Races of small molecule clinical trials for the treatment of COVID-19: An up-to-date comprehensive review.
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ABSTRACT:
SUBMITTER: Hu S
PROVIDER: S-EPMC8653368 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has a great potential to overwhelm the world healthcare systems that may lead to high morbidity and mortality. It also affects world economic development in the future. Currently, no proven effective drugs or vaccines are available for the management of COVID-19 disease. The pace of normal drug development progression is unacceptable in the context of the current pandemic. Therefore, repurposing the existing drugs that were used for the treatment of malaria, Ebola, and influenza helps rapid drug development for COVID-19. Currently, several repurposing candidate drugs are in a clinical trial including, chloroquine monoclonal antibodies, convalescent plasma, interferon, and antiviral therapies. Antiviral drugs like arbidol, remdesiv and favirnavir are the most promising due to the similarities of the viruses regarding viral entry, fusion, uncoating, and replication. This review article provides an overview of the potential therapeutic agent, which displayed better clinical treatment outcomes. Moreover, with further understanding of the SARS-CoV-2 virus, new drugs targeting specific SARS-CoV-2 viral components arise, and investigations on these novels anti-SARSCoV- 2 agents are also reviewed.
| S-EPMC7753885 | biostudies-literature
Project description:The global pandemic of COVID-19 caused by SARS-CoV-2 continues to spread and poses serious threats to public health and economic stability throughout the world. Thus, to protect the global population, developing safe and effective vaccines is mandatory to control the spread of SARS-CoV-2 pandemic. Since genomic sequences of SARS-CoV-2 and SARS-CoV-1 have similarity and use the same receptor (ACE2), it is important to learn from the development of SARS-CoV-1 vaccines for the development of SARS-CoV-2 vaccines. Normally vaccine development takes 10-15 years but vaccine development against SARS-CoV2 is going on at a very fast pace resulting in almost breakthrough methods of vaccine development by several research institutions. The whole process of vaccine development including clinical trials gets shortened and may be fast tracked to 15-18 months. Global collaborations and increased research efforts among the scientific community have led to more than 214 candidate vaccines globally. The current review highlights the different approaches and technologies used around the world for the design and development of the vaccines and also focuses on the recent status of the SARS-CoV-2 vaccine candidates under development by various institutions to combat the world threat of COVID-19 pandemic.
| S-EPMC7826065 | biostudies-literature
Project description:This study provides the longest follow-up yet for comprehensive behavioral (ComB) treatment of trichotillomania (TTM) (M = 24.59 months after pre-treatment and 15.92 months after the last follow-up point in a recent clinical trial (Carlson et al., 2021), which had shown ComB to be significantly more efficacious than minimal attention at post-treatment). This study also examined changes in TTM severity from before to during the COVID-19 pandemic. Participants (N = 23) completed a survey assessing current TTM symptoms, the impact of the pandemic on their coping with TTM, and their experience with ComB treatment. Self-reported symptom severity at this follow-up evaluation fell between the scores obtained at the clinical trial's pre-treatment assessment and at its last follow-up before the pandemic and did not significantly differ from either time point. Most participants (73%) reported some change in their TTM management since onset of the pandemic, with changes to their environment/routine (61%) and in anxiety (32%) being the most common. Pandemic-related changes were associated with variable outcomes, improving symptoms and management for some while worsening them for others. Use of strategies from ComB had declined since the most recent follow-up, but more than half (55%) of participants reported that strategies from ComB remained useful.
| S-EPMC8683380 | biostudies-literature
Project description:Coronavirus disease strain (SARS-CoV-2) was discovered in 2019, and it is spreading very fast around the world causing the disease Covid-19. Currently, more than 1.6 million individuals are infected, and several thousand are dead across the globe because of Covid-19. Here, we utilized the in-silico approaches to identify possible protease inhibitors against SARS-CoV-2. Potential compounds were screened from the CHEMBL database, ZINC database, FDA approved drugs and molecules under clinical trials. Our study is based on 6Y2F and 6W63 co-crystallized structures available in the protein data bank (PDB). Seven hundred compounds from ZINC/CHEMBL databases and fourteen hundred compounds from drug-bank were selected based on positive interactions with the reported binding site. All the selected compounds were subjected to standard-precision (SP) and extra-precision (XP) mode of docking. Generated docked poses were carefully visualized for known interactions within the binding site. Molecular mechanics-generalized born surface area (MM-GBSA) calculations were performed to screen the best compounds based on docking scores and binding energy values. Molecular dynamics (MD) simulations were carried out on four selected compounds from the CHEMBL database to validate the stability and interactions. MD simulations were also performed on the PDB structure 6YF2F to understand the differences between screened molecules and co-crystallized ligand. We screened 300 potential compounds from various databases, and 66 potential compounds from FDA approved drugs. Cobicistat, ritonavir, lopinavir, and darunavir are in the top screened molecules from FDA approved drugs. The screened drugs and molecules may be helpful in fighting with SARS-CoV-2 after further studies.
