cord-000182-ni6iyzdn	2010	title: Predicting Drug-Target Interaction Networks Based on Functional Groups and Biological Features Many researchers have made lots of efforts to develop useful algorithms and softwares to investigate various drug-related biological problems, such as HIV protease cleavage site prediction [18, 19] , identification of GPCR (G protein-coupled receptors) type [20, 21] , protein signal peptide prediction [22] , protein subcellular location prediction [23, 24, 25] , analysis of specificity of GalNAc-transferase protein [26] , identification of protease type [27, 28] , membrane protein type prediction [29, 30, 31, 32] , and a series of relevant webserver predictors as summarized in a recent review [33] . The drug-target benchmark datasets thus obtained for enzymes, ion-channels, GPCRs, and nuclear receptors are given in Online Supporting Information S1, S2, S3, and S4, respectively. Prediction of G-protein-coupled receptor classes based on the concept of Chou''s pseudo amino acid composition: an approach from discrete wavelet transform
cord-000204-hd12p867	2010	title: Peptide-Mediated Liposomal Drug Delivery System Targeting Tumor Blood Vessels in Anticancer Therapy One recognized strategy for improving the therapeutic effectiveness of conventional chemotherapeutics is to encapsulate anticancer drugs into targeting liposomes that bind to the cell surface receptors expressed on tumor-associated endothelial cells. This article reviews the current research in developing liposomal drug delivery systems that use peptide ligands to target blood vessels in solid tumors. One peptide-conjugated liposome can deliver over ten thousand anticancer drug molecules directly into target tumor cells efficiently and effectively. In the future, combining ligands that specifically bind to cancer cells (including cancer stem cells) and tumor blood vessels with multifunctional liposomal drug delivery systems may help improve the effectiveness of cancer treatment and minimize the side effects traditionally associated with chemotherapy. The potential use of ligand-conjugated liposome-encapsulated drugs to target tumor cells and vasculature is very promising.
cord-001072-pjv3wy80	2013	Dissolving and biodegradable microneedle technologies have been used for transdermal sustained deliveries of different drugs and vaccines. 13, 14 Microneedles are mostly applied for the transdermal delivery of drugs and vaccines that may require long exposure, among which the dissolving and biodegradable microneedle technologies are most commonly seen. Microneedle technologies for sustained drug delivery has long been recognized as a highly immune reactive tissue containing an abundance of antigen-presenting cells and immunocompetent cells, especially within the epidermal and dermal skin layers. 36 DeMuth et al 37 reported an approach for rapid implantation of vaccine-loaded polymer films carrying DNA, immune-stimulatory RNA, and biodegradable polycations using microneedles coated with releasable polyelectrolyte multilayers that promoted local transfection and controlled the persistence of DNA and adjuvants in the skin from days to weeks, with kinetics determined by the film composition. 29, 35 Altogether, dissolving and biodegradable microneedle technologies have a bright future for transdermal sustained delivery of drug and vaccine, and require further studies.
cord-001151-mdej7nhj	2013	The entrapment efficiency and in vitro drug release were studied in simulated gastric, intestinal, and colonic fluids containing rat cecal contents. The in vitro drug release study was carried out in simulated gastric fluid of pH 1.2, simulated intestinal fluid of pH 6.8, and simulated colonic fluid of pH 7.4 containing rat cecal contents under anaerobic conditions. The drug release studies from the microparticles were carried out in the simulated gastric fluid of pH 1.2, simulated intestinal fluid of pH 6.8, and simulated colonic fluid of pH 7.4 containing rat cecal contents [34, 35] . In the simulated colonic fluid containing rat cecal contents, the drug release was a bit more augmented with an initial burst release common for each of the designed The results predict the drug-polymer ratio to be the key factor for controlling the release.
cord-001244-qdld7hdc	2014	In the predictor, the drug compound concerned was formulated by a 256-D (dimensional) vector derived from its molecular fingerprint, and the NR by a 500-D vector formed by incorporating its sequential evolution information and physicochemical features into the general form of pseudo amino acid composition, and the prediction engine was operated by the SVM (support vector machine) algorithm. [59] did not provide a publicly accessible web-server for their method, and hence its practical application value is quite limited, particularly for the broad experimental scientists; (b) The prediction quality can be further enhanced by incorporating some key features into the formulation of NR-drug (nuclear receptor and drug) samples via the general form of pseudo amino acid composition [60] . Prediction of G-protein-coupled receptor classes based on the concept of Chou''s pseudo amino acid composition: An approach from discrete wavelet transform
cord-001470-hn288o97	2014	CONCLUSIONS: Drug sales data analyses appear to be a useful tool for surveillance of gastrointestinal and respiratory disease, and OTC drugs have the potential for early outbreak detection. Published articles were searched for on electronic databases (Pubmed, Embase, Scopus, LILACS, African Index Medicus, Cochrane Library), using combinations of the following key words: ("surveillance" OR outbreak detection OR warning system) AND (overthe-counter OR "prescription drugs" OR pharmacy OR (pharmaceutical OR drug OR medication) sales). Articles excluded based on fulltext review (no drug sales data, no infectious disease, no outbreak detection) N= 85 Figure 1 Flow chart of study selection process in a systematic review of drug sales data analysis for syndromic surveillance of infectious diseases. Nineteen of the 27 studies were descriptive retrospective studies assessing the strength of the correlation between drug sales and reference surveillance data of the corresponding disease or evaluating outbreak-detection performance [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] .
cord-002774-tpqsjjet	2017	
cord-003118-58ta20fg	2018	Individual patients with life-threatening or severely debilitating diseases can petition the U.S. Food and Drug Administration (FDA) through their physicians to have expanded access (EA) to drugs that are in clinical trials but have not reached full FDA approval (the "single-patient" investigational new drug [IND] application). Spurred by patient advocacy during the early days of the acquired immunodeficiency syndrome (AIDS) epidemic in the late 1980s, and facilitated by subsequent legislative efforts over the next 20 years, regulatory initiatives permit the FDA to release drugs for use in individual patients through expanded access (EA) INDs (4, 5) , in many cases allowing emergency treatment with nonapproved drugs within hours of application, and nonemergency treatment within an average of 4 days (6) . Releasing investigational new drugs to individual patients who are facing certain death or disability seems to be a relatively uncomplicated decision, but allowing EA to entire groups of patients for treatment with an investigational new drug presents more complex regulatory, logistical, and ethical challenges for scientists, commercial entities, and the FDA.
cord-004501-guiy89x8	2020	
cord-006226-fn7zlutj	1994	
cord-006229-7yoilsho	2016	It directly activates Protein Kinase A (PKA) or the Exchange protein directly activated by cAMP (Epac) which is a guanine exchange factor (GEF) for the small monomeric GTPase Rap. As Human umbilical vein endothelial cells (HUVEC) express both cAMP effectors (Epac1 and PKA), we investigated the role of cAMP-signaling using a spheroid based sprouting assay as an in vitro model for angiogenesis. After activation, S1P receptors regulate important processes in the progression of renal diseases, such as mesangial cell migration Methods and Results: Here we demonstrate that dexamethasone treatment lowered S1P 1 mRNA and protein expression levels in rat mesangial cells measured by TaqMan® and Western blot analyses. The aim of this study was to investigate the relevance of IGFBP5 in cardiogenesis and cardiac remodeling and its role as a potential target for ameliorating stress-induced cardiac remodeling Methods and Results: We investigated the expression of Igfbp5 in murine cardiac tissue at different developmental stages by qPCR normalized to Tpt1 (Tumor Protein, Translationally-Controlled 1).
cord-006479-iaocovf2	2009	In diesem Beitrag wird eine Übersicht über medikamentös induzierte Erkrankungen des Lungenparenchyms, aber auch Reaktionsmuster wie das nichtkardiogene Lungenödem, die diffuse alveoläre Hämorrhagie, das medikamenteninduzierte ARDS ("acute respiratory distress syndrome") und eosinophile Lungenparenchymerkrankungen gegeben. So ist beispielsweise die früher häufige Nitrofurantoinlunge heute selten geworden, eine früher ebenfalls häufige Goldlunge als Folge einer Therapie einer rheumatoiden Arthritis mit Goldpräparaten dürfte heute nicht mehr auftreten. Eine Schädigung des Lungenparenchyms durch Medikamente manifestiert sich meist, jedoch nicht immer in Form einer Alveolitis oder Lungenfibrose und kann durch eine Vielzahl von Arzneimitteln induziert werden (. Interstitial lung disease · Hemorrhage · Allergic reaction · Toxicity · Drug cessation Bei begründetem Verdacht ist eine Medikamentenkarenz und in Abhängigkeit vom Schweregrad der Reaktion eine Therapie mit Glukokortikosteroiden indiziert. Die pulmonale Toxizität von Zytostatika wird in eine früh, während der Therapie einsetzende ("early onset") Form (.
cord-007511-5d5authn	2007	By combining it with published in vitro pharmacodynamic and drug metabolism information, we review and predict the possible relevance, or lack of, of CYP2C8 polymorphisms in the present and future efficacy of amodiaquine. By combining it with published in vitro pharmacodynamic and drug metabolism information, we review and predict the possible relevance, or lack of, of CYP2C8 polymorphisms in the present and future efficacy of amodiaquine. This leaves drug therapy as the main tool for the global treatment and control of the disease, presently in the successful shape of the highly effective combination of artemisinine (ART) derivatives with longer half-life partners [4] .
cord-007798-9ht7cqhu	2010	In the context of analgesic, anti-inflammatory, anticholinergic, anticonvulsant, antihyperglycemic, antimicrobial, antineoplastic, cardiovascular, opioid, or sedative-hypnotic agents overdose, N-acetylcysteine, physostigmine, l-carnitine, dextrose, octreotide, pyridoxine, dexrazoxane, leucovorin, glucarpidase, atropine, calcium, digoxin-specific antibody fragments, glucagon, high-dose insulin euglycemia therapy, lipid emulsion, magnesium, sodium bicarbonate, naloxone, and flumazenil are specifically reviewed. As might be anticipated from the fact that supportive care suffices for the majority of poisoned patients, a typical study of routine administration of charcoal following oral overdose of primarily benzodiazepines, acetaminophen, and selective serotonin reuptake inhibitors could not demonstrate benefit [16, 17, 23] . Patient characteristics suggesting extracorporeal therapy include signs or symptoms of significant end organ toxicity; impaired elimination secondary to baseline comorbidities or critical illness-induced hypoperfusion; inability to tolerate or refractory to antidotal strategies (such as bicarbonate or saline); inadequate response to supportive care measures; concurrent electrolyte derangements (e.g., metformin-associated lactic acidosis); or serum drug concentrations historically associated with severe outcome [127] .
cord-009763-44fexcpt	2020	In this study, the development of an iontophoretic drug delivery device that could be controlled using a mobile is described. A mobile app was developed to control the two-channel iontophoretic device and to monitor the loose lead of the active and the passive patches. Taking the cue from the above discussion, a smartphone-based remote-controlled iontophoretic drug delivery device has been developed in this study. Eagle PCB design software was used for the designing of the PCB for the developed circuit of the iontophoretic device with loose-lead monitoring capability (see Fig. S2 available in the Supplemental Materials on the ASME Digital Collection). While doing the drug release study in the active mode, the iontophoretic device was put on using the developed mobile app. The components of the proposed device, namely, the signal generator, the iontophoretic setup, the loose-lead monitoring system, and the Android app based wireless control system, were tested for their proper functionality.
