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The NEI conducted the Age-Related Eye Disease Study (AREDS) and the follow-on AREDS2 to study cataract and age-related macular degeneration (AMD). Study researchers tested whether taking nutritional supplements could prevent or slow these diseases. The formulations tested in the trials are now sold as the AREDS and the AREDS2 formulas.

Trials 2 Se Keygen 17

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To date, there are no generally proven effective therapies for COVID-19 or antivirals against SARS-CoV-2, although some treatments have shown some benefits in certain subpopulations of patients or for certain end points (see later). Researchers and manufacturers are conducting large-scale clinical trials to evaluate various therapies for COVID-19. As of 2 October 2020, there were about 405 therapeutic drugs in development for COVID-19, and nearly 318 in human clinical trials (COVID-19 vaccine and therapeutics tracker). In the following sections, we summarize potential therapeutics against SARS-CoV-2 on the basis of published clinical data and experience.

SARS-CoV-2 uses ACE2 as the receptor and human proteases as entry activators; subsequently it fuses the viral membrane with the cell membrane and achieves invasion. Thus, drugs that interfere with entry may be a potential treatment for COVID-19. Umifenovir (Arbidol) is a drug approved in Russia and China for the treatment of influenza and other respiratory viral infections. It can target the interaction between the S protein and ACE2 and inhibit membrane fusion (Fig. 5). In vitro experiments showed that it has activity against SARS-CoV-2, and current clinical data revealed it may be more effective than lopinavir and ritonavir in treating COVID-19 (refs122,123). However, other clinical studies showed umifenovir might not improve the prognosis of or accelerate SARS-CoV-2 clearance in patients with mild to moderate COVID-19 (refs124,125). Yet some ongoing clinical trials are evaluating its efficacy for COVID-19 treatment. Camostat mesylate is approved in Japan for the treatment of pancreatitis and postoperative reflux oesophagitis. Previous studies showed that it can prevent SARS-CoV from entering cells by blocking TMPRSS2 activity and protect mice from lethal infection with SARS-CoV in a pathogenic mouse model (wild-type mice infected with a mouse-adapted SARS-CoV strain)126,127. Recently, a study revealed that camostat mesylate blocks the entry of SARS-CoV-2 into human lung cells47. Thus, it can be a potential antiviral drug against SARS-CoV-2 infection, although so far there are not sufficient clinical data to support its efficacy.

Replication inhibitors include remdesivir (GS-5734), favilavir (T-705), ribavirin, lopinavir and ritonavir. Except for lopinavir and ritonavir, which inhibit 3CLpro, the other three all target RdRp128,135 (Fig. 5). Remdesivir has shown activity against SARS-CoV-2 in vitro and in vivo128,136. A clinical study revealed a lower need for oxygen support in patients with COVID-19 (ref.137). Preliminary results of the Adaptive COVID-19 Treatment Trial (ACTT) clinical trial by the National Institute of Allergy and Infectious Diseases (NIAID) reported that remdesivir can shorten the recovery time in hospitalized adults with COVID-19 by a couple days compared with placebo, but the difference in mortality was not statistically significant138. The FDA has issued an emergency use authorization for remdesivir for the treatment of hospitalized patients with severe COVID-19. It is also the first approved option by the European Union for treatment of adults and adolescents with pneumonia requiring supplemental oxygen. Several international phase III clinical trials are continuing to evaluate the safety and efficacy of remdesivir for the treatment of COVID-19.

Favilavir (T-705), which is an antiviral drug developed in Japan to treat influenza, has been approved in China, Russia and India for the treatment of COVID-19. A clinical study in China showed that favilavir significantly reduced the signs of improved disease signs on chest imaging and shortened the time to viral clearance139. A preliminary report in Japan showed rates of clinical improvement of 73.8% and 87.8% from the start of favilavir therapy in patients with mild COVID-19 at 7 and 14 days, respectively, and 40.1% and 60.3% in patients with severe COVID-19 at 7 and 14 days, respectively140. However, this study did not include a control arm, and most of the trials of favilavir were based on a small sample size. For more reliable assessment of the effectiveness of favilavir for treating COVID-19, large-scale randomized controlled trials should be conducted.

Lopinavir and ritonavir were reported to have in vitro inhibitory activity against SARS-CoV and MERS-CoV141,142. Alone, the combination of lopinavir and ritonavir had little therapeutic benefit in patients with COVID-19, but appeared more effective when used in combination with other drugs, including ribavirin and interferon beta-1b143,144. The Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial, a national clinical trial programme in the UK, has stopped treatment with lopinavir and ritonavir as no significant beneficial effect was observed in a randomized trial established in March 2020 with a total of 1,596 patients145. Nevertheless, other clinical trials in different phases are still ongoing elsewhere.

