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Discovery and mechanism of action of Thonzonium bromide from an FDA-approved drug library with potent and broad-spectrum inhibitory activity against main proteases of human coronaviruses.

Although the effective drugs or vaccines have been developed to prevent the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), their efficacy may be limited for the viral evolution and immune escape. Thus, it is urgently needed to develop the novel broad-spectrum antiviral agents to control the coronavirus disease 2019 (COVID-19) global pandemic. The 3C-like protease (3CLpro) is a highly conserved cysteine proteinase that plays a pivotal role in processing the viral polyprotein to create non-structural proteins (nsps) for replication and transcription of SARS-CoV-2, ma

Identifying FDA-approved drugs with multimodal properties against COVID-19 using a data-driven approach and a lung organoid model of SARS-CoV-2 entry.

BACKGROUND: Vaccination programs have been launched worldwide to halt the spread of COVID-19. However, the identification of existing, safe compounds with combined treatment and prophylactic properties would be beneficial to individuals who are waiting to be vaccinated, particularly in less economically developed countries, where vaccine availability may be initially limited. METHODS: We used a data-driven approach, combining results from the screening of a large transcriptomic database (L1000) and molecular docking analyses, with in vitro tests using a lung organoid model of SARS-CoV-2 entry

Design characteristics, risk of bias, and reporting of randomised controlled trials supporting approvals of cancer drugs by European Medicines Agency, 2014-16: cross sectional analysis.

ObjectiveTo examine the design characteristics, risk of bias, and reporting adequacy of pivotal randomised controlled trials of cancer drugs approved by the European Medicines Agency (EMA).DesignCross sectional analysis.SettingEuropean regulatory documents, clinical trial registry records, protocols, journal publications, and supplementary appendices.Eligibility criteriaPivotal randomised controlled trials of new cancer drugs approved by the EMA between 2014 and 2016.Main outcome measuresStudy design characteristics (randomisation, comparators, and endpoints); risk of bias using the revised Co

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… approved by the EMA were associated with a single pivotal study. 3 Recently, cancer drugs have comprised the single largest category of new drug approvals in Europe. … Identification of pivotal trials supporting cancer drug approvals We included the pivotal studies that formed the basis of cancer drug approvals during our study period. …

Human pharmacokinetics prediction with an in vitro-in vivo correction factor approach and in vitro drug-drug interaction profile of bictegravir, a potent integrase-strand transfer inhibitor component in approved biktarvy® for the treatment of HIV-1 infection.

Bictegravir (BIC) is a potent small-molecule integrase strand-transfer inhibitor (INSTI) and a component of Biktarvy®, a single-tablet combination regimen that is currently approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. The in vitro properties, pharmacokinetics (PK), and drug-drug interaction (DDI) profile of BIC were characterised in vitro and in vivo.BIC is a weakly acidic, ionisable, lipophilic, highly plasma protein-bound BCS class 2 molecule, which makes it difficult to predict human PK using standard methods. Its systemic plasma clearance is low, and

FDA-approved drug library screen identifies antidepressants, antimicrobials, anti-COPD, and anti-CVD agents as blockers of NLRP3 inflammasome and sepsis in a sex-dependent manner.

The NLRP3 inflammasome pathway is central to host defense, but dysregulated activation of inflammasomes promotes diseases associated with metabolic syndrome (diabetes, obesity, CVD, MASLD), neurodegenerative diseases (Alzheimer's and Parkinson's), autoinflammatory conditions (CAPS, gout), and respiratory illnesses (asthma/COPD, and COVID-19). Therapeutic modulation of NLRP3 is challenging as it requires selective blockade of detrimental inflammasome activation without broadly suppressing innate immunity. Here, we used a phenotypic screen in THP-1 ASC-GFP monocytes to identify FDA-approved drug

Mass drug administration approved and candidate anthelmintics beginning on larval stage 1 Caenorhabditis elegans are generally potent, suggesting a novel, pre-infective control for helminths.

