Potential treatments of COVID-19: Drug repurposing and therapeutic interventions

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a new type of coronavirus disease 2019 (COVID-19). The infection is caused when Spike-protein (S-protein) present on the surface of SARS-CoV-2 interacts with human cell surface receptor, Angiotensin-converting enzyme 2 (ACE2). This binding facilitates SARS-CoV-2 entry into the human cells, which in turn causes infection. Since no specific drugs or approaches are available against COVID-19, drug repurposing is the only feasible solution for treating COVID-19. An effective therapeutic approach is needed to inactivate or block the entry of SARS-CoV-2 into human cells. This review is focused on the currently used and potential therapies for COVID-19 treatment, which include drug repurposing and drug-free therapies. Also, the available developed vaccines, clinical trials, and patents have been discussed to previse a potential therapeutic alternative against COVID-19.

Translating Microbiome Research From and To the Clinic.

Extensive research has elucidated the influence of the gut microbiota on human health and disease susceptibility and resistance. We review recent clinical and laboratory-based experimental studies associating the gut microbiota with certain human diseases. We also highlight ongoing translational advances that manipulate the gut microbiota to treat human diseases and discuss opportunities and challenges in translating microbiome research from and to the bedside.

Clinical translation of gold nanoparticles.

Gold nanoparticles display unique physicochemical features, which can be useful for therapeutic purposes. After two decades of preclinical progress, gold nanoconstructs are slowly but steadily transitioning into clinical trials. Although initially thought to be "magic golden bullets" that could be used to treat a wide range of diseases, current consensus has moved toward a more realistic approach, where gold nanoformulations are being investigated to treat specific disorders. These therapeutic applications are dictated by the pharmacokinetics and biodistribution profiles of gold nanoparticles. Here, we analyze the current clinical landscape of therapeutic gold nanoconstructs, discuss the shared characteristics that allowed for their transition from bench to bedside, and examine existing hurdles that need to be overcome before they can be approved for clinical use.

Research priorities for maternal and perinatal health clinical trials and methods used to identify them: A systematic review.

OBJECTIVE: Research prioritisation helps to target research resources to the most pressing health and healthcare needs of a population. This systematic review aimed to report research priorities in maternal and perinatal health and to assess the methods that were used to identify them. METHODS: A systematic review was undertaken. Projects that aimed to identify research priorities that were considered to be amenable to clinical trials research were eligible for inclusion. The search, limited to the last decade and publications in English, included MEDLINE, EMBASE, CINHAL, relevant Cochrane priority lists, Cochrane Priority Setting Methods Group homepage, James Lind Alliance homepage, Joanna Brigg's register, PROSPERO register, reference lists of all included articles, grey literature, and the websites of relevant professional bodies, until 13 October 2020. The methods used for prioritisation were appraised using the Reporting Guideline for Priority Setting of Health Research (REPRISE). FINDINGS: From the 62 included projects, 757 research priorities of relevance to maternal and perinatal health were identified. The most common priorities related to healthcare systems and services, pregnancy care and complications, and newborn care and complications. The least common priorities related to preconception and postpartum health, maternal mental health, contraception and pregnancy termination, and fetal medicine and surveillance. The most commonly used prioritisation methods were Delphi (20, 32%), Child Health Nutrition Research Initiative (17, 27%) and the James Lind Alliance (10, 16%). The fourteen projects (23%) that reported on at least 80% of the items included in the REPRISE guideline all used an established research prioritisation method. CONCLUSIONS: There are a large number of diverse research priorities in maternal and perinatal health that are amenable to future clinical trials research. These have been identified by a variety of research prioritisation methods.

A European update on transcatheter aortic valve implantation (TAVI) in the COVID era.

Minimally invasive approaches for aortic valve replacement are now at the forefront of pathological aortic valve treatment. New trials show comparability of these devices to existing therapies, not only in high-risk surgical cohorts but also in low-risk and intermediate-risk cohorts. This review provides vital clinical and anatomical background to aortic valvular disease treatment guidelines, while also providing an update on transcatheter aortic valve implantation (TAVI) devices in Europe, their interventional trials and associated complications.

BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies.