cord-014687-0am4l5ms	2012	This presentation will focus on recent developments that have lead to a better understanding of the embryopathogenesis for fibropolycystic liver diseases (including choledochal cysts and Caroli disease), histopathological findings that have led to new classification systems for of pediatric vascular anomalies, technological advances and contrast agents in magnetic resonance imaging that are useful to characterize and limit the differential diagnosis of hepatic masses. Disclosure: Dr. Annapragada has indicated that he is a stock holder and consultant for Marval Biosciences Inc. Paper #: PA-067 Cardiovascular Image Quality Using a Nanoparticle CT Contrast Agent: Preliminary Studies in a Pig Model Rajesh Krishnamurthy, Radiology, Texas Children''s Hospital, rxkrishn@texaschildrens.org; Ketan Ghaghada, Prakash Masand, Abhay Divekar, Eric Hoffman, Ananth Annapragada Purpose or Case Report: Image quality in a separate study using a long circulating, liposomal-based nanoscale blood pool iodinated contrast agent (NCTX) suggests clinical utility in pediatrics, potentially reducing difficulties in contrast-CT of children with congenital heart disease (CHD) including the size of intravenous cannula, need for accurate timing, inability to simultaneously opacify multiple targets of interest (requiring repeated contrast administration and/or repeated imaging).
cord-014875-xhzxhwgo	2003	The last chapter in the second focused area is by Pumpens and Grens, who provide an in-depth discussion of the use of viral vectors for delivering a desirable gene into target cells for protein production. The chapters don''t cover material in great depth (and if they did, this book will be many times larger) but they provide enough information to cover what someone new to the area would need to know to get started. As described above, this book does not intend to summarize transporters related to drugs rather tried to introduce many technologies to be used in future studies for molecular cloning, structure, functionality, regulation, and sorting in various point of views by using typical experimental results on physiologically important transporter molecules. Each chapter provides a polymer-based step-bystep description of not only basic information including various classification, application, and structure-property relationships, but also very practical descriptions of synthetic and analytic techniques that are believed to be good references in research laboratories.
cord-015334-8p124rwp	2008	Based on the results of the pharmacoeconomic analysis, development of clinical pharmacy and CIVAS for some drugs will be discussed with the paediatric department Background and Objective: Studies show that up to 38% of patients starting treatment with antidepressants fill only a single prescription at the pharmacy, apparently not accepting treatment. Main Outcome Measures: Data collected were: nurses'' profile (age, length of service, competencies'' self-assessment), knowledge on drugs prescribed to their patients (usage, administration, side-effects, drug interactions…), use of existing tools (i.e. drugs database) and possible tools to be developed by the pharmacy ward to help them in their daily practice. The objectives were:(1)To identify the most relevant minor ailments, agreeing on the specific criteria for referral to the GP.(2)To select the non-prescription drugs, with evidence of safety and effectiveness, for the treatment of the identified minor ailments Design: Qualitative study with an expert panel which was made up of 2 primary care physician from SEMFYC and six community pharmacists (two members of SEFAC and four members of GIAF-UGR).
cord-015684-q10sx1dm	2009	
cord-016283-b6yywn9f	2019	Notwithstanding the advances in modern science, clinical diagnosis sometimes remains elusive, owing principally to the frequent paucibacillary occurrence of the disease and the slow doubling time of the organism; empiric treatment is often fraught with risks in the era of increasing drug resistance. The line probe assays (LPA) can permit rapid identification of specific gene markers associated with rifampicin resistance alone or in combination with isoniazid, and provide clinically relevant information about the level of INH resistance (low level associated with the INH-A gene; versus high level associated with the kat-G gene) (WHO treatment guidance for drug resistant tuberculosis 2016). Anti-tubercular drugs require to be supplemented with carefully monitored steroid therapy in two circumstances: tubercular meningitis (a short course of dexamethasone or prednisolone is typically given, tapered over 6 to 8 weeks) and tuberculous pericarditis (Guidelines for treatment of drug-susceptible tuberculosis and patient care 2017).
cord-016309-6mw8okmt	2019	Those included usage restricted to a single virus and specific animal species, problems with high spectrum activity and low cytotoxicity, high costs of development of new chemical compounds and absence of rapid diagnostic techniques allowing prompt use of a specific antiviral agent in the course of an acute infection (Rollinson 1992a, b) . Nevertheless, several licensed human antiviral agents are being used with cascade principle for treatment of animal diseases (e.g. acyclovir, idoxuridine and trifluridine against feline herpesvirus-1 ocular infection in cats) (Thiry et al. The discovery of PAA (Fig. 22.4) as an antiviral drug gave rise to intense research on its biological activities, which demonstrated PAA and its derivatives'' ability to inhibit the replication of a number of viruses such as immunodeficiency, hepatitis and herpes viruses. To conclude with, equine herpesvirus type 1 (EHV-1) infection causes outbreak of respiratory and various neurological diseases in horses, against which acyclovir and valacyclovir are the most common drugs, but also IFN targeting IFNGR complex as a key mediator of virus-specific cellular immunity (Poelaert et al.
cord-016460-39yniw0t	2018	
cord-017062-dkw2sugl	2013	
cord-017583-72mbsib7	2014	The adaptive mechanisms of Mycobacterium tuberculosis to survive inside the macrophages are prevention of fusion of the phagosome with lysosomes by producing tryptophan-aspartate-containing coat protein (TACO). In case of Mycobacterium tuberculosis infection, alveolar macrophages (dust cells), along with dendritic cells engulf bacteria and exhibit innate as well as an adaptive immune response. Infection of macrophages leads to changes in the expression pattern of the concerned receptors, which can be exploited for targeted drug delivery employing nanocarriers. Table 3 .6 is a summary of the important receptors on macrophages and illustrative examples of ligands for the same that could play a role in designing targeted nanocarriers for infectious disease therapy. Targeted drug delivery to enhance effi cacy and shorten treatment duration in disseminated Mycobacterium avium infection in mi host factors infl uencing the preferential localization of sterically stabilized liposomes in klebsiella pneumoniae-infected rat lung tissue Targeted intracellular delivery of antituberculosis drugs to mycobacterium tuberculosis-infected macrophages via functionalized mesoporous silica nanoparticles
cord-017702-v46ye328	2013	
cord-018595-x3tleomb	2017	2. Delayed-type drug hypersensitivity: Delayed-type drug hypersensitivity reactions usually take several days to weeks following drug exposure, with variable clinical presentations that may include Maculopapular Eruption (MPE), Fixed Drug Eruption (FDE), Acute Generalized Exanthematous Pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Examples of strong associations of HLA alleles with specific drug-induced hypersensitivity reactions include abacavir, nevirapine, carbamazepine, and allopurinol (Table 25. [61] , who reported the weak associations of HLA-A29, B12, and MPE maculopapular drug eruption, DRESS drug reaction with eosinophilia and systemic symptoms, SJS/TEN Stevens-Johnson syndrome/toxic epidermal necrolysis DR7 in sulfonamide-related TEN, and HLA-A2, B12 in oxicam-related TEN in Europeans [61] . Drug specific cytotoxic T-cells in the skin lesions of a patient with toxic epidermal necrolysis
cord-018714-i291z2ju	2016	
cord-020766-0gacqii4	2006	
cord-022082-1dq623oe	2007	
cord-023509-tvqpv6fp	2011	As a general rule, exposure to silica dust extends over many years, often 20 or more, before the symptoms of silicosis first appear: by the time the disease becomes overt clinically, much irreparable damage has been inflicted on the lungs. Confusingly, the term ''acute silicosis'' has since been applied to a further effect of heavy dust exposure in tunnellers, sand blasters and silica flour workers, namely pulmonary alveolar lipoproteinosis (see below), 71, 72 whilst the terms ''accelerated silicosis'' or ''cellular phase silicosis'' have been substituted for ''acute silicosis'' in referring to the rapid development of early cellular lesions. Asbestosis is defined as diffuse interstitial fibrosis of the lung caused by exposure to asbestos dust. The finely divided fume of several metals is highly toxic to the lungs and capable of producing severe acute and chronic damage to both the conductive airways and the alveoli, resulting in acute tracheobronchitis and bronchiolitis, diffuse alveolar damage, obliterative bronchiolitis and pulmonary fibrosis.
cord-024833-e6vcf4un	2019	Approximately 80% of US hospitals rely on data and recommendations from the ECRI Institute to protect patients from unsafe practices and ineffective products, while the ISMP''s efforts to improve safety in patients have resulted in changes to clinical practice and public policy, including improvements in drug labelling, packaging, preparation and administration. The FDA has now announced the availability of a draft document entitled "Best Practices in Drug and Biological Product Postmarket Safety Surveillance for FDA Staff", which outlines the agency''s approach to timely postmarketing analyses of drugs and biologics, and "includes a high-level overview of tools, methods, and signal detection and evaluation activities, using varied data sources, for drug safety surveillance to provide a broader context and a general overview of our overarching effort and commitment in this area", says Woodcock. Analysis of spontaneous ADR reports to the European Medicine Agency''s EudraVigilance database has identified new safety signals for asthma drugs in paediatric patients, say authors of a study published in Drug Safety.
cord-032561-x3qbqy69	2020	demonstrated that nanodrug carriers with diselenides could release more drugs using poly (ester carbamate) triblock copolymers (PAUR-Se-Se) with Se-Se bonds compared with poly (ester carbamate) triblock copolymers (PAUR-S-S) [54, 55] Thioether Selenium Tellurium Besides the development of drug delivery systems, pH-responsive systems can also be used for tumor detection and image-guided surgery [46] . demonstrated that nanodrug carriers with diselenides could release more drugs using poly (ester carbamate) triblock copolymers (PAUR-Se-Se) with Se-Se bonds compared with poly (ester carbamate) triblock copolymers (PAUR-S-S) [65] PBA/PBE Besides the development of drug delivery systems, pH-responsive systems can also be used for tumor detection and image-guided surgery [46] . Therefore, pH responsive system can be combined with other stimulus conditions such as light, redox, enzymes and others with the aim of improved selectivity for drug release in diseased tissues [47, 48] . In addition to photothermal therapy and PDT, light-responsive strategies have also been applied in the design of prodrug systems and drug delivery carriers.
cord-033723-jy5fdsp9	2020	In many scientific problems explainable models are required, and the input data is semantically complex and unsuitable for DNNs. This is true in the fundamental problem of understanding the mechanism of cancer drugs, which requires complex background knowledge about the functions of genes/proteins, their cells, and the molecular structure of the drugs. This has changed with the success of deep neural-networks (DNNs), which has been based on their capacity to utilize multiple neural network layers, and large amounts of data, to learn how to convert raw propositional descriptors (e.g., image pixel values) into richer internal representations that are effective for learning. We hypothesized that we could improve both ML model explainability, and predictive accuracy, by including additional background knowledge in the learning process using a hybrid RL approach. Furthermore, there exist several other approaches for learning representations from graph or inherently relational data [3, 13] with varying levels of predictive performance and interpretability.
cord-034406-i1hbx3pz	2020	
cord-035236-7rfc73qb	2020	
cord-102823-zult69f2	2020	We propose a new model called GraphDTA that represents drugs as graphs and uses graph neural networks to predict drug--target affinity. We show that graph neural networks not only predict drug--target affinity better than non-deep learning models, but also outperform competing deep learning methods. Our results confirm that deep learning models are appropriate for drug--target binding affinity prediction, and that representing drugs as graphs can lead to further improvements. In this article, we propose GraphDTA, a new neural network architecture capable of directly modelling drugs as molecular graphs, and show that this approach outperforms state-of-the-art deep learning models on two drug-target affinity prediction benchmarks. Although we focus on drug-target affinity prediction, our GraphDTA model is a generic solution for any similar problem where either data input can be represented as a graph.
