimated to peak in plasma within 8h. Any systemically absorbed α-tocopherol was predicted to accumulate slowly in adipose tissue, but not in other tissues. Model evaluation and uncertainty analyses indicated acceptable fit, with the fraction of dose taken up into the lymphatics as most influential on plasma concentration. In summary, this study estimates the in vivo fate of α-tocopherol in adjuvanted influenza vaccine, may be relevant in explaining its immunodynamics in humans, and informs current regulatory risk-benefit analyses.

In vivo adverse effects of alpha-tocopherol on the semen quality of male bucks.

Oxidative stress has detrimental effects on semen quality during spermatogenesis and semen processing for artificial insemination. This work was conducted to study the effect of different levels of vitamin E on the semen traits, oxidative status and trace minerals in Beetal bucks. Thirty-six bucks of similar body weight and age (1 year) were randomly divided into four groups. One group was kept as control with no supplementation (group 1), and the others were supplemented with 200 (group 2), 400 (group 3) and 800 IU (group 4) vitamin E/animal/day for 2 months. At the end of the experiment, semen samples were collected and evaluated. Seminal plasma was separated to study the concentration of superoxide dismutase (SOD), glutathione peroxidase (GPx), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and trace minerals (Zn, Cu, Mn and Fe). Group 3 showed significantly higher (p < 0.05) semen volume and per cent motility and lower dead sperm percentage compared to control group. Superoxide dismutase, GPx, Zn, Cu and Mn were higher in the same group. The level of AST decreased in group 3 without any change on the concentration of ALT. It is suggested that vitamin E at the rate of 400 IU/buck/day supported higher semen volume, per cent motility, per cent live spermatozoa, antioxidants (SOD, GPx) and trace mineral levels (Zn, Cu, Mn) in the seminal plasma. The increased supplementation from 0 to 400 showed a general increasing trend in improving semen quality. However, the dose of 800 IU/kg had no useful effect in further improving the semen quality.

Long-term booster schedules with AS03A-adjuvanted heterologous H5N1 vaccines induces rapid and broad immune responses in Asian adults.

BACKGROUND: The pandemic potential of avian influenza A/H5N1 should not be overlooked, and the continued development of vaccines against these highly pathogenic viruses is a public health priority. METHODS: This open-label extension booster study followed a Phase III study of 1206 adults who had received two 3.75 µg doses of primary AS03A-adjuvanted or non-adjuvanted H5N1 split-virus vaccine (A/Vietnam/1194/2004; clade 1) (NCT00449670). The aim of the extension study was to evaluate different timings for heterologous AS03A-adjuvanted booster vaccination (A/Indonesia/5/2005; clade 2.1) given at Month 6, 12, or 36 post-primary vaccination. Immunogenicity was assessed 21 days after each booster vaccination and the persistence of immune responses against the primary vaccine strain (A/Vietnam) and the booster strain (A/Indonesia) was evaluated up to Month 48 post-primary vaccination. Reactogenicity and safety were also assessed. RESULTS: After booster vaccination given at Month 6, HI antibody responses to primary vaccine, and booster vaccine strains were markedly higher with one dose of AS03A-H5N1 booster vaccine in the AS03A-adjuvanted primary vaccine group compared with two doses of booster vaccine in the non-adjuvanted primary vaccine group. HI antibody responses were robust against the primary and booster vaccine strains 21 days after boosting at Month 12 or 36. At Month 48, in subjects boosted at Month 6, 12, or 36, HI antibody titers of ≥1:40 against the booster strain persisted in 39.2%, 61.2%, and 95.6% of subjects, respectively. Neutralizing antibody responses and cell-mediated immune responses also showed that AS03A-H5N1 heterologous booster vaccination elicited robust immune responses within 21 days of boosting at Month 6, 12, or 36 post-primary vaccination. The booster vaccine was well tolerated, and no safety concerns were raised. CONCLUSIONS: In Asian adults primed with two doses of AS03A-adjuvanted H5N1 pandemic influenza vaccine, strong cross-clade anamnestic antibody responses were observed after one dose of AS03A-H5N1 heterologous booster vaccine given at Month 6, 12, or 36 after priming, suggesting that AS03A-adjuvanted H5N1 vaccines may provide highly flexible prime-boost schedules. Although immunogenicity decreased with time, vaccinated populations could potentially be protected for up to three years after vaccination, which is likely to far exceed the peak of the a pandemic.