Bruton's tyrosine kinase (BTK) is an essential component of multiple signaling pathways that regulate B cell and myeloid cell proliferation, survival, and functions, making it a promising therapeutic target for various B cell malignancies and inflammatory diseases. Five small molecule inhibitors have shown remarkable efficacy and have been approved to treat different types of hematological cancers, including ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, and orelabrutinib. The first-in-class agent, ibrutinib, has created a new era of chemotherapy-free treatment of B cell malignancies. Ibrutinib is so popular and became the fourth top-selling cancer drug worldwide in 2021. To reduce the off-target effects and overcome the acquired resistance of ibrutinib, significant efforts have been made in developing highly selective second- and third-generation BTK inhibitors and various combination approaches. Over the past few years, BTK inhibitors have also been repurposed for the treatment of inflammatory diseases. Promising data have been obtained from preclinical and early-phase clinical studies. In this review, we summarized current progress in applying BTK inhibitors in the treatment of hematological malignancies and inflammatory disorders, highlighting available results from clinical studies.

Pralatrexate for Peripheral T-cell lymphoma (PTCL): Chance only supports the prepared mind. Systematic review.

BACKGROUND: Due to their primary effects on DNA synthesis, antimetabolites are most effective against actively dividing cells and significantly specific to the cell cycle phase. Pralatrexate (PDX), an antifolate metabolite designed to accumulate in cancer cells, was the first new agent approved by the US Food and Drug Administration for the treatment of resistant/recurrent peripheral T-cell lymphomas. PDX was a drug that is frequently used not only for PTCL, but also for cutaneous T-cell lymphoma (CTCL), extranodal natural killer (NK) / T-cell lymphoma. OBJECTIVE: This article reviews Pralatrexate's history, pharmacokinetics, clinical phase studies including phases I, II and III, types of cancers it is effective on, drug side effects, inhibition mechanism and even its use in the treatment of other cancers with innovative methods, including its antiviral effect against SARS-CoV-2 infection. METHODS: A comprehensive internet-based research was planned covering all published and unpublished studies on the subject. We conducted this review in accordance with Preferred Reporting Items for systematic reviews and meta-analysis (PRISMA-P), Cochrane Collaboration reporting items systematic reviews and meta-analysis. The results of the studies in the articles were recorded to include all phase studies. RESULTS: Pralatrexate was structurally designed to have enhanced cellular transport via RFC (reduced folate carrier type) and be subject to more polyglutamation compared to methotrexate. Enhanced polyglutamylating ability of pralatrexate is associated with increased tumor cell death and ultimately improved anticancer activity. Pralatrexate is considered as a promising drug for patients with recurrent and treatment-resistant PTCL with good survival advantage. At the same time, it is an antifolate agent which has a significant advantage over methotrexate as it does not cause myelosuppression. CONCLUSION: While there are manageable side effects such as thrombocytopenia, neutropenia, and mucositis, it is critical to explore new approaches, targeted agents, novel cellular therapies, and immunotherapies to determine optimal pretreatment in the rare but heterogeneous disease PTCL, and future studies and experienced haematologists are needed.

A Comprehensive Review of mRNA Vaccines.

mRNA vaccines have been demonstrated as a powerful alternative to traditional conventional vaccines because of their high potency, safety and efficacy, capacity for rapid clinical development, and potential for rapid, low-cost manufacturing. These vaccines have progressed from being a mere curiosity to emerging as COVID-19 pandemic vaccine front-runners. The advancements in the field of nanotechnology for developing delivery vehicles for mRNA vaccines are highly significant. In this review we have summarized each and every aspect of the mRNA vaccine. The article describes the mRNA structure, its pharmacological function of immunity induction, lipid nanoparticles (LNPs), and the upstream, downstream, and formulation process of mRNA vaccine manufacturing. Additionally, mRNA vaccines in clinical trials are also described. A deep dive into the future perspectives of mRNA vaccines, such as its freeze-drying, delivery systems, and LNPs targeting antigen-presenting cells and dendritic cells, are also summarized.

A community-partnered approach for diversity in COVID-19 vaccine clinical trials.