cord-103876-2rg2qtdq	2020	
cord-104431-3rblzyry	2020	RESULTS: Minimum estimated costs of production were US $0.93/day for remdesivir, $1.45/day for favipiravir, $0.08/day for hydroxychloroquine, $0.02/day for chloroquine, $0.10/day for azithromycin, $0.28/day for lopinavir/ritonavir, $0.39/day for sofosbuvir/daclatasvir and $1.09/day for pirfenidone. large donor organisations such as the global Fund for aiDs, TB and Malaria (gFaTM) and the President''s emergency Plan for aiDs relief (PePFar) order drugs to treat >20 million people with hiV, at prices close to the cost of production [20, 21] . We used all available costing data for each drug aPi found on Panjiva, excluding shipments <1kg in size, alongside the lowest and highest 15% of results based on prices per kg. Minimum costs to manufacture new treatments for cOViD-19 67 Different dosing protocols are being used for hydroxychloroquine, including 600 mg daily in the small, open-label, non-randomised French study by gautret et al.
cord-104493-yqf7tyo4	2020	
cord-130351-w9mij6c6	2020	
cord-178783-894gkrsk	2020	
cord-199630-2lmwnfda	2020	
cord-203191-7ftg6bfx	2020	title: Identification of Repurposal Drugs and Adverse Drug Reactions for Various Courses of Coronavirus Disease 2019 (COVID-19) Based on Single-cell RNA Sequencing Data To identify potentially repurposable drugs, we employed a systematic approach to mine candidates from U.S. FDA approved drugs and pre-clinical small-molecule compounds by integrating the gene expression perturbation data by chemicals from the Library of Integrated Network-Based Cellular Signatures (LINCS) project with publically available single-cell RNA sequencing dataset from mild and severe COVID-19 patients. We also collected a list of differentially expressed genes (DEGs) in SARS-CoV-2-infected lung BALF using a bulk RNA-Seq analysis to compare against the single-cell-based data. Repurposing analysis in severe COVID-19 patients 60 potent drugs were also selected in severe cases compared to controls (severe vs healthy group) according to their average CS between the replicates, and 25 of them involved in more than one cell subtype ( Figure 2B , Supplementary Tables S8 & S9) .
cord-203232-1nnqx1g9	2020	Using the National Center for Biotechnology Information virus protein database and the DrugVirus database, which provides a comprehensive report of broad-spectrum antiviral agents (BSAAs) and viruses they inhibit, we trained ANN models with virus protein sequences as inputs and antiviral agents deemed safe-in-humans as outputs. Using sequences for SARS-CoV-2 (the coronavirus that causes COVID-19) as inputs to the trained models produces outputs of tentative safe-in-human antiviral candidates for treating COVID-19. For Experiment II, we split the data on virus species, meaning the models were forced to predict drugs for a species that it was not trained on, and have to detect peptide substructures in the amino-acid sequences to suggest drugs. In post-processing, we applied a threshold to the sigmoid function outputs of the neural network, where we assigned each drug a probability of being a potential antiviral for a given amino acid sequence.
cord-214795-8jweuq50	2020	Results on our curated RNA drug virus association (DVA) dataset shows that the proposed approach excels over state-of-the-art graph regularized matrix completion techniques. It shows how the matrix completion framework can be used to computationally predict the drugs that could be effective against SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus responsible for the ongoing pandemic, COVID-19 (COrona VIrus Disease-2019). In this present work, we propose to solve the problem of drug-virus association prediction via graph regularized deep matrix factorization. Among all the methodologies compared in [52] , graph regularized matrix factorization based technique (GRMF) provided the best results for the validation setting where drugs are predicted for novel viruses. In our proposed technique, multi-graph regularization is incorporated in the deep matrix factorization formulation with the aim to incorporate the metadata associated with the drugs and viruses in the form of similarity information as shown below:
cord-232446-vvb2ffhv	2020	In view to assist acceleration of this process (by pruning down the search space), we create and share a publicly available DVA database, along with a number of matrix completion techniques (mentioned above) for drug-virus association prediction. Such a computational approach requires the chemical structure of the drugs and, in case of graph-regularized matrix completion techniques, the genome of the viruses, or existing associations otherwise. A clear observation from the experiments is that the graph regularized-based matrix completion algorithms that incorporate the similarity information associated with the drugs and viruses, perform fairly well giving an AUC greater or equal than 0.83 in CV1. It can be noted that the standard matrix completion methods, which do not take into account the metadata, fail to learn from the association data giving a near-random performance as far as the prediction on novel viruses is concerned, depicting how very important the similarity information is.
cord-252147-bvtchcbt	2011	
cord-252166-qah877pk	2007	
cord-253115-ekgdsv4f	2019	Commonly used drug delivery systems for respiratory diseases are polymer-based, lipid-based and peptide-based, and among these three, the lipid-based carriers are the most commonly used vectors for delivering RNAi. They include solid lipid nanoparticles, cationic liposomes, lipidoids, solid nanostructured lipid carriers and pH-responsive lipids [26] . The effective delivery of the drug and siRNA induced cell death of lung tumor cells by targeted gene silencing [56] . Glud et al., investigated pulmonary gene silencing effect of small interfering locked nucleic acid (siLNAs), targeting enhanced-greenfluorescent-protein (EGFP) in lung bronchoepithelium upon intravenous delivery of naked siLNAs and intranasal delivery of naked siLNA or chitosan based siLNA mucoadhesive nanoparticles. This study demonstrated that SAMiRNA nanoparticle is a stable siRNA silencing platform with less toxicity for effective in vivo targeting of genes involved in the pathogenesis of respiratory diseases [96] . Overcoming cisplatin resistance in non-small cell lung cancer with Mad2 silencing siRNA delivered systemically using EGFR-targeted chitosan nanoparticles
cord-255460-r5p5helx	2019	
cord-255895-6at9gelt	2020	
cord-256118-gxhhwqdd	2020	Based on a study of PWID in Colorado, Koester (2005) suggests that indirect sharing, which happens when powder drugs are diluted in water before been divided up in a cooker with the help of a syringe, is an efficient way of distributing drugs among injection partners. Nested within a study of social networks and HIV/ HCV risk among PWID in rural Puerto Rico, we propose an ethnographically informed approach to "caballo", the joint acquisition and sharing of drugs, as a window into the social production of an HCV epidemic among PWID. While drug sharing arrangements among PWID have been amply documented, an ethnographic study of caballo in Puerto Rico will illuminate the social context behind the joint acquisition and use of drugs and its related epidemiological risk.
cord-256852-lrz17bdx	2015	15 The U.S. Institute of Medicine (IOM) has published a report "Countering the Problem of Falsified and Substandard Drugs." 16 The IOM recommendations to "stem the global trade" in such products are laudable in advising that the U.S. Food and Drug Administration (FDA), the National Institute of Standards and Technology, and other U.S. and international pharmaceutical and financing agencies be more actively involved in setting standards and financing improvements; yet this report falls far short of making a strong call for standardized, agreed-upon quality assessment technologies; an international law convention; and a more activist, internationally recognized lead organization, all three of which are essential for stopping the many health threats of fake drugs.
cord-257144-3q0un5rl	2020	
cord-257318-jejgkcql	2012	
cord-257344-d13at1y5	2020	
cord-257496-mirh80gn	2020	These product variables in combination with patient variables, including co-ordination skill during inhaler use, intrinsic lung biology, disease and consequent pulmonary function, contribute to drug safety and efficacy outcomes. Figure 1 summarizes the requirements of matching the therapeutic agent to the desired treatment outcome while considering the overall host system barriers (deposition and clearance mechanisms) and target (receptor or pathogen) biology guiding selection or development of a suitable drug delivery technology. However, recently the use of liposomes to aid in drug preparation and delivery and to aid in targeting of macrophages has advanced formulation options [28, 29] .The use of ethanol in the solutions delivered from the Respimat™ soft mist inhaler, e.g. tiotropium (Spiriva®, Boehringer Ingelheim) enhances the solubilization properties of the medium and facilitates a hand held aqueous based system with accurate and reproducible performance in delivering very low doses (<10 µg) on a single breath analogous to a metered dose inhaler [30, 31] . The addition of low-density lipid particles to HFA as a dispersant for micronized drug has allowed for a range of new metered dose inhaler products to come to market [40] .
cord-258128-qtmjgrml	2020	
cord-258614-7unadw41	2020	Structure-based virtual screening and molecular dynamics (MD) simulation have been employed to study their inhibitory potential against the main protease (M(pro)) SARS-CoV-2. These phytocompounds showed strong and stable interactions with the active site amino acid residues of SARS-CoV-2 Mpro similar to the reference compound. Results obtained from this study showed that momordicine and momordiciode F2 exhibited good inhibition potential (best MMGBA-binding energies; −41.1 and −43.4 kcal/mol) against the M(pro) of SARS-CoV-2 when compared with FDA reference anti-viral drugs (Ribavirin, remdesivir and hydroxychloroquine). Thus, among the 86 phytocompounds and 3 antiviral drugs screened (Supplementary material Table S1 ), 6 phyto ligands exhibited appreciable binding energies against the SARS-CoV-2 M pro and strong interactions within the binding pocket. Analysis of the per-residue additional showed that studied compounds interact with these key amino acid residues in the active site of the main protease, suggesting that these phytocompounds could emerge as ideal candidate''s inhibitors against SARS-CoV-2 M pro and another virus protease.
cord-260215-gsnjlhjd	2016	
cord-261170-arnwk287	2017	
cord-261311-j6bmgmhz	2020	COVID-19 patients may present high risk in the use of medications and clinical pharmacists can contribute substantially as part of a multidisciplinary team to improve outcomes in drug therapy in severe and critical illness. The course of an intense inflammatory process leads to alterations in many Review of patients'' medical history Provision of real-time assessment and evidence-based (when possible) advice on drug therapy Support on safe use of medications brought from home Medication reconciliation at different levels of transition of care Simplification of drug administration schedule to reduce the exposure of nurses to COVID-19 patients Monitoring of potential drug-drug, drug-food interactions and adverse drug reactions Adjustments in dosing regimens according to liver and kidney functions Prevention of medication errors Optimization of drug therapy and electrolytes to minimize the risk of prolonged corrected QT intervals and torsade de pointes Support on lung-protective ventilation and neuromuscular blocking agents to facilitate ventilator synchrony Provision of conservative fluid strategies and monitoring of vasopressors use Monitoring of empirical antibiotics for suspected bacterial co-infection with rigorous de-escalation Employment of FASTHUG-MAIDENS mnemonic to identify drug-related problems in intensive care units Support on drug information to patients and multidisciplinary teams, following biosafety protocols Considerations on special situations (pediatrics, older adults, people with chronic diseases, allergies) Research and continuing education Precise documentation of pharmaceutical interventions laboratory tests in patients with acute or severe/critical illness.