About 1.5 billion people are infected with at least one of three soil-transmitted helminths (STHs) - roundworm, hookworm, and whipworm- which have devastating outcomes for growth, nutrition, cognition, and school attendance, trapping them in poverty. The WHO currently approves only two anthelmintics with only one mechanism of action for mass drug administration (MDA), and resistance has been documented. This calls for new drugs and new strategies to reduce worm burden. Previous research, beginning with larval stage 4 (L4) C. elegans as a model, used a health-rating system to score individual w

Использование реальных доказательств в США. Управление по контролю за продуктами питания и лекарственными препаратами и Европейское агентство по лекарственным препаратам утверждают онкологические продукты, поддерживаемые односторонними испытаниями (Advisory and Drug Argency and the European Medicals Agency (European Medicals Agency)2022-2025).

ВВЕДЕНИЕ: Усилился интерес регулирующих органов к реальным доказательствам (РВЭ) в дополнение к односторонним испытаниям (САТ) в области онкологии, однако по-прежнему отсутствует полное понимание того, как Управление по контролю за продуктами питания и лекарствами (ДПП) и Европейское агентство по медицине (ЕМА) оценивают такие доказательства. ЦЕЛЬ: Всеобъемлющая оценка недавних решений по онкологии, в которых СТА поддерживаются РВЭ, с описанием обратной связи по вопросам нормативного регулирования, методологических подходов, роли РВЭ в процессе принятия решений. Мы рассмотрели новые прикладные

Совпадение в полном тексте источника
… We therefore reviewed oncology drug approvals from Jan 2022 through August 2025 in which SATs were supplemented by RWE. … References 1 Agrawal S , Arora S , Amiri-Kordestani L , et al Use of single-arm trials for US Food and Drug Administration drug approval in oncology, 2002-2021 . …

Evaluating newly approved drugs in combination regimens for multidrug-resistant tuberculosis with fluoroquinolone resistance (endTB-Q): study protocol for a multi-country randomized controlled trial.

BACKGROUND: Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs suf

Computational screening of dual inhibitors from FDA approved antiviral drugs on SARS-CoV-2 spike protein and the main protease using molecular docking approach.

The deadly disease-causing novel coronavirus has recently swept across the world and endangered many human lives. Although, various research on therapeutic measures to solve this pandemic crisis has been published; no favourable results have been achieved. We propose the use of potential FDA-approved dual inhibitors which can inhibit two targets (either on entry-level or the main protease) for the effective treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We screened 12 FDA-approved antiviral inhibitors listed in Drug bank and analysed the ADMET properties of each dru

Structure-based virtual screening of phytochemicals and repurposing of FDA approved antiviral drugs unravels lead molecules as potential inhibitors of coronavirus 3C-like protease enzyme.

Coronaviruses are enveloped positive-strand RNA viruses belonging to family Coronaviridae and order Nidovirales which cause infections in birds and mammals. Among the human coronaviruses, highly pathogenic ones are Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome coronavirus (MERS-CoV) which have been implicated in severe respiratory syndrome in humans. There are no approved antiviral drugs or vaccines for the treatment of human CoV infection to date. The recent outbreak of new coronavirus pandemic, coronavirus disease 2019 (COVID-19) has caused

US Food and Drug Administration review of statistical analysis of patient-reported outcomes in lung cancer clinical trials approved between January, 2008, and December, 2017.

With the advent of patient-focused drug development, the US Food and Drug Administration (FDA) has redoubled its efforts to review patient-reported outcome (PRO) data in cancer trials submitted as part of a drug's marketing application. This Review aims to characterise the statistical analysis of PRO data from pivotal lung cancer trials submitted to support FDA drug approval between January, 2008, and December, 2017. For each trial and PRO instrument identified, we evaluated prespecified PRO concepts, statistical analysis, missing data and sensitivity analysis, instrument completion, and clini…

Undetectable Concentrations of a Food and Drug Administration-approved High-sensitivity Cardiac Troponin T Assay to Rule Out Acute Myocardial Infarction at Emergency Department Arrival.