Introduction: Communities of color have faced disproportionate morbidity and mortality from COVID-19, coupled with historical underrepresentation in US clinical trials, creating challenges for equitable participation in developing and testing a safe and effective COVID-19 vaccine. Methods: To increase diversity, including racial and ethnic representation, in local Los Angeles County NIH-sponsored Phase 3 SARS-CoV-2 vaccine clinical trials, we used deliberative community engagement approaches to form a Community Consultant Panel (CCP) that partnered with trial research teams. Thirteen members were recruited, including expertise from essential workers, community-based and faith-based organizations, or leaders from racial and ethnic minority communities. Results: Working closely with local investigators for the vaccine studies, the CCP provided critical insight on best practices for community trust building, clinical trial participation, and reliable information dissemination regarding COVID-19 vaccines. Modifying recruitment, outreach, and trial protocols led to majority-minority participants (55%-78%) in each of the three vaccine clinical trials. CCP's input led to cultural tailoring of recruitment materials, changes in recruitment messaging, and supportive services to improve trial accessibility and acceptability (transportation, protocols for cultural competency, and support linkages to care in case of an adverse event). Barriers to clinical trial participation unable to be resolved included childcare, requests for after-hours appointment availability, and mobile locations for trial visits. Conclusion: Using deliberative community engagement can provide critical and timely insight into the community-centered barriers to COVID-19 vaccine trial participation, including addressing social determinants of health, trust, clinical trial literacy, structural barriers, and identifying trusted messenger and reliable sources of information.

Jordanian Undergraduate Students' Views of Participation in Clinical Trials: The COVID-19 Example.

The emergence of the COVID-19 pandemic has necessitated broad public participation in clinical trials. Knowledge of the attitudes of the relatively young would provide a perspective on future representative public enrollment in clinical trials. This study investigated the attitudes of undergraduate university students toward participation in COVID-19 clinical trials and determined the predictors of their attitudes. Using a validated, web-based questionnaire, 61.2% of the 425 respondents had heard about clinical trials before. Web-based media were the main sources of this knowledge. Less than 20% expressed willingness to participate in COVID-19 clinical trials or support the participation of a family member. The predictors were personal and family protection from the disease. On the contrary, being a female, possible political exploitation of the vaccine or drug, and their potential inefficacy were predictors of unwillingness to participate. This study may inform different stakeholders in developing effective study recruitment strategies to combat current and emerging pathogens.

Omega-3 Polyunsaturated Fatty Acids (n-3 PUFAs) for Immunomodulation in COVID-19 Related Acute Respiratory Distress Syndrome (ARDS).

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), might be complicated by Acute Respiratory Distress Syndrome (ARDS) caused by severe lung damage. It is relevant to find treatments for COVID-19-related ARDS. Currently, DHA and EPA n-3 PUFAs, known for their immunomodulatory activities, have been proposed for COVID-19 management, and clinical trials are ongoing. Here, examining COVID-19-related ARDS immunopathology, we reference in vitro and in vivo studies, indicating n-3 PUFA immunomodulation on lung microenvironment (bronchial and alveolar epithelial cells, macrophages, infiltrating immune cells) and ARDS, potentially affecting immune responses in COVID-19-related ARDS. Concerning in vitro studies, evidence exists of the potential anti-inflammatory activity of DHA on airway epithelial cells and monocytes/macrophages; however, it is necessary to analyze n-3 PUFA immunomodulation using viral experimental models relevant to SARS-CoV-2 infection. Then, although pre-clinical investigations in experimental acute lung injury/ARDS revealed beneficial immunomodulation by n-3 PUFAs when extracellular pathogen infections were used as lung inflammatory models, contradictory results were reported using intracellular viral infections. Finally, clinical trials investigating n-3 PUFA immunomodulation in ARDS are limited, with small samples and contradictory results. In conclusion, further in vitro and in vivo investigations are needed to establish whether n-3 PUFAs may have some therapeutic potential in COVID-19-related ARDS.

Adapting international clinical trials during COVID-19 and beyond.