cord-262442-kjgpriow	2013	The quercetin SLMs were characterised for morphology, drug loading (15.5% ± 0.6, which corresponded to an encapsulation efficiency of 71.4%), particle size distribution, response to humidity, crystallinity, thermal behaviour and in vitro respirable fraction. Furthermore, the toxicity and the in vitro transport of the SLMs on an air liquid interface model of the Calu-3 cell line were also investigated using a modified twin-stage impinger apparatus. RESULTS: Results showed that quercetin SLMs could be formulated as dry powder suitable for inhalation drug delivery (20.5 ± 3.3% fine particle fraction ⩽4.46 μm) that was absorbed, via a linear kinetic model across the Calu-3 monolayer (22.32 ± 1.51% over 4 h). A modified in vitro aerosol testing apparatus (twin stage impinger TSI, Radleys, Essex, UK) that allows the attachment of a Transwell containing Calu-3 epithelial cells was used to study the mechanis m of drug deposition, dissolution and diffusion/transp ort (Haghi et al., 2010 (Haghi et al., , 2012 .
cord-263074-qxiynbl2	2020	
cord-263312-x7f0hn7f	2013	
cord-263803-0n41gylj	2020	
cord-263840-1t4ykc01	2020	Summary The rapid and global spread of a new human coronavirus (SARS-CoV-2) has produced an immediate urgency to discover promising targets for treatment of COVID-19. Here, we review current information concerning the global health issue of COVID-19 including promising approved drugs and ongoing clinical trials for prospective treatment options. At the genome 60 level, SARS-CoV-2 has 79·5% homology to SARS CoVCoV-2 and other coronaviruses, and its relative ease of sample acquisition and study, it has been widely 75 accepted that drug repositioning is a promising approach to make available an effective, safety-assured 76 treatment in a timely manner. In this review, we summarize diagnosis approaches, risk groups, available 77 treatment options, and drug repositioning studies related to COVID-19. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 525 2019 (COVID-19): The experience of clinical immunologists from China
cord-263874-q0egnzwf	2020	
cord-264779-71s7e18i	2020	
cord-264867-ezsy76mx	2020	
cord-265699-0socw0hp	2020	
cord-265848-afkeuwup	2007	With the use of drugs having a short duration of action, RSI also is advantageous because it is a measure that permits temporary airway control for the patient with mildly compromised airway reflexes who requires gastrointestinal decontamination (lavage followed by activated charcoal administration) but who does not require prolonged intubation. The management of gastrointestinal disturbance in the toxic patient includes following the general principles of blood, fluid, and electrolyte resuscitation, when indicated; judicious use of parenteral antiemetics to control persistent vomiting; specific measures such as antidotal therapy (e.g., in iron or organophosphate poisoning); or interventional therapy, such as charcoal hemoperfusion (in theophylline overdose) or hemodialysis (in lithium overdose), when indicated.
cord-266294-ua22udlc	2010	
cord-267608-0odu8lus	2020	Accordingly taking the advantage of interim analysis based on novel biomarker approach for detecting the pathogenesis-specific molecular alteration(s), an adaptive clinical study can select the drug-sensitive sub-population from patients with initially targeted disease or an alternative indication, to continue the investigation for an optimized therapeutic efficacy [7] . While human bioequivalence study is increasingly contributing to evaluation of emerging formulation and bio-similar agents besides chemical generics [4] , several adaptive trial designs have been capable of translating the scientific breakthroughs into novel therapeutic benefits with shorter processing time and lower financial costs, to address the unmet clinical needs [3, 19] . Of note, to preserve the strength of clear defining efficacy and safety of tested drugs, the innovative designs of clinical study are substantially overlapped with classic trial protocols of three phases which still serve as the mainstream approach of clinical investigation [3, 7] .
cord-267979-k70gnrdw	2020	This Special Issue brings together recent advances in the areas of inhalation device testing, aerosol formulation development, use of in vitro and in silico models in pulmonary drug deposition and drug disposition studies, and pulmonary delivery of complex drugs, such as vaccines, antibiotics and peptides, to or via the lungs. The development of modern-day inhalers, e.g., pressurised metered-dose inhalers (pMDIs) and more recently, dry powder inhalers (DPIs), jet and vibrating mesh nebulisers (VMNs), and soft mist inhalers (SMIs), has given pulmonary drug delivery a momentum boost that transformed a therapeutic niche into a market predicted to hit US$41.5 billion by 2026 [1] . Development of an innovative, carrier-based dry powder inhalation formulation containing spray-dried meloxicam potassium to improve the in vitro and in silico aerodynamic properties Excipient interactions in glucagon dry powder inhaler formulation for pulmonary delivery Inhalable dry powder of bedaquiline for pulmonary tuberculosis: In vitro physicochemical characterization, antimicrobial activity and safety studies
cord-268088-y4vg7frb	2020	Among the natural compounds that produce beneficial effects on human health, polyphenols have shown potential therapeutic applications in cancer due to their protective functions in plants, their use as food additives, and their excellent antioxidant properties. This review shows a wide range of trials in which polyphenolic compounds play a crucial role as anticancer medicines alone or in combination with other drugs at different stages of cancer: cancer initiation, promotion, and growth or progression. In point of fact, studies demonstrated that resveratrol has in vitro effects against a large range of human tumors: breast, skin, ovary, stomach, prostate, colon, liver, pancreas, cervix, thyroid carcinoma cells, lymphoid, and myeloid cancer cells [22] . In point of fact, studies demonstrated that resveratrol has in vitro effects against a large range of human tumors: breast, skin, ovary, stomach, prostate, colon, liver, pancreas, cervix, thyroid carcinoma cells, lymphoid, and myeloid cancer cells [22] .
cord-268283-eja8fkwv	2020	
cord-270516-9ol1209i	2016	
cord-270622-aofva2ab	2020	
cord-272060-o0wx0add	2020	
cord-273656-xo82zyi6	2020	
cord-273716-vv3pyft4	2007	This review will focus on nanoscale bioactive delivery and targeting mechanisms and the role of high-resolution imaging techniques in the evaluation and development of nanocarriers. Applications of nanotechnology in medicine are particularly promising and areas such as molecular imaging, disease diagnosis, bioactive encapsulation and targeted delivery at specific sites in the body are being intensively investigated and some products undergoing clinical trials (Moghimi et al., 2005; Shaffer, 2005; Wilkinson, 2003) . Usefulness of high-resolution scanning probe imaging in the study of lipidic gene transfer vectors and the interaction between liposomes and DNA molecules have recently been reviewed by Mozafari et al. Modern nanocarrier systems such as nanoliposomes, niosomes, solid lipid nanoparticles (Saupe and Rades, 2006) , as well as silicon-, carbon-and polymer-based nanocarriers play an important role in controlled delivery of the bioactive agents to the desired site of action, limiting the side effects at nontarget sites (Ruozi et al., 2007) .
cord-273941-gu6nnv9d	2017	
cord-274307-kl0uvrbw	2020	
cord-274401-pjyvg53w	2020	
cord-274474-u2fdicgz	2020	The present review summarizes recent advances in the development of nanocarrier based therapeutics for local and targeted delivery of drugs, nucleic acids and imaging agents for diagnostics and treatment of various diseases such as cancer, cystic fibrosis, and coronavirus. [1, 2] Therefore, methods of developing new therapeutic solutions as well as improving the current therapies for the common lung diseases such as asthma, cystic fibrosis, chronic obstructive pulmonary disease, lung cancer, and coronavirus infections remain the main focus in the fields of targeted drug delivery. In this review, we will summarize recent reports on the development of lipid and polymer based nanocarriers for targeted delivery of drugs and nucleic acids for the treatment of lung cancer. In a similar study, we used a complex liposomal drug delivery system containing anticancer drug doxorubicin and both MRP1 and BCL2 targeting antisense oligonucleotides for inhalation treatment in lung cancer cells.
cord-275772-pmf6stua	2020	Drug repositioning lies in repurposing an active pharmaceutical ingredient that is already on the market for a new indication. This original definition of drug repositioning has since been extended to include active substances that failed the clinical phase of their development on account of their toxicity or insufficient efficacy, as well as drugs withdrawn from the market because of safety concerns. Instead, repositioning makes use in a new indication of either the biological properties for which the drug has already been approved (possibly according to a different formulation, at a new dose or via a new route of administration), or the side properties of a drug that are responsible for its adverse effects. This example illustrates how even drugs with an exceptionally poor toxicity profile can be repositioned if the new indication is a rare disease (the estimated incidence of leprosy is 250 000 cases per year according to http://www.orpha.net, accessed November, 21th 2019). Drug repositioning: identifying and developing new uses for existing drugs
cord-275827-r86ygqmy	2020	
cord-275828-c6d6nk7x	2016	-SBT/ABPC, intravenous drip, 3 g/3e4 times a day -CTRX, intravenous drip, 1 g/twice a day or 2 g/once a day -CTX, intravenous drip, 1e2 g/2e3 times a day -LVFX, intravenous drip, 500 mg/once a day (2) Cases of late-onset hospital-acquired pneumonia or ventilator-associated pneumonia in which the risk of resistant bacteria is high An antimicrobial drug with anti-pseudomonal activity that targets non-glucose-fermentative gram-negative rod should be administered [50, 51, 68] -To treat polymicrobial infection, the administration of an antimicrobial drug with an activity against obligate anaerobe is not always necessary [67, 70] . -SBT/ABPC, intravenous drip, 3 g/3e4 times a day -CTRX, intravenous drip, 2 g/once a day or 1 g/twice a day -CTX, intravenous drip, 1e2 g/2e3 times a day -LVFX, intravenous drip, 500 mg/once a day (2) Late-onset hospital-acquired pneumonia or cases in which there is a risk of multi-drug-resistant bacteria In addition to the above pathogens, the involvement of non-glucose-fermentative gram negative bacteria or ESBLproducing enteric bacteria must be considered. For the treatment of immunodeficiency-/blood disease-related pneumonia in children, antimicrobial drug therapy should also be basically selected, considering causative microorganisms.
cord-276886-vcmkz8lh	2020	
cord-277535-u283k70i	2020	
cord-278362-pwi48i20	2020	
cord-279106-3ffa9djf	2020	
cord-280158-3fhhuzg5	2020	
cord-280819-z6ucnwk0	2020	
cord-281561-r10y2sgb	2020	
cord-283287-073r80s7	2020	
cord-283956-zgrtux7i	2020	
cord-284208-8fsqgkw5	2008	
cord-284479-75zgljet	2019	
cord-284648-yznlgzir	2020	Albumin is the most abundant protein in human plasma and has a set of properties that make it a unique molecular carrier for drugs: (i) it is a natural physiological carrier of native ligands and nutrients; (ii) it bypasses systemic clearance and degradation by the body''s own innate mechanisms, so that it has an exceptionally long half-life of 19 days in humans, and similarly long half-lives in most animal species [123] [124] [125] [126] ; (iii) it preferentially accumulates at sites of vascular leakiness; (iv) it is highly internalized and metabolized by rapidly growing, nutrient-starved cancer cells; and (v) it is biodegradable and has no known systemic toxicity. Other notable examples of albumin-based delivery systems involve the genetic fusion of ABD to various therapeutic proteins including affibodies [165, 166] , human soluble complement receptor type 1 [167] , single chain antibody-drug conjugates [168] , insulin-like growth factor II [169] , immunotoxins [170] , and respiratory syncytial virus subgroup A (RSV-A) G protein (G2Na) [171] .
