Objectives Sofosbuvir and daclatasvir are direct-acting antivirals highly effective against hepatitis C virus. There is some in silico and in vitro evidence that suggests these agents may also be effective against SARS-CoV-2. This trial evaluated the effectiveness of sofosbuvir in combination with daclatasvir in treating patients with COVID-19. Methods Patients with a positive nasopharyngeal swab for SARS-CoV-2 on RT–PCR or bilateral multi-lobar ground-glass opacity on their chest CT and signs of severe COVID-19 were included. Subjects were divided into two arms with one arm receiving ribavirin and the other receiving sofosbuvir/daclatasvir. All participants also received the recommended national standard treatment which, at that time, was lopinavir/ritonavir and single-dose hydroxychloroquine. The primary endpoint was time from starting the medication until discharge from hospital with secondary endpoints of duration of ICU stay and mortality. Results Sixty-two subjects met the inclusion criteria, with 35 enrolled in the sofosbuvir/daclatasvir arm and 27 in the ribavirin arm. The median duration of stay was 5 days for the sofosbuvir/daclatasvir group and 9 days for the ribavirin group. The mortality in the sofosbuvir/daclatasvir group was 2/35 (6%) and 9/27 (33%) for the ribavirin group. The relative risk of death for patients treated with sofosbuvir/daclatasvir was 0.17 (95% CI 0.04–0.73, P = 0.02) and the number needed to treat for benefit was 3.6 (95% CI 2.1–12.1, P < 0.01). Conclusions Given these encouraging initial results, and the current lack of treatments proven to decrease mortality in COVID-19, further investigation in larger-scale trials seems warranted.

Myocardial infarction is the acute condition of myocardial necrosis that occurs as a result of imbalance between coronary blood supply and myocardial demand. Air pollution increases the risk of death from cardiovascular diseases (CVDs). The aim of this study was to investigate the effects of particulate matter (PM) on oxidative stress, the expression of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) messenger RNA (mRNA) level induced by ischemia-reperfusion injury, and the protective effects of vanillic acid (VA) in the isolated rat heart. Male Wistar rats were randomly divided into eight groups (n = 10), namely control, VAc, sham, VA, PMa (0.5 mg/kg), PMb (2.5 mg/kg), PMc (5 mg/kg), and PMc + VA groups. Particles with an aerodynamic diameter <10 μm (PM10) was instilled into the trachea through a fine intubation tube. Two days following the PM10 instillation, the animal's hearts were isolated and transferred to a Langendorff apparatus. The hearts were subjected to 30 min of global ischemia followed by 60 min of reperfusion. The activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), xanthine oxidase (XOX), and lactate dehydrogenase (LDH) were measured using special kits. Reverse transcription polymerase chain reaction (RT-PCR) was used to determine levels of iNOS and eNOS mRNA. An increase in left ventricular end-diastolic pressure (LVEDP), S-T elevation, and oxidative stress in PM10 groups was observed. Ischemia-reperfusion (I/R) induction showed a significant augment in the expression of iNOS mRNA level and a significant decrease in the expression eNOS mRNA level. This effect was more pronounced in the PM groups than in the control and sham groups. Vanillic acid caused a significant decrease in LVEDP, S-T elevation, and also a significant difference in eNOS mRNA expression level, antioxidant enzymes, iNOS mRNA expression level, and oxidative stress occurred on myocardial dysfunction after I/R in isolated rat hearts. This study showed that PM10 exposure had devastating effects on the myocardial heart, oxidative stress, and eNOS and iNOS mRNA expression levels. Vanillic acid was able to improve these parameters. Vanillic acid as a potent antioxidant could also provide protection against particulate matter-induced toxicity.