BACKGROUND: The COVID-19 pandemic and resulting restrictions, particularly travel restrictions, have had significant impact on the conduct of global clinical trials. Our clinical trials programme, which relied on in-person visits for training, monitoring and capacity building across nine low- and middle-income countries, had to adapt to those unprecedented operational challenges. We report the adaptation of our working model with a focus on the operational areas of training, monitoring and cross-site collaboration. THE NEW WORKING MODEL: Adaptations include changing training strategies from in-person site visits with three or four team members to a multi-pronged virtual approach, with generic online training for good clinical practice, the development of a library of study-specific training videos, and interactive virtual training sessions, including practical laboratory-focused training sessions. We also report changes from in-person monitoring to remote monitoring as well as the development of a more localized network of clinical trial monitors to support hybrid models with in-person and remote monitoring depending on identified risks at each site. We established a virtual network across different trial and study sites with the objective to further build capacity for good clinical practice-compliant antimalarial trials and foster cross-country and cross-study site collaboration. CONCLUSION: The forced adaptation of these new strategies has come with advantages that we did not envisage initially. This includes improved, more frequent engagement through the established network with opportunities for increased south-to-south support and a substantially reduced carbon footprint and budget savings. Our new approach is challenging for study sites with limited prior experience but this can be overcome with hybrid models. Capacity building for laboratory-based work remains difficult using a virtual environment. The changes to our working model are likely to last, even after the end of the pandemic, providing a more sustainable and equitable approach to our research.

Plant-Derived Products with Therapeutic Potential against Gastrointestinal Bacteria.

The rising burden of antimicrobial resistance and increasing infectious disease outbreaks, including the recent COVID-19 pandemic, has led to a growing demand for the development of natural products as a valuable source of leading medicinal compounds. There is a wide variety of active constituents found in plants, making them an excellent source of antimicrobial agents with therapeutic potential as alternatives or potentiators of antibiotics. The structural diversity of phytochemicals enables them to act through a variety of mechanisms, targeting multiple biochemical pathways, in contrast to traditional antimicrobials. Moreover, the bioactivity of the herbal extracts can be explained by various metabolites working in synergism, where hundreds to thousands of metabolites make up the extract. Although a vast amount of literature is available regarding the use of these herbal extracts against bacterial and viral infections, critical assessments of their quality are lacking. This review aims to explore the efficacy and antimicrobial effects of herbal extracts against clinically relevant gastrointestinal infections including pathogenic Escherichia coli, toxigenic Clostridioides difficile, Campylobacter and Salmonella species. The review will discuss research gaps and propose future approaches to the translational development of plant-derived products for drug discovery purposes for the treatment and prevention of gastrointestinal infectious diseases.

Adapting an In-Home Randomized Intervention Trial Protocol for COVID-19 Precautions.

BACKGROUND: The COVID-19 pandemic has significantly impacted the status of clinical trials in the United States, requiring researchers to reconsider their approach to research studies. In light of this, we discuss the changes we made to the protocol of the Home Air Filtration for Traffic-Related Air Pollution (HAFTRAP) study, a randomized crossover trial of air filtration in homes next to a major highway. The senior authors designed the trial prior to the pandemic and included in-person data collection in participants' homes. Because of the pandemic, we delayed the start of our trial in order to revise our study protocol to ensure the health and well-being of participants and staff during home visits. To our knowledge, there have been few reports of attempts to continue in-home research during the pandemic. METHODS: When pandemic-related protective measures were imposed in March 2020, we were close to launching our trial. Instead, we postponed recruitment, set a new goal of starting in September 2020, and spent the summer of 2020 revising our protocol by developing increased safety precautions. We reviewed alternative approaches to installing portable air filtration units in study participants' homes, in order to reduce or eliminate entry into homes. We also developed a COVID-19 safety plan that covered precautionary measures taken to protect both field team staff and study participants. RESULTS: Our primary approach was to minimize contact with participants when collecting the following measures in their homes: (1) placing portable air filtration units; (2) conducting indoor air quality monitoring; (3) obtaining blood samples and blood pressure measurements; and (4) administering screening, consent, and follow-up questionnaires that coincided with collection of biological measures. Adapting our public health trial resulted in delays, but also helped ensure ethical and safe research practices. Perceived risk of COVID-19 infection appeared to have been the primary factor for an individual in deciding whether or not to participate in our trial, particularly at the beginning of the pandemic, when less was known about COVID-19. CONCLUSIONS: We needed to be flexible, creative, and calm when collaborating with community members, the IRB, and the universities, while repeatedly adjusting to changing guidelines as we determined what worked and what did not for in-home data collection. We learned that high-quality air monitoring data could be collected with minimal in-person contact and without compromising the integrity of the trial. Furthermore, we were able to collect blood pressure and phlebotomy data with minimal risk to the participant.