New strategy of α- and γ-tocopherol to prevent contrast-induced acute kidney injury in chronic kidney disease patients undergoing elective coronary procedures.

BACKGROUND: Contrast-induced acute kidney injury (CI- AKI) increases the likelihood of patient morbidity and mortality following coronary procedures. Volume supplement with saline is the standard treatment to prevent CI-AKI. Additional antioxidant prophylaxis has often yielded conflicting results. The present study was conducted to examine the role of novel application vitamin E (tocopherol) in preventing CI-AKI. METHODS: This prospective, double-blind, randomized and placebo-controlled trial was carried out in 305 patients with chronic kidney disease (CKD) undergoing coronary procedures. All patients were randomly assigned to prophylaxis administration with 0.9% saline infusions plus daily oral medication comprised of either (i) placebo (n = 101), (ii) α-tocopherol (n = 102) or (iii) γ-tocopherol (n = 102) starting 5 days before and ending 2 days after coronary procedures. The CI-AKI risk score of each patient was calculated. All coronary procedures were performed using a low-osmolar, non-ionic contrast agent. RESULTS: CI-AKI developed in 14.9% in the placebo group, 4.9% in the α-tocopherol group (P = 0.02 versus the placebo group) and 5.9% in the γ-tocopherol group (P = 0.04 versus the placebo group). In patients with diabetes, hypertension, anaemia, aged over 55 years, male gender or with contrast agent dosages >120 mL, α-tocopherol showed a larger effect than γ-tocopherol when compared with the placebo group (P < 0.05). CONCLUSIONS: Prophylaxis administration with oral α- or γ-tocopherol in combination with 0.9% saline is effective in protecting against CI-AKI in CKD patients undergoing elective coronary procedures.

Cardiotoxicity induced by dietary oxidized sunflower oil in rats: pro- and antioxidant effects of α-tocopherol.

This study highlighted the pro-oxidative functions of α-tocopherol (αT) on the heart antioxidant system and tissue histopathology of oxidized sunflower oil (OSO)-exposed rats.Four groups of male Wistar rats were fed with different diets: 1) control diet containing FSO (fresh sunflower oil); 2) diet containing 5 % OSO; 3) diet containing 5 % OSO, supplemented with 600 mg αT kg-1; and 4) diet containing 5 % OSO, supplemented with 1200 mg αT kg-1. The hearts were then isolated, and the antioxidant enzymatic activities were assessed. Body weight and catalase (CAT), glutathione peroxidase (GPx) activities significantly decreased in groups fed with OSO, while the lipid peroxidation (LPO) level significantly increased. Administration of OSO with αT (600 mg · kg-1) returned the body weight values and LPO levels to similar values as the control group. The CAT and GPx activities increased but remained significantly lower compared to the control group. In the OSO group with αT (1200 mg · kg-1), the CAT and GPx activities also decreased, while LPO significantly increased. Heart tissue sections obtained from the groups revealed the presence of large areas of necrosis. This study suggested that OSO induced oxidative stress and that administration of a moderate dose of αT restored the antioxidant balance, but that high levels of αT supplementation result in a pro-oxidant effect.

A randomized, controlled non-inferiority trial comparing A(H1N1)pmd09 vaccine antigen, with and without AS03 adjuvant system, co-administered or sequentially administered with an inactivated trivalent seasonal influenza vaccine.

