Project description:Infection with severe acute respiratory syndrom coronavirus 2 (SARS-CoV-2) is more likely to lead to poor outcomes in the elderly and those with cardiovascular disease, obesity or metabolic syndrome. Here, we consider mechanisms by which dyslipidaemia and the use of cholesterol-modifying drugs could influence the virus-host relationship. Cholesterol is essential for the assembly, replication and infectivity of enveloped virus particles; we highlight several cholesterol-modifying drugs with the potential to alter the SARS-CoV-2 life cycle that could be tested in in vitro and in vivo models. Although cholesterol is an essential component of immune cell membranes, excess levels can dysregulate protective immunity and promote exaggerated pulmonary and systemic inflammatory responses. Statins block the production of multiple sterols, oxysterols and isoprenoids, resulting in a pleiotropic range of context-dependent effects on virus infectivity, immunity and inflammation. We highlight antiviral, immunomodulatory and anti-inflammatory effects of cholesterol-modifying drugs that merit further consideration in the management of SARS-CoV-2 infection.
Project description:The development of clinically effective drugs that could complement existing vaccines is urgently needed to reduce the morbidity and mortality associated with COVID-19. Drug-metabolizing enzymes, membrane-associated drug transporters, and inflammatory responses can partly determine the safety and efficacy of COVID-19 drugs by controlling their concentrations in both the systemic circulation and in peripheral tissues. It is still unknown how these factors affect how well COVID-19 drugs work in the clinic. We explore how drug metabolism and transport, as well as SARS-CoV-2-associated inflammatory response at disease target sites, may affect the clinical outcomes of COVID-19 drugs. In addition, we provide expert opinion on potential strategies for overcoming the clinical pharmacology and pathophysiological obstacles to improve COVID-19 drug effectiveness.
Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent responsible for the COVID-19 pandemic, has outspread at full tilt across the world. Although several effective vaccines continue to be deployed, reliable antiviral treatments have yet to be developed against this disease. Currently, available therapeutics for COVID-19 include repurposed, and a few novel drugs. Many drugs have been promising in preclinical studies, but a majority of these drugs have shown little or no efficacy in clinical studies. One of the major reasons is the insufficient drug concentration in the lung, the primary target site of infection for SARS-CoV-2, from the administration of drugs through oral or intravenous routes. Higher effective doses administered through these routes could also lead to adverse side effects. For this reason, inhaled treatments are being tested as an efficient approach for COVID-19, allowing lower doses of drugs ensuring higher concentrations of the drug(s) in the lung. The inhaled treatment combining two or more antiviral drugs will increase potency and reduce the possibility of selecting for SARS-CoV-2 variants with reduced drug susceptibility. Finally, the appropriate drug combination needs to be delivered using a suitable system. Here, we review the current treatment for COVID-19 and their limitations, discussing the advantages of mono and combinational inhaled therapy with a brief outline of the recently reformulated anti-SARS-CoV-2 agents as inhaled formulations. The selection of appropriate delivery devices for inhalation and associated key considerations including the formulation challenges are also discussed.
Project description:The majority of the medical fraternity is continuously involved in finding new therapeutic schemes, including antimalarial medications (AMDs), which can be useful in combating the 2019-nCoV: coronavirus disease (COVID-19). For many decades, AMDs have been widely used in the treatment of malaria and various other anti-inflammatory diseases, particularly to treat autoimmune disorders of the connective tissue. The review comprises in vitro and in vivo studies, original studies, clinical trials, and consensus reports for the analysis, which were available in medical databases (e.g., PubMed). This manuscript summarizes the current knowledge about chloroquine (CQ)/hydroxychloroquine (HCQ) and shows the difference between their use, activity, recommendation, doses, and adverse effects on two groups of patients: those with rheumatic and viral diseases (including COVID-19). In the case of connective tissue disorders, AMDs are prescribed for a prolonged duration in small doses, and their effect is observed after few weeks, whereas in the case of viral infections, they are prescribed in larger doses for a short duration to achieve a quick saturation effect. In rheumatic diseases, AMDs are well tolerated, and their side effects are rare. However, in some viral diseases, the effect of AMDs is questionable or not so noticeable as suggested during the initial prognosis. They are mainly used as an additive therapy to antiviral drugs, but recent studies have shown that AMDs can diminish the efficacy of some antiviral drugs and may cause respiratory, kidney, liver, and cardiac complications.