cord-285121-3cjr1rol	2018	
cord-285603-f4572w5m	2020	In order to gain a deeper understanding if the pharmacokinetic parameters of the SARS-CoV2 protease inhibitors could be related to positive outcomes in the therapy, we analyzed the ADME parameters of famotidine and compared with several known antiviral drugs such as ribavirin, lopinavir, and nafamostat, which were evaluated against SARS-CoV2. Chemical structures and administration, distribution, metabolism, and elimination (ADME) parameters for famotidine, ribavirin, lopinavir, and nafamostat, drugs that were evaluated as SARS-CoV2 inhibitors, are shown. Chemical structures and administration, distribution, metabolism, and elimination (ADME) parameters for famotidine, ribavirin, lopinavir, and nafamostat, drugs that were evaluated as SARS-CoV2 inhibitors, are shown. Altogether, in this study, we showed that famotidine could be used as an antiviral agent against SARS-CoV2, targeting proteases involved in the virus replication, mostly the main protease, as well as the viral PLpro and human host Tmprss2.
cord-287758-da11ypiy	2020	
cord-288026-vcp8o5xn	2020	PLA has shown promise as a biomaterial in a plethora of healthcare applications such as tissue engineering or regenerative medicine, cardiovascular implants, dental niches, drug carriers, orthopedic interventions, cancer therapy, skin and tendon healing, and lastly medical tools / equipment. Blending with PLA-based stereocomplexed polymers, such as PLLA and PLDA, has demonstrated improved thermal stability and decelerated degradation rate. Manufacturing techniques may take advantage of the strong interactions between PDLA and PLLA blocks, which result from the formation of stereocomplex crystallization as well as improved mechanical properties and thermal stability. Degradation rate is dependent upon a number of factors: polymer composition, pH, device geometry, molecular weight, crystallinity, addition of drugs and/or additives, sterilization, mechanical stress, and fabrication processing. This is likely due to the controlled drug release and enhanced anti-tumor effects seen in doxorubicin-loaded PLA-based scaffolds, such as the one described by Niu et al. Effect of molecular weight and crystallinity on poly(lactic acid) mechanical properties
cord-289321-ahl46ql9	2018	Differential visualization of drug-resistant and -susceptible RNA genomes within cells revealed that resistant variants of NS3/4A protease and NS5A phosphoprotein are cis-dominant, ensuring their direct selection from complex environments. Our goal was to screen the HCV-encoded viral proteins that are current targets of antiviral compounds to determine the intracellular dominance relationships between drug-resistant and drug-susceptible genomes. To test whether susceptibility to NS5A inhibitors was dominant in the context of viral infections, we analyzed U, S, S + R and R cell populations by flow cytometry as previously performed for the NS3/4A inhibitor in Figure 3 . To test whether exogenously expressed drug-susceptible NS5A proteins could co-assemble with drug-resistant NS5A, we utilized the previously described HCV plasmid that expresses HA-tagged and GFP-tagged NS5A within the same polyprotein but does not support genome replication ( Figure 5A) . Failure of NS5A proteins to mix during infection is a likely explanation for the cis-dominance of drug resistance observed in cultured cells (Figure 4) .
cord-289382-bnl9i9oy	2010	
cord-291180-xurmzmwj	2020	
cord-292041-a65kfw80	2020	At present, there is no vaccine or effective standard treatment for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection (or coronavirus disease-19 (COVID-19)), which frequently leads to lethal pulmonary inflammatory responses. Therefore, due to its poly-pharmacology, fenretinide administration by pulmonary formulations may be expected to be protective against acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS) caused by SARS-CoV infection and could represent a useful tool in a multimodal therapy aimed at establishing a rapid anti-inflammatory and antiviral effect. Pulmonary delivery of fenretinide could be a valuable tool in COVID-19 due to the possibility of obtaining a very high drug concentration in the airway and alveolar epithelia, thus triggering a rapid onset of local anti-inflammatory response. Moreover, the pulmonary administration of fenretinide, in combination with the drugs that are currently used in SARS-CoV-2 infection, could represent a new, effective tool in COVID-19 treatment.
cord-293860-6kz0iws6	2020	
cord-294582-flkjekyo	2020	
cord-295807-68sukdb1	2020	
cord-297010-imciixde	2020	81 Similar doses of the two drugs produced 11-fold variations in the blood concentrations in patients with rheumatoid arthritis 47, 63, 82, 83 and in healthy volunteers, 52, 64 suggesting different extend of metabolism among individuals. Determination of CYP3A, CYP2C8 and CYP2D6 polymorphism and, therefore, activity is important to establish safe and efficient dosing of chloroquine and hydroxychloroquine for treatment of COVID-19 patients. 125 Overall, the results suggest that CYP2C8, CYP2D6 and CYP3A genetic polymorphisms may influence chloroquine and hydroxychloroquine pharmacokinetics and COVID-19 patients treated with the same dose of CQ or HCQ may exhibit lack of efficacy or adverse reactions. Despite the evidence of the influence of genetic polymorphisms on the pharmacokinetics of chloroquine and hydroxychloroquine, no large pharmacogenomics studies have been conducted to provide guidance on the use, dosing, and duration of the therapy in COVID-19 patients.
cord-298033-kzdp9edn	2019	Quasispecies dynamics in disease prevention and control following statement will be obvious to the reader: "If a single mutation is able to confer resistance to an antiviral agent, and the mutation does not cause a significant selective disadvantage to the virus (fitness decrease) in the considered environment, a drug-resistant virus mutant will be present in most, if not all, virus populations" (Domingo, 1989) . The phenotypic barrier to drug resistance is equivalent to the fitness cost inflicted upon the virus by the mutations and corresponding amino acid substitution(s) required for resistance [Fitness cost is treated in Chapter 4 (Section 4.6) and in Chapter 7 (Section 7.4.2) in connection with the frequency of monoclonal antibody-or cytotoxic T-cell-escape mutants in viral populations]. For viruses that replicate in cell culture, it is possible to estimate the minimal viral population size needed to select a drug-resistant mutant which is generally positively correlated with the genetic barrier ( Fig. 8.5 ).
cord-298369-66ifwtlp	2018	The importance of plasma protein binding primarily resides in its impact on pharmacokinetic properties such as clearance (CL) and volume of distribution (V ss ), with serum albumin, lipoproteins and alpha-1 acid glycoprotein (AAG) being the major proteins involved in sequestering drugs in plasma (1) . While AAG represents a relatively small portion (~1-3%) of the total plasma proteins, compared to~60% composition of albumin, it can play a significant role in drug binding and pharmacokinetics (PK) (43) . Since AAG levels increase in most disease states (46) , drugs with a high affinity may demonstrate higher binding (lower fraction unbound, f u ) and altered PK properties (e.g. lower total CL), lower V ss . Effect of the plasticizer DEHP in blood collection bags on human plasma fraction unbound determination for Alpha-1-Acid Glycoprotein (AAG) binding drugs
cord-299225-exbdg3x9	2018	These results confirm the safety of cholesterol-triglyceride carrier systems for subcutaneous drug delivery in laboratory animals and suggest that this model may be used to study long-term effects of opiate therapy. We examined the safety of cholesterol-triglyceride suspensions of buprenorphine in mice and rats using US Food and Drug Administration (FDA) Target Animal Safety (TAS) drug-development protocols. Histopathology examinations were performed on mice and rats treated with up to tenfold excess of the intended dose of drug and control animals following 4-and 12-day drug trials [19] [20] [21] . The label dose of 0.65 mg/kg of buprenorphine, which provides 2-3 days of clinically significant blood levels of drug, was established in bioequivalence trials and efficacy studies using male and female rats [21] . The objective of this study was to evaluate the long-term safety of a lipid suspension of buprenorphine for delivery of an opiate analgesic in female F344 rats.
cord-299400-j18pj11d	2020	We propose that the antiviral activity of (hydroxy)chloroquine and azithromycin is shared among all strong lysosomotropic drugs and is a consequence of their extremely high accumulation in cells and membranes, and subsequently of all the processes affected by this pharmacokinetic property. Among listed drugs with antiviral effects, the CADs include: psychoactive drugs (chlorpromazine, fluoxetine, clomipramine); antiarrhythmics (amiodarone); antimalarials (chloroquine, hydroxychloroquine, amodiaquine, mefloquine, quinacrine); channel blockers (amiodarone, verapamil, manidipine); antibacterial (azithromycin); estrogen receptor modulators (tamoxifen, raloxifene, toremifene); two antivirals, the only ones known to utilize CADs mechanism of J o u r n a l P r e -p r o o f antiviral action via the inhibition of endosomal pathway (arbidol (umifenovir) and tilorone (with additional activity of interferon induction)) (Boriskin et al., 2008 , Ekins et al., 2018 .
cord-299424-qy3lccjq	2020	
cord-299911-v95pf3eg	2020	Based on the conclusions drawn from the currently rapidly evolving knowledge about COVID-19, our hypothesis is built on the potential modulation of CYPs activity by the inflammatory environment provoked by SARS-CoV-2 infection, as well as the pathologic involvement of the liver which harbors the majority of the drug metabolizing enzymes (DMEs). Systemic inflammation and immune response represent a substantial element in many acute and chronic diseases which is strongly implicated in altering drug pharmacokinetics through, mainly, modulating the expression and activity of DMEs. As a main contributor to the metabolic biotransformation of most drugs, CYPs are widely involved in such disease-drug interactions [19] . For decades, IL-6 has been recognized as the major inflammatory element that provokes a significant repressive effect on the expression and activity of different CYPs. Human recombinant interleukin 6 (rhIL-6) has shown concentration-dependent blocking of phenobarbital-mediated induction of CYP2B1/2 mRNA and activity in rat hepatocytes [48] .
cord-301026-spgidqh3	2020	
cord-302018-3rlya16w	2020	The topics covered in this issue provide the necessary and updated knowledge for all allergists involved in labeling and delabeling procedures, aiming to broaden drug choices and treatment options for patients in this unknown world of COVID-19 pandemic and other disease states. Target populations for receiving a drug allergy label include the following: (1) children with approximately 70,000 visits to the emergency department reported annually for adverse drug events with penicillins, cephalosporins, and sulfamethoxazole-trimethoprim as the most frequent medications; and (2) hospitalized patients with cancer, of whom 23% have a label of antibiotic allergy. The authors concluded that current and future efforts should focus on preventing penicillin allergy labels that can carry over into adulthood, providing education and decision support in the electronic medical record, and testing low-risk drug administration strategies in low-risk patients. As more mechanisms of drug allergy are uncovered and new biomarkers become available, they can be incorporated into this flexible classification, guiding clinicians toward an optimal approach for patient labeling or delabeling, treatment, and management.
cord-302312-1pm17l5d	2017	
cord-302947-flgwxc57	2020	
cord-303089-fbxtj8ij	2015	
cord-303237-xvba5mqq	2020	
cord-303555-mwu72q7w	2020	Thus, by the mid-to late-1980s a large body of literature existed which argued that signal transduction pathways consisted of a receptor linked to a large GTP-binding protein which in turn regulated an enzyme that generated "second messengers;" the second messengers would then diffuse throughout the cytosol activating cellular processes, predominantly for metabolism. For the EGFR and other subsequently discovered membrane associated tyrosine kinases, e.g. the non-receptor SCR family and the fibroblast growth factor receptor (FGFR) family, understanding how these enzymes signaled into the cell again initially rested on studies using traditional biochemical methods. [71] [72] [73] [74] [75] [76] Contemporaneously with these studies, researchers were determining how receptor tyrosine kinases regulated RAS family small GTP binding proteins, and other groups determining how RAS proteins signaled downstream off the plasma membrane and into the cytosol.