BACKGROUND: At the time of the influenza A(H1N1)pmd09 pandemic it was not known if concurrent or sequential administration of seasonal trivalent influenza vaccine (TIV) with pandemic vaccine was preferred. METHODS: Immunogenicity and safety were assessed in 871 healthy subjects aged 19-40 years who were randomised into six groups to receive co-administration or sequential administration of TIV and two doses of A(H1N1)pmd09 vaccine (either unadjuvanted or adjuvanted with AS03, an α-tocopherol and squalene-based oil-in-water emulsion). RESULTS: Safety and immunogenicity data (by haemagglutination inhibition [HI] assay) after each dose and six months post-Dose 1 are reported here. Co-administration of A(H1N1)pmd09 vaccine with TIV reduced the HI immune responses to A(H1N1)pmd09 vaccine. However, serologic responses with both co-administration and sequential schedules met the European and US regulatory criteria for pandemic and seasonal influenza vaccines up to six months following the first vaccine dose. The AS03-adjuvanted formulation elicited higher immune responses at all time points. Prior administration or co-administration of A(H1N1)pmd09 vaccine did not affect immune responses to TIV. CONCLUSIONS: Co-administration of TIV and A(H1N1)pmd09 vaccine negatively influenced A(H1N1)pmd09 vaccine immunogenicity but had no effect on TIV responses. The non-adjuvanted and adjuvanted vaccines demonstrated strong immune responses against all vaccine strains for up to six months following the first vaccine dose.

Safety, immunogenicity, and protection provided by unadjuvanted and adjuvanted formulations of a recombinant plant-derived virus-like particle vaccine candidate for COVID-19 in nonhuman primates.

Although antivirals are important tools to control severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, effective vaccines are essential to control the current coronavirus disease 2019 (COVID-19) pandemic. Plant-derived virus-like particle (VLP) vaccine candidates have previously demonstrated immunogenicity and efficacy against influenza. Here, we report the immunogenicity and protection induced in rhesus macaques by intramuscular injections of a VLP bearing a SARS-CoV-2 spike protein (CoVLP) vaccine candidate formulated with or without Adjuvant System 03 (AS03) or cytidine-phospho-guanosine (CpG) 1018. Although a single dose of the unadjuvanted CoVLP vaccine candidate stimulated humoral and cell-mediated immune responses, booster immunization (at 28 days after priming) and adjuvant administration significantly improved both responses, with higher immunogenicity and protection provided by the AS03-adjuvanted CoVLP. Fifteen micrograms of CoVLP adjuvanted with AS03 induced a polyfunctional interleukin-2 (IL-2)-driven response and IL-4 expression in CD4 T cells. Animals were challenged by multiple routes (i.e., intratracheal, intranasal, and ocular) with a total viral dose of 106 plaque-forming units of SARS-CoV-2. Lower viral replication in nasal swabs and bronchoalveolar lavage fluid (BALF) as well as fewer SARS-CoV-2-infected cells and immune cell infiltrates in the lungs concomitant with reduced levels of proinflammatory cytokines and chemotactic factors in the BALF were observed in animals immunized with the CoVLP adjuvanted with AS03. No clinical, pathologic, or virologic evidence of vaccine-associated enhanced disease was observed in vaccinated animals. The CoVLP adjuvanted with AS03 was therefore selected for vaccine development and clinical trials.

[Vitamin E for gonarthrosis and coxarthrosis--results of a postmarketing surveillance study]. / Vitamin E bei Gon- und Coxarthrose. Ergebnisse einer Anwendungsbeobachtung.

BACKGROUND: Inflammatory processes release reactive oxygen species, destroying cartilage tissue. Vitamin E is an antioxidant and protects cartilage tissue. Dietary intake of vitamin E is often low in patients with osteoarthrosis, and short term clinical studies have shown symptomatic relief in pain. Therefore, efficacy and tolerability of vitamin E are investigated in routine use of medical practitioners. PATIENTS AND METHODS: Open, multicentric observational study including 151 patients with osteoarthritis (knee, hip): 85 patients were treated with 333,5 mg RRR-alpha-tocopherol (monotherapy), 61 patients with 333,5 mg RRR-alpha-tocopherol and a further analgesic (combination therapy). 5 patients (2 monotherapy, 3 combination) failed to turn up for follow-up (dropout). According to the study design, the physician was free in his treatment (assignment to treatment, choice of analgesic). After 4, 8, and 12 weeks the efficacy and tolerability were determined by physicians and by patients. RESULTS: Demographic data were comparable in both groups, however clinical condition was slightly worse in the combination group. In the course of the treatment, all parameters improved in both groups. Monotherapy was somewhat less effective and set on later. There were two adverse events in the monotherapy group (total endoprosthesis, itching). Tolerability of monotherapy was rated slightly better than combination therapy by physicians and by patients. CONCLUSIONS: For patients with gonarthrosis or coxarthrosis the supplementation of Vitamin E to an analgetic medication is reasonable and well tolerated.

