Can changing the prodrug moiety in remdesivir be a life-saving strategy in COVID-19 infection?
Ontology highlight
ABSTRACT:
SUBMITTER: Prabha PK
PROVIDER: S-EPMC10284358 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
Publications
Can changing the prodrug moiety in remdesivir be a life-saving strategy in COVID-19 infection?
Prabha Praisy K PK Prakash Ajay A Medhi Bikash B
The Indian journal of medical research 20230101 1
Similar Datasets
Project description:On the 30th of January 2020, the World Health Organization fired up the sirens against a fast spreading infectious disease caused by a newly discovered Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and gave this disease the name COVID-19. While there is currently no specific treatment for COVID-19, several off label drugs approved for other indications are being investigated in clinical trials across the globe. In the last decade, theranostic nanoparticles were reported as promising tool for efficiently and selectively deliver therapeutic moieties (i.e. drugs, vaccines, siRNA, peptide) to target sites of infection. In addition, they allow monitoring infectious sides and treatment responses using noninvasive imaging modalities. While intranasal delivery was proposed as the preferred administration route for therapeutic agents against viral pulmonary diseases, NP-based delivery systems offer numerous benefits to overcome challenges associated with mucosal administration, and ensure that these agents achieve a concentration that is many times higher than expected in the targeted sites of infection while limiting side effects on normal cells. In this article, we have shed light on the promising role of nanoparticles as effective carriers for therapeutics or immune modulators to help in fighting against COVID-19.
| S-EPMC7254986 | biostudies-literature
Project description:The pandemic of COVID-19 has arrested the life of 7.8 million people living on this earth. However, some people are more vulnerable to the risk of this deadly virus. The frailty of senior citizens put them at the top of this list. The past 6 months have not only presented a threat to their physical health but to mental health also. Although lockdown was necessary to check the spread of the coronavirus it culminated in an exponential rise in the problems of loneliness, anxiety, fear, helplessness, and depression. The present paper reviews the role of social networking sites, apps, and other digital platforms in saving and enriching the lives of the elderly, especially those who spent the lockdown alone and were devoid of a regular support system due to unavailability of transport and administrative restrictions on the movement of people. It also analyzes the efficiency of the virtual world in reducing their anxiety of being alone by connecting them with others and also make them feel empowered. The review is based on the online data collected about the insurgence in the percentage of elderly people using such platforms, recent studies analyzing the effects of the COVID 19 pandemic on senior citizens. Besides this personal telephonic discussions were conducted with some elderly people who spent their lockdown alone in their homes. The study was primarily focused on three objectives. Firstly it attempts to understand the ways in which senior citizens made use of social networking sites and various digital platforms for managing life better. Secondly, it analyses the process of adopting technology, and finally, it examined the width and depth of the impact technology created in their life and also the permanence of this change. The analysis clearly suggests an increase in the digital life of elderly people. The process moved in distinct stages from utter confusion to relative ease in using technology, thereby significantly reducing the loneliness, and bringing relatively stable change in the way they lead their life.
| S-EPMC8040793 | biostudies-literature
Project description:Dexamethasone is a life-saving treatment for severe COVID-19, yet its mechanism of action is unknown, and many patients deteriorate or die despite timely treatment initiation. Here, we identify dexamethasone treatment-induced cellular and molecular changes associated with improved survival in COVID-19 patients. We observed a reversal of transcriptional hallmark signatures in monocytes associated with severe COVID-19 and the induction of a monocyte substate characterized by the expression of glucocorticoid-response genes. These molecular responses to dexamethasone were detected in circulating and pulmonary monocytes, and they were directly linked to survival. Monocyte single-cell RNA sequencing (scRNA-seq)-derived signatures were enriched in whole blood transcriptomes of patients with fatal outcome in two independent cohorts, highlighting the potential for identifying non-responders refractory to dexamethasone. Our findings link the effects of dexamethasone to specific immunomodulation and reversal of monocyte dysregulation, and they highlight the potential of single-cell omics for monitoring in vivo target engagement of immunomodulatory drugs and for patient stratification for precision medicine approaches.