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Particulate matter (PM) inhalation is an established trigger of cardiovascular events such as cardiac arrhythmias that occur within hours to days after exposure. Higher daily PM levels are related to acute increases in systemic arterial blood pressure (BP). The aim of the present study was to evaluate the effects of PM10 on electrocardiogram (ECG) parameters, blood pressure, lipid peroxidation (MDA), xanthine oxidase, and antioxidant enzyme in healthy rats and also to examine the protective effects of vanillic acid (VA) in this respect. Eighty male Wistar rats were divided into eight groups (n = 10), namely control (normal saline, gavage), VAc (10 mg/kg), sham (normal saline, intratracheal instillation), VA (10 mg/kg VA, 10 days gavage +0.1 ml normal saline, intratracheal instillation), PM1 (0.5 mg/kg), PM2 (2.5 mg/kg), PM3 (5 mg/kg), PM3 + VA (5 mg/kg, intratracheal instillation + 10 mg/kg VA, 10 days, gavage) groups. The rats were anesthetized and 0.1 ml of saline as well as a certain concentration of PM10 was instilled into the trachea and it was repeated after 48 h, then 30 min after that, PR interval, QTc, and systolic blood pressure were measured. The activities of antioxidant enzymes, xanthine oxidase (XOX), and malondialdehyde (MDA) were measured in plasma by special Kits. A significant increase in blood pressure (BP), PR interval, QTc, MDA, and XOX and a significant decrease in antioxidant enzyme (CAT, SOD, and GPx) occurred in PM10 groups. Vanillic acid ameliorated blood pressure, QTc, PR interval, XOX, MDA, and increased antioxidant enzymes (SOD, CAT, and GPx) significantly. In the present study, it was shown that PM10 had devastating effects on the heart and blood pressure, probably due to the increased oxidative stress in healthy rats. Vanillic acid could improve the symptoms of PM10 exposure and can be used as an antioxidant agent against the harmful effects of PM10.

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Background The combination of sofosbuvir and daclatasvir has shown preliminary efficacy for hospitalized patients with COVID-19 in four open-label studies with small sample sizes. This larger trial aimed to assess if the addition of sofosbuvir/daclatasvir to standard care improved clinical outcomes in hospitalized patients with COVID-19. Methods This was a placebo-controlled, double-blind, randomized clinical trial in adults hospitalized with COVID-19 at 19 hospitals in Iran. Patients were randomized to oral sofosbuvir/daclatasvir 400/60 mg once-daily or placebo in addition to standard of care. Patients were included if they had positive PCR or diagnostic chest CT, O2 saturation &lt;95% and compatible symptoms. The primary outcome was hospital discharge within 10 days of randomization. Secondary outcomes included mortality and time to clinical events. The trial is registered on the Iran Registry of Clinical Trials under IRCT20200624047908N1. Results Between July and October 2020, 1083 patients were randomized to either the sofosbuvir/daclatasvir arm (n = 541) or the placebo arm (n = 542). No significant difference was observed in the primary outcome of hospital discharge within 10 days, which was achieved by 415/541 (77%) in the sofosbuvir/daclatasvir arm and 411/542 (76%) in the placebo arm [risk ratio (RR) 1.01, 95% CI 0.95–1.08, P = 0.734]. In-hospital mortality was 60/541 (11%) in the sofosbuvir/daclatasvir arm versus 55/542 (10%) in the placebo arm (RR 1.09, 95% CI 0.77–1.54, P = 0.615). No differences were observed in time to hospital discharge or time to in-hospital mortality. Conclusions We observed no significant effect of sofosbuvir/daclatasvir versus placebo on hospital discharge or survival in hospitalized COVID-19 patients.

Background: MicroRNA expression signature and reactive oxygen species (ROS) production have been associated with the development of cardiovascular diseases (CVDs). This study aimed to evaluate oxidative stress, inflammation, apoptosis, and the expression of miRNA-208a and miRNA-1 in cardiovascular patients. Methods: The study population included four types of patients (acute coronary syndromes (ACS), myocardial infarction (MI), arrhythmia, and heart failure (HF)), with 10 people in each group, as well as a control group. Quantitative real-time PCR was performed to measure mir-208 and miR-1 expression, the mRNAs of inflammatory mediators (TNFα, iNOS/eNOS), and apoptotic factors (Bax and Bcl2). XOX, MDA, and antioxidant enzymes (CAT, SOD, and GPx) were measured by ZellBio GmbH kits by an ELISA Reader. Results: The results showed significant decreases in the activity of antioxidant enzymes (CAT, SOD, and Gpx) and a significant increase in the activity of the MDA and XOX in cardiovascular patients. Significant increases in IL-10, iNos, iNOS / eNOS, and TNF-α in cardiovascular patients were also observed. Also, a significant increase in the expression of miR-208 (HF> arrhythmia> ACS> MI) and a significant decrease in the expression of miR-1 (ACS> arrhythmia> HF> MI) were found in all four groups in cardiovascular patients. Conclusions:The results showed increases in oxidative stress, inflammation, apoptotic factors, and in the expression of miR-208a in a variety of cardiovascular patients (ACS, MI, arrhythmia, and HF). It is suggested that future studies determine the relationships that miR-1, miR-208, and oxidative stress indices have with inflammation and apoptosis.

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