cord-303865-vd3qr32o	2020	
cord-304506-6el2ryl8	2020	In this work, we examine the hypothesis that these drugs act primarily as mechanism-based inhibitors by comparing hydrated excess proton stabilization during proton transport in M2 with the interactions revealed in the crystal structures, using the Multiscale Reactive Molecular Dynamics (MS-RMD) methodology. Along with an earlier qualitative MD simulation study that guided the design of the spiro-adamantyl amine inhibitors, 44 the crystallographic analysis provided potential insights into the mechanism of inhibition, suggesting that the backbone carbonyls of pore-lining residues act as "physiochemical chameleons", able to engage in both hydrophobic and hydrophilic interactions, and that the drug is tilted off the channel''s axis and interacts with waters in the Ala30 layer. Most recently, we further analyzed the MS-RMD simulations to explore the detailed interactions between the hydrated excess proton and the channel and found that the proton dynamically, as a function of its position, alters several properties of the protein and pore waters, including the hydrogen bonding network and the protein structure.
cord-304617-5ozf18lg	2020	
cord-308994-4nljzm8a	2020	We focus specifically on SARS-CoV-2 and the detailed role that nanotechnology can play in addressing this pandemic, including i) using FDA-approved nanomaterials for drug/vaccine delivery, including further exploration of the inhalation pathway; ii) introducing promising nanomaterials currently in clinical trials for drug/vaccine delivery; iii) designing novel biocompatible nanomaterials to combat the virus via interfering in its life cycle; and iv) promoting the utilization of nanomaterials in pneumonia treatment. To summarize, the advantages of nanotechnology in antiviral research include the following: 1) promotes the delivery of water-insoluble drugs; [39] 2) enhances the circulation time of drugs in vivo; [40] 3) achieves co-delivery of drugs; [40] 4) improves drug utilization efficiency and reduce side effects through targeting antibody modification; [41] 5) protects DNA and mRNA vaccines, overcoming bottlenecks for in vivo applications; [42] and 6) the physicochemical properties of nanomaterials can also be employed directly against viruses.
cord-309025-jo0rqy3y	2020	
cord-309871-y17puao2	2020	title: Intracellular ABCB1 as a Possible Mechanism to Explain the Synergistic Effect of Hydroxychloroquine-Azithromycin Combination in COVID-19 Therapy The first one is related to the inverted influx transport of ABCB1, meaning that the azithromycin molecules, in addition to their passive diffusional uptake, are actively captured and trapped inside the vesicles, even if the vesicular intraluminal pH increases and the percentage of protonic drug molecules decreases enabling the backward diffusion of neutral species to the cytosol (Fig. 1) . To sum up, the intracellular ABCB1 could represent a potent target for enhancing the antiviral and antiinflammatory activities of the aminoquinolines when lysosomotropic ABCB1 substrates like azithromycin or ciprofloxacin are combined. In conclusion, we hypothesize that the intracellular ABCB1 may serve as a possible new target for improving the effects of the aminoquinolines when co-administered with a lysosomotropic drug, such as azithromycin or ciprofloxacin in COVID-19 chemotherapy.
cord-311730-189vax2m	2020	The SNS exists under the authority of the United States Department of Health and Human Services (HHS) and accepted 30 million doses of hydroxychloroquine sulfate donated by Sandoz™, the Novartis™ generics and biosimilars division, and one million doses of chloroquine phosphate donated by Bayer Pharmaceuticals™ for potential use in treating patients who were hospitalized with COVID-19 or for use in clinical trials. The adverse effects associated with taking hydroxychloroquine are similar to those observed with chloroquine and include nausea, vomiting, diarrhea, AV conduction defects, a prolonged QTc interval with torsades de pointe ventricular tachycardia, hypokalemia, hypotension and circulatory collapse. Similarly, patients with Covid-19 for whom a clinician believes that either chloroquine or hydroxychloroquine is indicated must receive information, preferably in the form of a fact sheet that clearly summarized the dose, duration of treatment, potential risks, side-effects and drug-drug interactions.
cord-313268-j51zyodw	2020	
cord-314827-yqr7110e	2020	Since HCC almost exclusively develops in patients with chronic liver diseases, injury of liver cells can promote the progression to HCC over a long period of time [11] driven by a number of cytokines and inflammatory mediators along with aberrant activity of several signaling pathways, as shown in Fig. 8 .1 (will be discussed later). Successful stories of drug repurposing for cancer therapy in hepatocellular carcinoma and HBV-and HCV-related proteins induction are among the mechanisms by which the Ras/ Raf/MAPK pathway can be activated toward HCC development [30] . Successful stories of drug repurposing for cancer therapy in hepatocellular carcinoma (genetically induced liver tumors and patientderived xenografts [PDXs]) for HCC to show significant reduction in the tumor growth after oral administration of NEN compared to niclosamide. Successful stories of drug repurposing for cancer therapy in hepatocellular carcinoma phenotypic events starting with induction of cell cycle arrest at G0/G12 phase accompanied with significant reduction in cell growth with elevated levels of KLF6/p21 protein content in HepG-2 cell line.
cord-315702-pn8247j2	2020	
cord-315918-12rbbe8c	2019	To test the inhibitory activity of a new antiviral agent, it is first necessary to select the host cell system(s) in which the virus replication can be measured. (d) Assay systems based on the measurement of specialized functions and viral products; a number of viruses do not produce plaques nor do they cause CPE readily, but they may be quantified by certain specialized functions based on their unique properties, for example, hemagglutination and hemadsorption tests used to study the antiviral activity against myxoviruses and ELISA, used to determine the extent of virus replication and, thus, obtain a measure of the inhibitory effect of various antiviral agents on virus replication, etc. On the other hand, the antiviral activity is determined by comparing the virus titers of infected cells, which have been cultured with a maintenance medium containing plant extracts or test substances and a maintenance medium without test material (Colegate and Molyneux, 1993) .
cord-316029-z708c3ex	2020	This review will offer key clinical pharmacology considerations for developing small molecules for the treatment of COVID-19 based on the major disease complications that impact drug absorption, distribution, metabolism, and elimination (ADME). Of major concern is sepsis, defined as "life-threatening organ dysfunction caused by a dysregulated host response to infection." 12 In 1 study, septic shock, which is distinguished by persistent hypotension, elevated serum lactate levels, and increased mortality, was a complication in about 6% of severely ill COVID-19 patients. For water-soluble investigational therapies that are intended for administration in the severely ill COVID-19 population, thought should be given to targeting serum drug concentrations and the drug''s exposure-response profile when determining if increased doses would be beneficial for patients receiving intravenous fluids. 21 The clinical impact of these potential changes in free drug fractions on investigational therapies that are highly proteinbound is an important consideration when empirically selecting doses for critically ill COVID-19 patients.
cord-316792-89f8g0m8	2020	Over the course of evolution, toxins with exceptional specificity and high potency for their intended molecular targets have prevailed, making venoms an invaluable and almost inexhaustible source of bioactive molecules, some of which have found use as pharmacological tools, human therapeutics, and bioinsecticides. Current biomedically-focused research on venoms is directed towards their use in delineating the physiological role of toxin molecular targets such as ion channels and receptors, studying or treating human diseases, targeting vectors of human diseases, and treating microbial and parasitic infections. Since many venoms and toxins exert these biological effects through actions on cell membranes, receptors and ion channels, high-throughput techniques assessing changes in cellular signalling have proven particularly insightful. Spider-venom peptides have been crucial for uncovering the key role of ASICs in stroke-induced brain damage, and validating these channels as a target for neuroprotective drugs [134] [135] [136] [137] .
cord-317435-4yuw7jo3	2020	
cord-317971-kuwargnp	2020	
cord-317993-012hx4kc	2020	SIMPLE SUMMARY: This commentary focuses on the methods currently available to test the efficacy and safety of new orally inhaled drugs for the treatment of uncurable respiratory diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis or lung cancer, prior to entering human experimentation. Inhalation is the preferred administration method for treating respiratory diseases [13] , as: (i) it delivers the drug directly at the site of action, resulting in a rapid therapeutic onset with considerably lower drug doses, (ii) it is painless and minimally invasive thus improving patients'' compliance, and (iii) it avoids first-pass metabolism, providing optimal pharmacokinetic conditions for drug absorption and reducing systemic side effects [14] [15] [16] . In the context of OID preclinical testing, lung organoids can be used for modeling respiratory diseases and, therefore, as a platform for screening the efficacy of inhalation therapies [115, 116] .
cord-318048-6nvi63rq	2020	An indication of the degree to which candidate drugs are expected to accumulate in lung (a presumed site of primary efficacy and for prevention of SARS-CoV-2 infection) was provided by calculation of unbound Accepted Article lung to plasma tissue partition coefficient (K p U lung ) according to the methodology of Rodgers and Rowland (20-22). All rights reserved Simulated exposure relative to reported anti-SARS-CoV-2 activity in lung and other tissues Lung K p U was simulated for all molecules for which the necessary physicochemical properties and in vitro drug binding information were available. The rank order of lung Cmax/EC 90 ratio was chloroquine > atazanavir (ritonavir boosted) > tipranavir (ritonavir boosted) > hydroxychloroquine > mefloquine > ivermectin > lopinavir (ritonavir boosted) > azithromycin > nitazoxanide > ritonavir > gilteritinib > amodiaquine > imatinib > oxprenolol (data excluded due to this analysis only being possible for 33 of the 56 drugs).
cord-320172-qw47pf9r	2000	In common with other changes induced in the digestive tract of rats and cynomolgus monkeys by the administration of recombinant human epidermal growth factor, the tongue showed squamous epithelial hyperplasia characterised by a uniform increase in the thickness of the squamous epithelium in both species (Breider et al., 1996; Reindel et al., 1996) . Detailed study of hypertrophy, protein synthesis, and intracellular cAMP activity in the salivary glands of rats treated for 10 days with isoprenaline (isoproterenol), a series of β-adrenergic receptor agonists and the phosphodiesterase inhibitors, theophylline and caffeine, showed that similar effects occurred with all agents although differences in the degree of hypertrophy, the nature of pro-tein and glycoprotein synthesis and Golgi membrane enzyme activity were recorded (Wells and Humphreys-Beher, 1985) . Studies in the rat have shown that diffuse atrophy of the gastric glands characterised by a decrease in the number and size of parietal, chief and mucous cells occurs transiently following truncal vagotomy but histological features return to normal by about 1 month after surgery (Nakamura, 1985) .
cord-321230-b5a1z14w	2020	
cord-321267-ihd30qi0	2020	
cord-321379-7bpl5n3j	2020	
cord-321657-2s1npse5	2020	4 In this paper, we used mathematical modeling to investigate the dynamics of the viral infection/replication inside a human host, in particular, the influenza and the SARS-CoV-2 virus, as well as the interactions of target cells with the innate and AIRs. Our model suggests that most of the differences between the two types of infections can potentially be attributed to the timing mismatch between the two immune responses. More specifically, influenza is a very acute infection; all vulnerable cells are completely depleted and viruses are more or less cleared by the innate immune response, before the adaptive immune response (AIR), which has a transient nature, reaches a significant level. We proposed an immune-suppressing treatment based on the leanings of our modeling study, which is to apply immunosuppressive drugs during the early phase of infection to reduce the AIRs to a level low enough not to interfere with the innate immune response.