Non-invasive assessment of liver fibrosis progression in hepatitis C patients retreated for 96 weeks with antiviral therapy: a randomized study.

BACKGROUND: The efficacy of a maintenance therapy in non-responder patients with chronic hepatitis C has been essentially evaluated by histological semiquantitative scores. AIM: The aim was to evaluate the efficiency of 2 years of treatment with peginterferon alpha-2a vs alpha-tocopherol in these patients by histology, morphometry and blood markers of fibrosis. METHOD: Hundred and five HCV patients with a Metavir fibrosis score > or = 2 were randomized to receive peginterferon alpha-2a 180 microg/week (PEG) (n=55) or alpha-tocopherol (TOCO) 1000 mg/day (n=50) for 96 weeks. The primary endpoint was improvement or stabilization of the Metavir fibrosis score by biopsy performed at week 96. Secondary endpoints included a quantitative assessment of fibrosis by morphometry and changes in blood markers of fibrosis. RESULTS: There was no difference at baseline between PEG and TOCO according to the metavir (83.3 vs 86.8%, P=0.751) stage. The median fibrosis rate, measured with morphometry was 2.72 and 2.86% at day 0, and 3.66 and 2.82% at week 96, in the PEG and TOCO groups (P=0.90) respectively. However, the percentage of patients with metavir activity grade improvement was significantly higher in the PEG group vs the TOCO group (52.8 vs 23.7%, P=0.016). Non-invasive markers analysis did not show any significant change in both groups. CONCLUSION: Long-term therapy with peginterferon alpha-2a did not reduce liver fibrosis degree assessed by morphometry and blood tests as compared with alpha-tocopherol. Blood tests could be useful to assess liver fibrosis changes in clinical trials.

Very-high-dose alpha-tocopherol supplementation increases blood pressure and causes possible adverse central nervous system effects in stroke-prone spontaneously hypertensive rats.

Tocopherols and tocotrienols constitute the vitamin E family. Although alpha-tocotrienol is the most neuroprotective form of vitamin E proved to be effective against stroke, alpha-tocopherol is the most abundant in nature and is used most often for disease prevention/treatment. A recent metaanalysis of human studies suggested that alpha-tocopherol supplementation increases all-cause mortality. Therefore, we investigated the effects of alpha-tocopherol ( approximately 44 mg/kg body weight; equivalent to 2,600 mg/human/day) on the central nervous system (CNS) of stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP treated with high dose alpha-tocopherol had significantly higher blood pressure than untreated controls fed a basal diet that contained approximately 4 mg tocopherols/kg body weight, but neither group experienced a change in degree of lipid peroxidation in serum or CNS tissue. Biochemical/immunohistochemical analyses demonstrated that expressions of phosphorylated neurofilament H protein, glial fibrillary acidic protein and cathepsin D in the CNS tissue were significantly enhanced in alpha-tocopherol-supplemented rats, whereas expressions of SOD2 and Bcl-xL were diminished in response to alpha-tocopherol supplementation. Similarly, the frequency of cathepsin D-positive cells, corresponding mostly to microglial cells, was significantly increased in alpha-tocopherol-supplemented rats. Alpha-tocopherol supplementation also increased the number of lysosomes and lipofuscin granules in perikarya of both hippocampal pyramidal and Purkinje cells. Furthermore, alpha-tocopherol supplementation increased the frequency of glial filaments and lipofuscin granules in astrocytes and lysosomes in microglial cells that were frequently occupied with phagocytosed inclusion structures. The present results are the first to suggest that a very high dose of alpha-tocopherol supplementation increases blood pressure in SHRSP rats and influences the CNS tissue in a manner that seems adverse.