BACKGROUND: The objective of this study was to quantify the sensitivity of very low concentrations of high-sensitivity cardiac troponin T (hsTnT) at ED arrival for acute myocardial infarction (AMI) in a large cohort of chest pain patients evaluated in real-world clinical practice. METHODS: This retrospective study included consecutive ED patients with suspected cardiac chest pain evaluated in four urban EDs, excluding those with ST-elevation AMI, cardiac arrest or abnormal kidney function. The primary outcomes were AMI at 7, 30, and 90 days. Secondary outcomes included major adverse cardiac e

Target-Centered Drug Repurposing Predictions of Human Angiotensin-Converting Enzyme 2 (ACE2) and Transmembrane Protease Serine Subtype 2 (TMPRSS2) Interacting Approved Drugs for Coronavirus Disease 2019 (COVID-19) Treatment through a Drug-Target Interaction Deep Learning Model.

Previously, our group predicted commercially available Food and Drug Administration (FDA) approved drugs that can inhibit each step of the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using a deep learning-based drug-target interaction model called Molecule Transformer-Drug Target Interaction (MT-DTI). Unfortunately, additional clinically significant treatment options since the approval of remdesivir are scarce. To overcome the current coronavirus disease 2019 (COVID-19) more efficiently, a treatment strategy that controls not only SARS-CoV-2 replication but also

US Food and Drug Administration Approval Summary: Capivasertib With Fulvestrant for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced or Metastatic Breast Cancer With PIK3CA/AKT1/PTEN Alterations.

PURPOSE: The US Food and Drug Administration (FDA) approved capivasertib in combination with fulvestrant for adult patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced, or metastatic breast cancer (MBC) who have received at least one previous endocrine therapy and whose tumors harbor one or more phosphatidylinositol 3-kinase (PIK3CA)/AKT Serine/Threonine Kinase 1 (AKT1)/phosphatase and tensin homolog (PTEN) alterations, as detected by an FDA-approved test. PATIENTS AND METHODS: Approval was based on CAPItello-291, a randomized, do

An estimate of rate of deviation from NCCN guideline recommendations for central nervous system imaging in trials forming basis for drug approval in first line advanced non-small cell lung cancer (NSCLC).

IMPORTANCE: It is unknown whether and to what degree trials submitted to the US FDA to support drug approval adhere to NCCN guideline-recommended care in their baseline and surveillance CNS imaging protocols. OBJECTIVE: We sought to characterize the frequency with which the trials cited in US FDA drug approvals for first line advanced NSCLC between 2015 and 2020 deviated from NCCN guideline-recommended care for baseline and surveillance CNS imaging. DESIGN, SETTING, AND PARTICIPANTS: Retrospective observational analysis using publicly available data of (1) list of trials cited by the FDA in …

Gemfibrozil and fenofibrate, Food and Drug Administration-approved lipid-lowering drugs, up-regulate tripeptidyl-peptidase 1 in brain cells via peroxisome proliferator-activated receptor α: implications for late infantile Batten disease therapy.

The classical late infantile neuronal ceroid lipofuscinosis (LINCLs) is an autosomal recessive disease, where the defective gene is Cln2, encoding tripeptidyl-peptidase I (TPP1). At the molecular level, LINCL is caused by accumulation of autofluorescent storage materials in neurons and other cell types. Currently, there is no established treatment for this fatal disease. This study reveals a novel use of gemfibrozil and fenofibrate, Food and Drug Administration-approved lipid-lowering drugs, in up-regulating TPP1 in brain cells. Both gemfibrozil and fenofibrate up-regulated mRNA, protein, and

Discovery of potential SARS-CoV 3CL protease inhibitors from approved antiviral drugs using: virtual screening, molecular docking, pharmacophore mapping evaluation and dynamics simulation.

The spread of corona-virus disease 2019 (COVID-19) has been faster than any other corona-viruses that have succeeded in crossing the animal-human barrier. This disease, caused by the severe acute respiratory syndrome corona-virus 2 (SARS-CoV-2/2019-nCoV) posing a serious threat to global public health and local economies. There are three responsible for this disease; SARS-CoV-2, SARS-CoV and MERS-CoV. Whereas our goal is to test the affinity for a new class of compounds obtained from a hybridization of Chloroquine, Amodiaquine and Mefloquine with three targets SARS-CoV-2, SARS-CoV and MERS-CoV