cord-321741-aq76s37x	2020	Although the concept of BSAAs has been around for almost 50 years, the field received a new impetus with recent outbreaks of Ebola, Zika, Dengue, influenza and other viral infections, the discovery of novel host-directed agents, as well as development of drug repositioning methodology. The discovery of novel activities of BSAAs starts with exposing cells to the candidate antiviral agent at different concentrations and infecting the cells with a virus or mock. Given that emetine also inhibits ZIKV, EBOV, RABV, CMV, HCoV-OC43 and HIV-1 infections (Chaves Valadao et al., 2015; MacGibeny et al., 2018; Mukhopadhyay et al., 2016; Shen et al., 2019; Yang et al., 2018) , and that it is an FDA-approved anti-protozoal drug, it may represent a promising safe-in-man BSAA candidate. Thereby, novel antiviral activities of BSAAs should be further validated in primary human cells using different viral strains (including wild-type viruses), different viral loads, different times of compound addition, different endpoint measurements and compound concentration range.
cord-322885-ob5euspo	2020	One Sentence Summary Radiation-damage-free high-resolution SARS-CoV-2 main protease SFX structures obtained at near-physiological-temperature offer invaluable information for immediate drug-repurposing studies for the treatment of COVID19. Radiation-damage-free SFX method which enables obtaining the novel high-resolution ambient-temperature structures of the binding pocket of Mpro provides an unprecedented opportunity for identification of highly effective inhibitors for drug repurposing by using a hybrid approach that combines structural and in silico methods. We determined two radiation-damage-free SFX crystal structures of SARS-CoV-2 Mpro in two crystal forms at 1.9 Å and 2.1 Å resolutions with the following PDB IDs: 7CWB and 7CWC, respectively (Fig. 1A, B) (Supplementary Table 1&2 The diffraction data collected remotely at the MFX instrument of the LCLS at SLAC National Laboratory, Menlo Park, CA (Sierra et al., They reveal novel active site residue conformations and dynamics at atomic level, revealing several differences compared to the prior ambient-temperature structure of SARS-CoV-2 Mpro that was obtained at a home X-ray source (Fig. 1A, B ).
cord-322915-zrjx31ev	2009	Evidence of the importance of natural products in the discovery of leads for the development of drugs for the treatment of human diseases is provided by the fact that close to half of the best selling pharmaceuticals in 1991 were either natural products or their derivatives. In addition to the antibiotic-resistance problem, new families of anti-infective compounds are needed to enter the marketplace at regular intervals to tackle the new diseases caused by evolving pathogens. 28 Among the novel class of antimicrobial agents used in treating resistance to Gram-positive infections, we can also mention the cyclic lipopeptide antibiotic daptomycin produced by Streptomyces roseosporus. 44 Other applications include antitumor drugs, enzyme inhibitors, gastrointestinal motor stimulator agents, hypocholesterolemic drugs, ruminant growth stimulants, insecticides, herbicides, coccidiostats, antiparasitics vs coccidia, helminths and other pharmacological activities. Considering that animal health research and the development of new anti-infective product discovery have decreased, the discovery of new antibiotics has decreased over the past 15 years, with few new drug approvals.
cord-323940-ubazgvov	2020	
cord-324166-6ydn2bvy	2020	
cord-324660-w81jgw7p	2020	To the Editor: As noted by Choo and Rajkumar 1 in the June 2020 issue of Mayo Clinic Proceedings, the COVID-19 (coronavirus disease 19) pandemic has exposed extreme vulnerabilities in our nation''s drug supply chain. d Create a national database for tracking of essential drug supplies and use predictive analytics to identify surge, production problems, and future shortages. 1 As supply chain management leaders at Mayo Clinic, we appreciate the attention these authors draw towards the issue of drug shortages and drug costs. 5 Because of the high use of vasopressin in critically ill COVID-19 patients and the greater than 6000% price increase that has occurred after completing the Unapproved Drugs Initiative process, vasopressin will likely become a top 10 drug expense within the hospital sector by the end of 2020. The FDA Unapproved Drugs Initiative: an observational study of the consequences for drug prices and shortages in the United States
cord-325019-hznnoxw6	2020	
cord-325315-m3do6t1j	2020	Given the activation of the immune system syndrome induced by the virus and the widespread off-label use of this drug, we suggest a careful monitoring of skin and mucous membranes in all COVID-19 positive patients treated with hydroxychloroquine in order to early detect early signs of toxicities. Another salient aspect of the case is the favorable evolution of the patient given that this type of SCAR is typically associated with a bad prognosis [35] [36] [37] , even more so because the patient displayed all the negative typical prognostic factors also for COVID-19 [38] [39] [40] [41] , indeed the calculation of the severity-of-illness score for toxic epidermal necrolysis (SCORTEN) in our patient led to an estimated mortality rate of 58.3% (CI 36,6 -77,59) ( Table 2 ) [42, 43] .
cord-325473-hrdanbn1	2020	
cord-326922-bajpr5a2	2020	In the modern-day United States (US), medications are by-inlarge manufactured in commercial facilities, and this production is regulated and overseen by the US Food and Drug Administration (FDA). Furthermore, a new form of large-scale compounding has become commonplace, whereby pharmacies produce bulk volumes of medications which are not available commercially, and broadly distribute them to healthcare practices and individual patients. Patient harm caused by compounded medications has been the focus of media, medical, and legislative attention in recent years, especially following a multistate, multi-fatality outbreak of fungal meningitis caused by contaminated steroid injections compounded at a pharmacy in Framingham, MA [2, 3, 5, 6] . We categorized errors under the conceptual framework described by Sarah Sellers, PharmD, MPH, former board member for the FDA''s Advisory Committee on Pharmacy Compounding, in testimony to the US Senate Committee on Health, Education, Labor, and Pensions, namely, that "suprapotency," "subpotency," and "contamination" are the primary risks associated with pharmaceutical compounding [59] .
cord-328559-2qvxw896	2020	
cord-328705-024y5k72	2020	
cord-329318-eo8auo1f	2020	[Image: see text] Chemical similarity-based approaches employed to repurpose or develop new treatments for emerging diseases, such as COVID-19, correlates molecular structure-based descriptors of drugs with those of a physiological counterpart or clinical phenotype. In this study, we propose a novel set of drug screening descriptors based on COSMO-RS σ-profiles, augmented by dipole moment and induced charge of the phosphorus atom, to evaluate the chemical similarity of the drugs with nucleotides, as RNA replication transcription initiation activators. A novel set of descriptors based on COSMO-RS σ-profiles and chemical thermodynamics is proposed and evaluated using PCA for the initial screening of a series of nucleotides and nucleotide-analog RdRp replication inhibitor drugs to help accelerate the discovery of COVID-19 treatments. The PCA results show that the novel σ-profile-based descriptor set I clearly correlates the leading COVID-19 drugs remdesivir and EIDD-2801 in monophosphate forms and highlights weaker correlations with drugs that have been reported to exhibit anti-SARS-CoV-2 activity.
cord-329881-9vnz5zzg	2020	
cord-330380-wnbyy1gk	2016	With the improvement of high-performance technologies, HPC and supercomputers are being applied to an increasing number of emerging fields including deep learning, big data mining, computational finance, and precision medicine, with the expectation that it will accelerate innovation. A series of CDDD approaches based on the 3D structures of biological macromolecules (e.g. proteins and nucleic acids), such as the highthroughput virtual screening method, have greatly improved the efficiency of drug discovery. This review mainly focuses on the application of HPC to the field of drug discovery and molecular simulation at CAS in recent years, including several cases involving virtual screening (molecular docking), MD simulation, and protein folding. Taken together, our study not only demonstrated that the α-helix/β-sheet intermediate structures revealed by the aforementioned simulations could be used as a binding target for inhibitor design, but also provided new insights into the molecular events involved in the conformational transition of Aβ peptides in fibrillogenesis.
cord-331633-ix5un6c9	2020	
cord-332038-icyut3xa	2020	
cord-332271-slouuryl	2020	
cord-333122-xw8o189s	2020	
cord-333381-wz70o9tt	2020	
cord-334170-85x5vmyi	2020	title: Synthetic repurposing of drugs against hypertension: a datamining method based on association rules and a novel discrete algorithm RESULTS: A novel two-step data mining method, which is based on the If-Then association rules as well as a novel discrete optimization algorithm, was introduced and applied to the synthetic repurposing of drugs for HT. CONCLUSION: Since the proposed synthetic method uses medications in small dosages, it might revive some failed drug development projects and put forward a suitable plan for treating different diseases such as COVID-19 and HT. Based on the obtained results, it can be concluded that Trader (the newly introduced algorithm) is more efficient than the other state-of-the-art algorithms and proposes some better synthetic drug lists to treat HT. To discover the hidden applications of the existing drugs, a drug repositioning method, which is based on the newly introduced discrete optimization algorithm (Trader) and If-Then association rules, was proposed.
cord-334511-lx9608vy	2020	The nearly ubiquitous use of virtual screening is due to its efficiency in searching massive chemical databases in order to generate lead molecules [313] that inhibit protein-protein interactions [314] , and its ability to help identity ligand (drug) binding sites on the target of interest [310] to lend insight to the mechanisms of action for lead compounds [315, 316] . The nearly ubiquitous use of virtual screening is due to its efficiency in searching massive chemical databases in order to generate lead molecules [313] that inhibit protein-protein interactions [314] , and its ability to help identity ligand (drug) binding sites on the target of interest [310] to lend insight to the mechanisms of action for lead compounds [315, 316] . Clearly, combining virtual screening with NMR-based methods is advantageous in studying how ligands (drugs) bind and interact with targets (proteins) of interest. The interactions between targets (proteins) and ligands (small molecules) can be analyzed independently of the biological systems by using ''cell-based'' NMR drug design approaches.
cord-334881-x9nxxled	2020	BACKGROUND: It is reasonable to think that cancer patients undergoing chemotherapy, targeted therapy or immunotherapy could have a more aggressive course if positive for Coronavirus disease CoV-2 (COVID19). METHODS: We conducted a literature review on https://www.ncbi.nlm.nih.gov/pubmed/, https://scholar.google.com, www.arxiv.org, www.biorxiv.org, of all articles published using the keywords COVID-19 therapy or treatment and cancer until May 2, 2020. Sarilumab is an interleukin-6 (IL-6) receptor antagonist indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs) (53). AIFA has licensed a randomized phase 2 trial to evaluate the efficacy, safety and tolerability of J o u r n a l P r e -p r o o f baricitinib in addition to the usual treatment in patients with pneumonia in COVID-19 (Barcivid study) (74).
cord-336554-n8n5ii5k	2020	Number of drugs such as remdesivir, favipiravir, ribavirin, lopinavir, ritonavir, darunavir, arbidol, chloroquine, hydroxychloroquine, tocilizumab and interferons have shown inhibitory effects against the SARS-CoV2 in-vitro as well as in clinical conditions. Outbreaks of novel emerging infections such as coronavirus disease 2019 (COVID19) have unique challenges in front of the health professionals to select appropriate therapeutics/pharmacological treatments in the clinical setup with very little time available for the new drug discovery [3] . Currently, with the lack of effective agents against SARS-CoV2 as well as public-health emergency, WHO has identified some therapies which doctors and researchers believe are the most promising, such as a combination of two HIV drugs (lopinavir and ritonavir), anti-malarial drugs (chloroquine and hydroxychloroquine), and an experimental antiviral compound remdesivir. Ribavirin at a dose rate of 500 mg 2-3 times/day in combination with other drugs such as lopinavir/ritonavir or interferon (IFN)-α through intravenous route for not more than 10 days made the SARS-CoV2 infected patients more resistant to respiratory distress syndrome as well as death [41] .