The interferon response is one of the major innate immunity defences against virus invasion. Interferons induce the expression of diverse interferon-stimulated genes, which can interfere with every step of virus replication. Previous studies identified type I interferons as a promising therapeutic candidate for SARS149. In vitro data showed SARS-CoV-2 is even more sensitive to type I interferons than SARS-CoV, suggesting the potential effectiveness of type I interferons in the early treatment of COVID-19 (ref.150). In China, vapor inhalation of interferon-α is included in the COVID-19 treatment guideline151. Clinical trials are ongoing across the world to evaluate the efficacy of different therapies involving interferons, either alone or in combination with other agents152.

Vaccination is the most effective method for a long-term strategy for prevention and control of COVID-19 in the future. Many different vaccine platforms against SARS-CoV-2 are in development, the strategies of which include recombinant vectors, DNA, mRNA in lipid nanoparticles, inactivated viruses, live attenuated viruses and protein subunits159,160,161. As of 2 October 2020, 174 vaccine candidates for COVID-19 had been reported and 51 were in human clinical trials (COVID-19 vaccine and therapeutics tracker). Many of these vaccine candidates are in phase II testing, and some have already advanced to phase III trials. A randomized double-blinded phase II trial of an adenovirus type 5-vectored vaccine expressing the SARS-CoV-2 S protein, developed by CanSino Biologicals and the Academy of Military Medical Sciences of China, was conducted in 603 adult volunteers in Wuhan. The vaccine has proved to be safe and induced considerable humoral and cellular immune response in most recipients after a single immunization162. Another vectored vaccine, ChAdOx1, was developed on the basis of chimpanzee adenovirus by the University of Oxford. In a randomized controlled phase I/II trial, it induced neutralizing antibodies against SARS-CoV-2 in all 1,077 participants after a second vaccine dose, while its safety profile was acceptable as well163. The NIAID and Moderna co-manufactured mRNA-1273, a lipid nanoparticle-formulated mRNA vaccine candidate that encodes the stabilized prefusion SARS-CoV-2 S protein. Its immunogenicity has been confirmed by a phase I trial in which robust neutralizing antibody responses were induced in a dose-dependent manner and increased after a second dose164. Regarding inactivated vaccines, a successful phase I/II trial involving 320 participants has been reported in China. The whole-virus COVID-19 vaccine had a low rate of adverse reactions and effectively induced neutralizing antibody production165. The verified safety and immunogenicity support advancement of these vaccine candidates to phase III clinical trials, which will evaluate their efficacy in protecting healthy populations from SARS-CoV-2 infection.

At this time, the evidence is inconsistent on whether dietary vitamin C intake affects cancer risk. Results from most clinical trials suggest that modest vitamin C supplementation alone or with other nutrients offers no benefit in the prevention of cancer.

Emerging research suggests that the route of vitamin C administration (intravenous vs. oral) could explain the conflicting findings [1,46,47]. Most intervention trials, including the one conducted by Moertel and colleagues, used only oral administration, whereas Cameron and colleagues used a combination of oral and intravenous (IV) administration. Oral administration of vitamin C, even of very large doses, can raise plasma vitamin C concentrations to a maximum of only 220 micromol/L, whereas IV administration can produce plasma concentrations as high as 26,000 micromol/L [47,48]. Concentrations of this magnitude are selectively cytotoxic to tumor cells in vitro [1,67]. Research in mice suggests that pharmacologic doses of IV vitamin C might show promise in treating otherwise difficult-to-treat tumors [49]. A high concentration of vitamin C may act as a pro-oxidant and generate hydrogen peroxide that has selective toxicity toward cancer cells [49-51]. Based on these findings and a few case reports of patients with advanced cancers who had remarkably long survival times following administration of high-dose IV vitamin C, some researchers support reassessment of the use of high-dose IV vitamin C as a drug to treat cancer [3,47,49,52].

Results from most clinical intervention trials have failed to show a beneficial effect of vitamin C supplementation on the primary or secondary prevention of cardiovascular disease. In the Women's Antioxidant Cardiovascular Study, a secondary prevention trial involving 8,171 women aged 40 years or older with a history of cardiovascular disease, supplementation with 500 mg/day vitamin C for a mean of 9.4 years showed no overall effect on cardiovascular events [63]. Similarly, vitamin C supplementation (500 mg/day) for a mean follow-up of 8 years had no effect on major cardiovascular events in male physicians enrolled in the Physicians' Health Study II [64].

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