2024-07-04 | GSE270901 | GEO
Project description:Infectious pandemics result in hundreds and millions of deaths, notable examples of the Spanish Flu, the Black Death and smallpox. The current pandemic, caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), is unprecedented even in the historical term of pandemics. The unprecedentedness is featured by multiple surges, rapid identification of therapeutic options and accelerated development of vaccines. Remdesivir, originally developed for Ebola viral disease, is the first treatment of COVID-19 (Coronavirus disease 2019) approved by the United States Food and Drug Administration. As demonstrated by in vitro and preclinical studies, this therapeutic agent is highly potent with a broad spectrum activity against viruses from as many as seven families even cross species. However, randomized controlled trials have failed to confirm the efficacy and safety. Remdesivir improves some clinical signs but not critical parameters such as mortality. This antiviral agent is an ester/phosphorylation prodrug and excessive hydrolysis which increases cellular toxicity. Remdesivir is given intravenously, leading to concentration spikes and likely increasing the potential of hydrolysis-based toxicity. This review has proposed a conceptual framework for improving its efficacy and minimizing toxicity not only for the COVID-19 pandemic but also for future ones caused by remdesivir-sensitive viruses.
| S-EPMC8422062 | biostudies-literature
Project description: Not available
| S-BSST563 | biostudies-other
Project description:Coronavirus infection or COVID 19 was first reported in December 2019 in Wuhan, China, and has rapidly spread to more than 200 countries. The pandemic has also taken a toll of over 2.2 million. But the elusive search for an effective antidote is still on. Pending multiple and robust randomized controlled studies, some drugs are being used globally based on in-vitro studies, in -vivo evidence, observational studies, and small nonrandomized studies. Remdesivir is a nucleotide analog. It inhibits viral RNA-dependent RNA polymerase enzyme. Several studies have hitherto demonstrated the promising in-vitro and in-vivo antiviral activities of the molecule against severe acute respiratory syndrome coronavirus (SARS-CoV-1) and the Middle East respiratory syndrome coronavirus (MERS-CoV) strains. It has now exhibited potential in vitro activity against SARS-CoV-2 strains too. Based on pivotal studies, remdesivir is now being used to treat moderate to severe patients through emergency use authorizations and other access programs around the world. This review aims to summarize the evidence and clinical trials of remdesivir as a potential therapeutic option for COVID-19.
| S-EPMC8208188 | biostudies-literature
Project description: Not available
| S-EPMC9577989 | biostudies-literature
Project description:Remdesivir (RDV, Veklury®) is an FDA-approved prodrug for the treatment of hospitalized patients with COVID-19. Recent in vitro studies have indicated that human carboxylesterase 1 (CES1) is the major metabolic enzyme catalyzing RDV activation. COVID-19 treatment for hospitalized patients typically also involves a number of antibiotics and anti-inflammatory drugs. Further, individuals who are carriers of a CES1 variant (polymorphism in exon 4 codon 143 [G143E]) may experience impairment in their ability to metabolize therapeutic agents which are CES1 substrates. The present study assessed the potential influence of nine therapeutic agents (hydroxychloroquine, ivermectin, erythromycin, clarithromycin, roxithromycin, trimethoprim, ciprofloxacin, vancomycin, and dexamethasone) commonly used in treating COVID-19 and 5 known CES1 inhibitors on the metabolism of RDV. Additionally, we further analyzed the mechanism of inhibition of cannabidiol (CBD), as well as the impact of the G143E polymorphism on RDV metabolism. An in vitro S9 fraction incubation method and in vitro to in vivo pharmacokinetic scaling were utilized. None of the nine therapeutic agents evaluated produced significant inhibition of RDV hydrolysis; CBD was found to inhibit RDV hydrolysis by a mixed type of competitive and noncompetitive partial inhibition mechanism. In vitro to in vivo modeling suggested a possible reduction of RDV clearance and increase of AUC when coadministration with CBD. The same scaling method also suggested a potentially lower clearance and higher AUC in the presence of the G143E variant. In conclusion, a potential CES1-mediated DDI between RDV and the nine assessed medications appears unlikely. However, a potential CES1-mediated DDI between RDV and CBD may be possible with sufficient exposure to the cannabinoid. Patients carrying the CES1 G143E variant may exhibit a slower biotransformation and clearance of RDV. Further clinical studies would be required to evaluate and characterize the clinical significance of a CBD-RDV interaction.
| S-EPMC9367181 | biostudies-literature
Project description:Despite broad agreement on the negative consequences of vaccine inequity, the distribution of COVID-19 vaccines is imbalanced. Access to vaccines in high-income countries (HICs) is far greater than in low- and middle-income countries (LMICs). As a result, there continue to be high rates of COVID-19 infections and deaths in LMICs. In addition, recent mutant COVID-19 outbreaks may counteract advances in epidemic control and economic recovery in HICs. To explore the consequences of vaccine (in)equity in the face of evolving COVID-19 strains, we examine vaccine allocation strategies using a multistrain metapopulation model. Our results show that vaccine inequity provides only limited and short-term benefits to HICs. Sharper disparities in vaccine allocation between HICs and LMICs lead to earlier and larger outbreaks of new waves. Equitable vaccine allocation strategies, in contrast, substantially curb the spread of new strains. For HICs, making immediate and generous vaccine donations to LMICs is a practical pathway to protect everyone.
| S-EPMC8873023 | biostudies-literature