| S-EPMC7212534 | biostudies-literature
Project description:Therapeutic clinical and preclinical studies using cultured cells are on the rise, especially now that the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) a "public health emergency of international concern", in January, 2020. Thus, this study aims to review the outcomes of ongoing clinical studies on stem cells in Severe Acute Respiratory Syndrome (SARS), Acute Respiratory Distress Syndrome (ARDS), and Middle East Respiratory Syndrome (MERS). The results will be associated with possible applications to COVID-19. Only three clinical trials related to stem cells are considered complete, whereby two are in Phase 1 and one is in Phase 2. Basically, the ongoing studies on coronavirus are using mesenchymal stem cells (MSCs) derived from bone marrow or the umbilical cord to demonstrate their feasibility, safety, and tolerability. The studies not related to coronavirus are all in ARDS conditions; four of them are in Phase 1 and three in Phase 2. With the COVID-19 boom, many clinical trials are being carried out using different sources with an emphasis on MSC-based therapy used to inhibit inflammation. One of the biggest challenges in the current treatment of COVID-19 is the cytokine storm, however MSCs can prevent or mitigate this cytokine storm through their immunomodulatory capacity. We look forward to the results of the ongoing clinical trials to find a treatment for the disease. Researchers around the world are joining forces to help fight COVID-19. Stem cells used in the current clinical studies are a new therapeutic promise for COVID-19 where pharmacological treatments seem insufficient.Graphical Abstract.
| S-EPMC7442550 | biostudies-literature
Project description:BackgroundCOVID-19 led to a rapid acceleration in the number of systematic reviews. Readers need to know how up to date evidence is when selecting reviews to inform decisions. This cross-sectional study aimed to evaluate how easily the currency of COVID-19 systematic reviews published early in the pandemic could be determined and how up to date these reviews were at the time of publication.MethodsWe searched for systematic reviews and meta-analyses relevant to COVID-19 added to PubMed in July 2020 and January 2021, including any that were first published as preprints. We extracted data on the date of search, number of included studies, and date first published online. For the search date, we noted the format of the date and where in the review this was reported. A sample of non-COVID-19 systematic reviews from November 2020 served as a comparator.ResultsWe identified 246 systematic reviews on COVID-19. In the abstract of these reviews, just over half (57%) reported the search date (day/month/year or month/year) while 43% failed to report any date. When the full text was considered, the search date was missing from 6% of reviews. The median time from last search to publication online was 91 days (IQR 63-130). Time from search to publication was similar for the subset of 15 rapid or living reviews (92 days) but shorter for the 29 reviews published as preprints (37 days). The median number of studies or publications included per review was 23 (IQR 12-40). In the sample of 290 non-COVID SRs, around two-thirds (65%) reported the search date while a third (34%) did not include any date in the abstract. The median time from search to publication online was 253 days (IQR 153-381) and each review included a median of 12 studies (IQR 8-21).ConclusionsDespite the context of the pandemic and the need to easily ascertain the currency of systematic reviews, reporting of the search date information for COVID-19 reviews was inadequate. Adherence to reporting guidelines would improve the transparency and usefulness of systematic reviews to users.
| S-EPMC10193307 | biostudies-literature
Project description:BackgroundThe current endpoints for therapeutic trials of hospitalized COVID-19 patients capture only part of the clinical course of a patient and have limited statistical power and robustness.MethodsWe specify proportional odds models for repeated measures of clinical status, with a common odds ratio of lower severity over time. We also specify the proportional hazards model for time to each level of improvement or deterioration of clinical status, with a common hazard ratio for overall treatment benefit. We apply these methods to Adaptive COVID-19 Treatment Trials.ResultsFor remdesivir versus placebo, the common odds ratio was 1.48 (95% confidence interval (CI) = 1.23-1.79; p < 0.001), and the common hazard ratio was 1.27 (95% CI = 1.09-1.47; p = 0.002). For baricitinib plus remdesivir versus remdesivir alone, the common odds ratio was 1.32 (95% CI = 1.10-1.57; p = 0.002), and the common hazard ratio was 1.30 (95% CI = 1.13-1.49; p < 0.001). For interferon beta-1a plus remdesivir versus remdesivir alone, the common odds ratio was 0.95 (95% CI = 0.79-1.14; p = 0.56), and the common hazard ratio was 0.98 (95% CI = 0.85-1.12; p = 0.74).ConclusionsThe proposed methods comprehensively characterize the treatment effects on the entire clinical course of a hospitalized COVID-19 patient.