A peer says the government is "in deep shit,” and it couldn't be more real

Study after study in The BMJ and other major journals has indicated the effectiveness of this vaccine technology (doi:10.1136/bmj.o2865 doi:10.1136/bmj-2022-073070 doi:10.1136/bmj-2022-072065).567 Now, a new study in The BMJ shows that maternal mRNA covid-19 vaccination during pregnancy protects infants against SARS-CoV-2 infection and hospital admission (doi:10.1136/bmj-2022-074035).8 It is perfectly reasonable to hold an evidence informed view that mRNA vaccines are effective against SARS-CoV-2 and should be widely administered while demanding full disclosure of the safety data (doi:10.1136/bmj.o102).9 As this study of vaccination in pregnancy highlights, there are also other nuances that must be considered before research evidence becomes policy, such as timing of treatment (doi:10.1136/bmj.p241).10 Vaccine manufacturers' next goal is to develop mRNA vaccines to prevent cancer, one of the original ambitions for this breakthrough science (doi:10.1136/bmj.o3041).1 Research is already advanced, although a reasoned debate on the wider application of mRNA vaccines seems unlikely. The political or commercial control of public interest data is an undesirable endpoint worthy of Warneresque levels of plain speaking condemnation. 1 Baraniuk C. When will the world get cancer vaccines? BMJ 2023;380: o3041. 10.1136/bmj.o3041 36609365 2 McEvoy J. Microchips, magnets and shedding: here are 5 (debunked) covid vaccine conspiracy theories spreading online. Vaccine effectiveness of primary series and booster doses against covid-19 associated hospital admissions in the United States: living test negative design study.

Impact of COVID-19 pandemic on psychiatric patients at clinical trial sites

Introduction: Recent research on the COVID-19 pandemic suggests that individuals who suffer from serious mental illness (SMI) are at heightened risk of infection and have increased mortality due to their illness and/or lack of access to healthcare. Consequently, progress in developing new treatments for SMIs has been disrupted, with many interruptions to clinical trials in psychiatry due to concerns regarding the pandemic and its risks to patients with SMI. Objective: This study aimed to examine the impact of the COVID-19 pandemic on patients with SMI, specifically relating to psychiatric morbidity, pandemic-induced stress, and ability to cope with pandemic-related precautionary measures, restrictions, and disruptions to daily life. Design: A cross-sectional survey study of 94 clinical trial patients diagnosed with bipolar disorder, major depressive disorder (MDD), or schizophrenia was conducted in three geographically distinct clinical trial sites between June and September 2020. Prevalence rates were calculated for sample characteristics and demographics, and low versus high stress groups were compared on survey variables using Pearson's Chi-squared test of independence. Results: The results from the surveys indicated that COVID-19 knowledge, awareness, and the use of precautionary safety measures (e.g., handwashing, personal protective equipment [PPE], and social distancing) were robust and mirrored the general population. While the majority of patients reported experiencing moderate or extreme levels of distress (61.5%, n = 56), high levels of stress were correlated with positive coping skills. Conclusion: These findings suggest that clinical trial patients with SMI can safely participate in clinical trials despite the increase safety risks posed by the COVID-19 pandemic. (PsycInfo Database Record (c) 2023 APA, all rights reserved)

Albert Bourla: leading Pfizer's successful vaccine rollout to tackle the Covid-19 pandemic

Research methodology: This case study was prepared through secondary research. The secondary data was collected in electronic format from the internet. Archived data from the company sources as well as other resources available online was used. Financial reporting about Pfizer Inc. (Pfizer) was done using data from the company's annual reports. Case overview/synopsis: This case discusses US-based pharmaceutical giant Pfizer's successful rollout of the Covid-19 vaccine under the leadership of its Chief Executive Officer Albert Bourla (Bourla). In March 2020, when the World Health Organization declared Covid-19 a pandemic, leaders of pharmaceutical giants worldwide were in no way prepared to find a cure for the disease caused by the novel coronavirus. On the other hand, Bourla stood up like a true leader and sought to do something to address the problem. Bourla's huge gamble paid off. In December 2020, the Food and Drug Administration approved the Covid-19 vaccine developed by Pfizer. Pfizer was ready with 50 million vaccine doses for global distribution. Complexity academic level: This case is intended for use in MBA/MS level programs as part of the curriculum on Effective Leadership and Decision-making, and Crisis Management. © 2022, Emerald Publishing Limited.