cord-337738-2qck1j1w	2020	
cord-342588-berrojmq	2020	
cord-342756-rgm9ffpk	2020	Here, we aimed at presenting a critical view of ongoing drug repurposing efforts for COVID-19 as well as discussing opportunities for development of new treatments based on current knowledge of the mechanism of infection and potential targets within. In the following topic, we will review SARS-CoV-2 structure and mechanism of infection in order to discuss molecular targets from the virus or its human host that are being considered for drug repurposing and perhaps future development of new drugs. (128) Its role as a functional receptor of SARS-CoV-2 S protein in host cells makes this protein a potential drug target to treat COVID-19. (138) TMPRSS2 has a major role in SARS-CoV-2 cell entry and replication, and thus represents an interesting therapeutic target since its inhibitors could potentially block virus infection in its initial stages. (199) A robust preclinical drug discovery pipeline comprising in vitro, and in vivo models of SARS-CoV-2 infection is particularly important to identify new antivirals for human COVID-19 treatment.
cord-343620-64i1balq	2015	
cord-344934-m0q7rm6z	2020	
cord-345059-t6hojshj	2020	
cord-347579-aqgauumt	2020	• Drug courts overall have had limited success in improving access to OUD treatment and other health and social services needed to achieve significant reduction in overdose death. • Drug courts overall have had limited success in improving access to OUD treatment and other health and social services needed to achieve significant reduction in overdose death. In the face of such a crisis, it might be supposed that policy-makers would do everything possible to reduce overdose risk, including improving access to the several authorized forms of proven treatment for opioid use disorder (OUD). A 2013 national survey of drug courts found that although virtually all of the courts reported having participants with opioid use disorders, only 47% offered agonist therapy as an option for court-supervised treatment (Matusow, Dickman, Rich, Fong, Dumont, Hardin et al., 2013) .
cord-347986-ds5hm731	2007	The neuraminidase inhibitors, oseltamivir and zanamivir, have in vitro activities against the human H5N1 isolates; however, recent data suggest that higher doses for longer periods may be required to be effective. Human immunodeficiency virus (HIV), Ebola virus, hantavirus pulmonary syndrome, monkey pox and multidrug-resistant Mycobacterium tuberculosis (MDR-TB), Severe Acute Respiratory Syndrome (SARS) associated coronavirus and avian influenza are examples of emerging infections. Through a discussion of avian influenza and MDR-TB, primarily, we will demonstrate the magnitude of the problems of infectious diseases in the developing world and discuss approaches that can be taken to in an attempt to monitor and contain these new threats as they emerge. In fact, a recent Cochrane review covering appropriate studies to address the problem of treating latent tuberculosis infection in people exposed to MDR-TB found there were no randomized controlled trials in the database that have assessed the effectiveness of treatment [11] .
cord-348102-k0s9j9sz	2020	
cord-348245-pf5mlzrw	2020	On the first day of April 2020, Informative Note nº 6/2020-DAF/SCTIE/MS was published, establishing that the Brazilian Ministry of Health (MS) would make the medications available for use, in confirmed cases and at medical criteria, chloroquine and hydroxychloroquine as adjunctive therapy in the treatment of severe forms in hospitalized patients, without other supportive measures being neglected in their favor 1 . On April 6, the MS published "Guidelines for the diagnosis and treatment of Covid-19", in which it also instructed on the use of chloroquine and hydroxychloroquine as adjuvant therapy in severe forms of the disease, in confirmed cases and upon medical discretion 2 . Given the above and the associated risks, the Brazilian Society of Nephrology advises its associate doctors to prescribe one of these drugs according to the recommendations established by CFM and MS, which recommend a 50% reduction in the recommended dose of chloroquine and hydroxychloroquine in patients with glomerular filtration rate <10 mL/min/1.72 m 2 , in dialysis or conservative treatment.
cord-349682-kpg0vley	2020	
cord-349794-mhviub6e	2020	We applied a computational drug repositioning pipeline to SARS-CoV-2 differential gene expression signatures derived from publicly available data. By infecting human adenocarcinomic alveolar basal epithelial cells with SARS-CoV-2 and comparing to controls, the authors generated a list of 120 differentially expressed genes. Here, we applied our existing computational drug repositioning pipeline to identify drug profiles with significantly reversed differential gene expression compared to predicted inhibitors (including one tested in Calu-3) were incubated with SARS-CoV-2 infected human embryonic kidney 293T cells overexpressing ACE2 (293T-ACE2) with viral replication determined using an immunofluorescence-based assay. In this study, we applied our drug repositioning pipeline to SARS-CoV-2 differential gene expression signatures derived from publicly available RNA-seq data ( Figure 1 ). Here, we used a transcriptomics-based drug repositioning pipeline to predict therapeutic drug hits for three different input SARS-CoV-2 signatures, each of which came from distinct human cell or tissue origins.
cord-350571-6tapkjb6	2017	Possible solutions might be to use shared communication tools like Internet based communication programs and to introduce the patient as a participant at the IMRs. Please specify your abstract type: Research abstract Background and objective: International good pharmacy practice guidelines describe how pharmacists should counsel the patients about their medicines, offer additional services where needed, and intervene at drug related problems. Please specify your abstract type: Descriptive abstract (for projects) Background and objective: In order to improve the medication reconciliation and to implement training programs for the medical team in an associated to general hospital nursing (ASNH) home we measured the discrepancies between pharmacy registered treatments (PRT) and medical prescriptions (MP), and we analysed potentially inappropriate prescriptions according to ''''American Geriatrics Society 2015 Beers Criteria'''' and ''''STOPP-START 2014 criteria.
cord-350703-vrqltz3s	2016	
cord-351185-3y3gou6v	2020	However, rapid drug addition to cultured macrophages revealed four distinct classes of effects on the leading edge pseudopod: (i) non-perturbing drug exposures yielded no detectable change in pseudopod morphology (acetylsalicylic acid, diclofenac); (ii) adaptive exposures yielded temporary collapse of the extended pseudopod and its signature PI(3,4,5)P(3) lipid signal followed by slow recovery of extended pseudopod morphology (ibuprofen, acetaminophen); (iii) disruptive exposures yielded long-term pseudopod collapse (Gö6976, wortmannin); and (iv) activating exposures yielded pseudopod expansion (PDGF). In contrast, ibuprofen and acetaminophen are classified as adaptive because rapid addition of either drug to polarized cells yields short-term collapse of the leading edge pseudopod and loss of the PIP 3 signal, followed by slow recovery. In contrast to the four therapeutic adaptive drugs, the two non-clinical control inhibitors wortmannin and Gö6976 are each known to directly inhibit key components of the leading edge positive feedback loop and rapid addition is observed herein to trigger long term collapse of the pseudopod with no detected recovery as previously observed [26, 30, [50] [51] [52] [53] [54] .
cord-351222-9bfchw4u	2008	
cord-351517-npcuo1ld	2020	
cord-352579-ndcbmgfj	2020	
cord-353524-3w970ycx	2020	Given that SARS-CoV-2 and SARS-CoV share very high identical sequence in their 3CLpro, these HIV protease inhibitors are currently again repurposed for the treatment of COVID-19 (Chinese Clinical Trial Registry: ChiCTR2000029539). 30, 31 The interplay of the ACE receptor in cardiovascular diseases (with the well-known drug class of ACE inhibitors) and as the docking point for SARS-CoV-2 cellular infection is a current point of intense debate and research. For example, the crystal structure of SARS-CoV-2 N protein RNA-binding domain was just published and will give structural insight as a potential drug target. Potential broad spectrum inhibitors of the coronavirus 3CLpro: A virtual screening and structure-based drug design study Severe acute respiratory syndrome coronavirus papain-like novel protease inhibitors: design, synthesis, protein-ligand X-ray structure and biological evaluation Crystal structure of SARS-CoV-2 nucleocapsid protein RNA binding domain reveals potential unique drug targeting sites
cord-353572-b4mdiont	2020	Using network proximity analyses of drug targets and known HCoV-host interactions in the human protein-protein interactome, we computationally identified 135 putative repurposable drugs for the potential prevention and treatment of HCoVs. In addition, we prioritized 16 potential anti-HCoV repurposable drugs (including melatonin, mercaptopurine, and sirolimus) that were further validated by enrichment analyses of drug-gene signatures and HCoV-induced transcriptomics data in human cell lines. In summary, this study offers powerful network-based methodologies for rapid identification of candidate repurposable drugs and potential drug combinations toward future clinical trials for HCoVs. Coronaviruses (CoVs) typically affect the respiratory tract of mammals, including humans, and lead to mild to severe respiratory tract infections [1] . These network proximity analyses offer putative repurposable candidates for potential prevention and treatment of HCoVs. To further validate the 135 repurposable drugs against HCoVs, we first performed gene set enrichment analysis (GSEA) using transcriptome data of MERS-CoV and SARS-CoV infected host cells (see Methods).
cord-354006-j1y42oxu	2006	
cord-354180-6esn3t2b	2020	The arrival of the COVID-19 pandemic comes at time when North America is in the midst of a protracted overdose epidemic caused by a toxic illegal drug supply. Overdose deaths are likely to rise when people are isolated, social support programs are cut back, and the illicit drug supply is further compromised. Safer opioid distribution in response to a toxic street drug supply is a pragmatic and effective way to reduce overdose deaths. Even if emergency housing can be found and mitigation strategies to reduce COVID-19 transmission are put in place, the need to access an illegal drug supply makes staying in place extremely unlikely (Bodkin et al., 2020) . A waning tolerance to opioids means that the first exposure to street drugs can be deadly and it is critical that proper discharge planning and supports are in place (Bukten et al.,2017) Many people who use drugs rely on public services for medical care, harm reduction supplies, street outreach, and food distribution.
cord-354445-lnvc7mmf	2019	Abstract Outbreaks of infection transmission due to contaminated flexible endoscopes have focused the attention of health care personnel, senior management, device manufacturers, and regulators on the need to improve the approach used to offer this valuable service. Salmonella is a serious primary pathogen, and Pseudomonas is ubiquitous in many water sources, and although both these pathogens have been associated most frequently with endoscopic transmission, they are both sensitive to multiple agents, including glutaraldehyde, and other HLDs. Transmission of bacterial pathogens from flexible endoscopes has been rare since the adoption of the current 2011 multisociety reprocessing guideline, 45, 160 with the exception of duodenoscope-related infections (discussed later). Society of Gastroenterology Nurses and Associates: Guideline for use of high level disinfectants & sterilants for reprocessing flexible gastrointestinal endoscopes Society of Gastroenterology Nurses and Associates: Guideline for use of high level disinfectants & sterilants for reprocessing flexible gastrointestinal endoscopes
cord-355971-99mhacqa	2020	title: Anticancer drugs and COVID-19 antiviral treatments in cancer patients: what can we safely use? • More safety data is needed to treat COVID-19 symptomatic patients with anticancer drugs known to increase infections. • A ready-to-use table synthetize these pharmacokinetic and pharmacodynamic interactions between antiviral and anticancer drugs. 1 In any of these settings, clinical trials and incoming standard of care could lead to the prescription of antiviral drugs concomitant to non-immunosuppressive anticancer treatments. Favipiravir, an anti-EBOV drug, also a candidate for the COVID-19 treatment, is an inhibitor of CYP2C8, 3 and therefore may increase anticancer drug metabolized through this pathway, such as dabrafenib and enzalutamide. The table (part B) summarizes pharmacokinetic and pharmacodynamics interactions between some currently tested drugs against COVID-19 and anticancer drugs. Orange boxes are for anticancer drugs prolonging QT without known Torsade-de-Pointes risk and moderate risk for renal and liver toxicities.