Project description:It is well established that pre-existing comorbid conditions such as hypertension, diabetes, obesity, cardiovascular diseases (CVDs), chronic kidney diseases (CKDs), cancers, and chronic obstructive pulmonary disease (COPD) are associated with increased severity and fatality of COVID-19. The increased death from COVID-19 is due to the unavailability of a gold standard therapeutic and, more importantly, the lack of understanding of how the comorbid conditions and COVID-19 interact at the molecular level, so that personalized management strategies can be adopted. Here, using multi-omics data sets and bioinformatics strategy, we identified the pathway crosstalk between COVID-19 and diabetes, hypertension, CVDs, CKDs, and cancers. Further, shared pathways and hub gene-based targets for COVID-19 and its associated specific and combination of comorbid conditions are also predicted towards developing personalized management strategies. The approved drugs for most of these identified targets are also provided towards drug repurposing. Literature supports the involvement of our identified shared pathways in pathogenesis of COVID-19 and development of the specific comorbid condition of interest. Similarly, shared pathways- and hub gene-based targets are also found to have potential implementations in managing COVID-19 patients. However, the identified targets and drugs need further careful evaluation for their repurposing towards personalized treatment of COVID-19 cases having pre-existing specific comorbid conditions we have considered in this analysis. The method applied here may also be helpful in identifying common pathway components and targets in other disease-disease interactions too.
Project description:During the early phase of the coronavirus disease 2019 (COVID-19) pandemic, design, development, validation, verification and implementation of diagnostic tests were actively addressed by a large number of diagnostic test manufacturers. Hundreds of molecular tests and immunoassays were rapidly developed, albeit many still await clinical validation and formal approval. In this Review, we summarize the crucial role of diagnostic tests during the first global wave of COVID-19. We explore the technical and implementation problems encountered during this early phase in the pandemic, and try to define future directions for the progressive and better use of (syndromic) diagnostics during a possible resurgence of COVID-19 in future global waves or regional outbreaks. Continuous global improvement in diagnostic test preparedness is essential for more rapid detection of patients, possibly at the point of care, and for optimized prevention and treatment, in both industrialized countries and low-resource settings.
Project description:Dexamethasone improves the survival of COVID-19 patients in need of supplemental oxygen therapy. Hospitalized COVID-19 patients eligible for dexamethasone therapy were recruited from the general care ward in several centers in Greece and the Netherlands and whole blood transcriptomic analysis was performed before and after starting dexamethasone treatment. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy individuals and COVID-19 patients and stimulated with inactivated SARS-CoV-2 ex vivo in the presence or absence of dexamethasone and their transcriptome was assessed.
Project description:As a result of the 2019 novel human coronavirus (COVID-19) global spread, medical examiner/coroner offices will inevitably encounter increased numbers of COVID-19-infected decedents at autopsy. While in some cases a history of fever and/or respiratory distress (eg, cough or shortness of breath) may suggest the diagnosis, epidemiologic studies indicate that the majority of individuals infected with COVID-19 develop mild to no symptoms. Those dying with-but not of-COVID-19 may still be infectious, however. While multiple guidelines have been issued regarding autopsy protocol in cases of suspected COVID-19 deaths, there is some variability in the recommendations. Additionally, limited recommendations to date have been issued regarding scene investigative protocol, and there is a paucity of publications characterizing COVID-19 postmortem gross and histologic findings. A case of sudden unexpected death due to COVID-19 is presented as a means of illustrating common autopsy findings, as well as diagnostic and biosafety considerations. We also review and summarize the current COVID-19 literature in an effort to provide practical evidence-based biosafety guidance for medical examiner-coroner offices encountering COVID-19 at autopsy.