COMT and Alpha-Tocopherol Effects in Cancer Prevention: Gene-Supplement Interactions in Two Randomized Clinical Trials.

BACKGROUND: Vitamins are among the most frequently used supplements (48% of US adults). However, little is known about contributions of genetic variation to their efficacy and safety. Multiple pathways link catechol-O-methyltransferase (COMT) to the vitamin E supplement, alpha-tocopherol, and cancer. METHODS: Here we determined if COMT exerted pharmacogenetic effects on cancer prevention in two randomized trials of alpha-tocopherol supplementation. Pharmacogenetic effects of common COMT rs4680 (val158met), which encodes a nonsynonymous valine-to-methionine substitution, were examined in the trial plus a 10-year post-trial follow-up (overall) period of The Women's Genome Health Study (WGHS, N = 23 294), a 10-year alpha-tocopherol and aspirin trial with 10 years post-trial follow-up. Results were validated in a case/control (N = 2396/2235) subset of the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC, N = 29 133). The primary outcome was total cancers. Rates of cancer types prevalent in women (colorectal, breast, lung, uterine, and lymphoma/leukemia) were also examined. All statistical tests were two-sided. RESULTS: Random-effects meta-analysis of rs4680 genotype strata, in WGHS and ATBC overall periods, revealed differential alpha-tocopherol effects compared with placebo: met/met (hazard ratio [HR] = 0.88; 95% confidence interval [CI] = 0.80 to 0.97; P = .01), val/met (HR = 0.99; 95% CI = 0.92 to 1.06; P = .74), and val/val (HR = 1.18; 95% CI = 1.06 to 1.31; P = .002) with a statistically significant COMT by alpha-tocopherol interaction (Pinteraction <.001). Timing of effects differed, with stronger effects in WGHS trial and ATBC post-trial. CONCLUSION: Pharmacogenetic analysis of COMT and cancer prevention in two large randomized trials revealed statistically significant COMT by alpha-tocopherol interaction, such that alpha-tocopherol was beneficial among rs4680 met-allele (28.0%), but not val-allele (22.8%) homozygotes. These effects indicate the need for additional studies of genetic variation as a determinant of the benefits and possible harms of over-the-counter supplements, like alpha-tocopherol, used for health promotion.

Safety of AS03-adjuvanted influenza vaccines: A review of the evidence.

Clinical and post-licensure data have demonstrated that AS03-adjuvanted inactivated split virion vaccines, many with reduced antigen content, are effective against influenza infection. The objective of this review is to provide a comprehensive assessment of the safety of trivalent seasonal, monovalent pre-pandemic and pandemic AS03-adjuvanted influenza vaccines, based on non-clinical, clinical and post-licensure data in various populations. Non-clinical studies on local tolerance, toxicology and safety pharmacology did not raise any safety concerns with AS03 administered alone or combined with various influenza antigens. Data from clinical trials with over 55,000 vaccinated subjects showed that AS03-adjuvanted influenza vaccines were generally well tolerated and displayed an acceptable safety profile, although the power to detect rare events was limited. Approximately 90 million doses of A/H1N1pdm09 pandemic influenza vaccines (Pandemrix and Arepanrix H1N1) were administered worldwide, which contributed post-licensure data to the collective safety data for AS03-adjuvanted influenza vaccines. An association between Pandemrix and narcolepsy was observed during the A/H1N1pdm09 pandemic, for which a role of a CD4 T cell mimicry sequence in the haemagglutinin protein of A/H1N1pdm09 cannot be excluded. Provided that future AS03-adjuvanted influenza vaccines do not contain this putative mimicry sequence, this extensive safety experience supports the further development and use of AS03-adjuvanted inactivated split virion candidate vaccines against seasonal and pandemic influenza infections.