| S-EPMC11304635 | biostudies-literature
Project description:The novel coronavirus SARS-CoV-2 has become a global health concern. The morbidity and mortality of the potentially lethal infection caused by this virus arise from the initial viral infection and the subsequent host inflammatory response. The latter may lead to excessive release of pro-inflammatory cytokines, IL-6 and IL-8, as well as TNF-? ultimately culminating in hypercytokinemia ("cytokine storm"). To address this immuno-inflammatory pathogenesis, multiple clinical trials have been proposed to evaluate anti-inflammatory biologic therapies targeting specific cytokines. However, despite the obvious clinical utility of such biologics, their specific applicability to COVID-19 has multiple drawbacks, including they target only one of the multiple cytokines involved in COVID-19's immunopathy. Therefore, we set out to identify a small molecule with broad-spectrum anti-inflammatory mechanism of action targeting multiple cytokines of innate immunity. In this study, a library of small molecules endogenous to the human body was assembled, subjected to in silico molecular docking simulations and a focused in vitro screen to identify anti-pro-inflammatory activity via interleukin inhibition. This has enabled us to identify the loop diuretic furosemide as a candidate molecule. To pre-clinically evaluate furosemide as a putative COVID-19 therapeutic, we studied its anti-inflammatory activity on RAW264.7, THP-1 and SIM-A9 cell lines stimulated by lipopolysaccharide (LPS). Upon treatment with furosemide, LPS-induced production of pro-inflammatory cytokines was reduced, indicating that furosemide suppresses the M1 polarization, including IL-6 and TNF-? release. In addition, we found that furosemide promotes the production of anti-inflammatory cytokine products (IL-1RA, arginase), indicating M2 polarization. Accordingly, we conclude that furosemide is a reasonably potent inhibitor of IL-6 and TNF-? that is also safe, inexpensive and well-studied. Our pre-clinical data suggest that it may be a candidate for repurposing as an inhaled therapy against COVID-19.
| S-EPMC7350920 | biostudies-literature
Project description:Respiratory viruses are transmitted and acquired via the nasal mucosa, and thereby may influence the nasal metabolome composed of biochemical products produced by both host cells and microbes. Studies of the nasal metabolome demonstrate virus-specific changes that sometimes correlate with viral load and disease severity. Here, we evaluate the nasopharyngeal metabolome of COVID-19 infected individuals and report several small molecules that may be used as potential therapeutic targets. Specimens were tested by qRT-PCR with target primers for three viruses: Influenza A (INFA), respiratory syncytial virus (RSV), and SARS-CoV-2, along with unaffected controls. The nasopharyngeal metabolome was characterized using an LC-MS/MS-based screening kit capable of quantifying 141 analytes. A machine learning model identified 28 discriminating analytes and correctly categorized patients with a viral infection with an accuracy of 96% (R2 = 0.771, Q2 = 0.72). A second model identified 5 analytes to differentiate COVID19-infected patients from those with INFA or RSV with an accuracy of 85% (R2 = 0.442, Q2 = 0.301). Specifically, Lysophosphatidylcholines-a-C18:2 (LysoPCaC18:2) concentration was significantly increased in COVID19 patients (P < 0.0001), whereas beta-hydroxybutyric acid, Methionine sulfoxide, succinic acid, and carnosine concentrations were significantly decreased (P < 0.0001). This study demonstrates that COVID19 infection results in a unique nasopharyngeal metabolomic signature with carnosine and LysoPCaC18:2 as potential therapeutic targets.
| S-EPMC9200216 | biostudies-literature
Project description:Since coronavirus disease-2019 (COVID-19) outbreak in January 2020, several pieces of evidence suggested an association between the spectrum of Guillain-Barré syndrome (GBS) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Most findings were reported in the form of case reports or case series, whereas a comprehensive overview is still lacking. We conducted a systematic review and searched for all published cases until July 20th 2020. We included 73 patients reported in 52 publications. A broad age range was affected (mean 55, min 11-max 94 years) with male predominance (68.5%). Most patients showed respiratory and/or systemic symptoms, and developed GBS manifestations after COVID-19. However, asymptomatic cases for COVID-19 were also described. The distributions of clinical variants and electrophysiological subtypes resemble those of classic GBS, with a higher prevalence of the classic sensorimotor form and the acute inflammatory demyelinating polyneuropathy, although rare variants like Miller Fisher syndrome were also reported. Cerebrospinal fluid (CSF) albuminocytological dissociation was present in around 71% cases, and CSF SARS-CoV-2 RNA was absent in all tested cases. More than 70% of patients showed a good prognosis, mostly after treatment with intravenous immunoglobulin. Patients with less favorable outcome were associated with a significantly older age in accordance with previous findings regarding both classic GBS and COVID-19. COVID-19-associated GBS seems to share most features of classic post-infectious GBS and possibly the same immune-mediated pathogenetic mechanisms. Nevertheless, more extensive epidemiological studies are needed to clarify these issues.
| S-EPMC7445716 | biostudies-literature