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Illicit drug use causes over half a million deaths worldwide every year. Drugs of abuse are commonly smuggled through customs and border checkpoints and, increasingly, through parcel delivery services. Improved methods for detection of trace drug residues from surfaces are needed. Such methods should be robust, fieldable, sensitive, and capable of detecting a wide range of drugs. In this work, commercially produced paper with a pressure-sensitive adhesive coating was utilized for the collection and analysis of trace drug residues by paper spray mass spectrometry (MS). This modified substrate was used to combine sample collection of drug residues from surfaces with rapid detection using a single paper spray ticket. The all-in-one ticket was used to probe different surfaces commonly encountered in forensic work including clothing, cardboard, glass, concrete, asphalt, and aluminum. A total of 10 drugs (acetyl fentanyl, fentanyl, clonazolam, cocaine, heroin, ketamine, methamphetamine, methylone, U-47700, and XLR-11) were evaluated and found to be detectable in the picogram range using a benchtop mass spectrometer and in the low nanogram range using a portable ion trap MS. The novel approach demonstrates a simple yet effective sampling strategy, allowing for rapid identification from difficult surfaces via paper spray mass spectrometry.

Chemotherapeutic drugs have been widely used in the treatment of cancer disease for about 70 years. The development of new treatments has not hindered their use, and oncologists still prescribe them routinely, alone or in combination with other antineoplastic agents. However, all chemotherapeutic agents can induce hypersensitivity reactions (HSRs), with different incidences depending on the culprit drug. These reactions are the third leading cause of fatal drug-induced anaphylaxis in the United States. In Europe, deaths related to chemotherapy have also been reported. In particular, most reactions are caused by platinum compounds, taxanes, epipodophyllotoxins and asparaginase. Despite their prevalence and relevance, the ideal pathways for diagnosis, treatment and prevention of these reactions are still unclear, and practice remains considerably heterogeneous with vast differences from center to center. Thus, the European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology organized a task force to provide data and recommendations regarding the allergological work-up in this field of drug hypersensitivity reactions. This position paper aims to provide consensus on the investigation of HSRs to chemotherapeutic drugs and give practical recommendations for clinicians that treat these patients, such as oncologists, allergologists and internists. Key sections cover risk factors, pathogenesis, symptoms, the role of skin tests, in vitro tests, indications and contraindications of drug provocation tests and desensitization of neoplastic patients with allergic reactions to chemotherapeutic drugs. Statements, recommendations and unmet needs were discussed and proposed at the end of each section.

To date, very few treatments have been demonstrated to reduce the burden of morbidity and mortality from COVID-19. Although corticosteroids have been proven to reduce mortality in severe disease, there has been little convincing evidence on interventions that may prevent disease, reduce hospitalizations, and reduce the numbers of people progressing to critical disease and death. Ivermectin is a well-known medicine that is approved as an antiparasitic by the World Health Organization and the US Food and Drug Administration. It is widely used in lowand middle-income countries to treat worm infections. Also used for the treatment of scabies and lice, it is one of the World Health Organization’s Essential Medicines.1 With total doses of ivermectin distributed apparently equalling one-third of the present world population,1 ivermectin at the usual doses (0.2–0.4 mg/kg) is considered extremely safe for use in humans.1 In addition to its antiparasiticactivity, it has been noted to have antiviral and anti-inflammatory properties, leading to an increasing list of therapeutic indications. South African authorities approved the use of a drug used to control parasites in humans and livestock to treat coronavirus patients. Additionally, in January 2021, the South African Health Products Regulatory Authority (SAHPRA) announced that ivermectin, would be allowedfor use on compassionate grounds in a controlled-access program. Ivermectin locally has been used for the prevention and/or management of Covid-19 infection. This has resulted in a huge black market trade of ivermectin in South Africa as many health professionals and others have taken to social media and other platforms to profile this drug as an effective treatment for the covid-19 viral infection. Roman and colleagues (2021)1 conducted a systematic review and meta-analysis to evaluate treatment effects of Ivermectin (IVM) on clinical outcomes and adverse events (AEs) in people with COVID-19.

Introduction. Drug checking services for harm reduction and overdose prevention have been implemented in many jurisdictions as a public health intervention in response to the opioid overdose crisis. This study demonstrates the first on-site use of paper spray mass spectrometry for quantitative drug checking to address the limitations of current on-site drug testing technologies. Methods. Paper spray mass spectrometry was used to provide on-site drug checking services at a supervised consumption site in the Downtown Eastside of Vancouver, British Columbia, Canada during a 2-day pilot test in August 2019. The method included the targeted quantitative measurement of 49 drugs and an untargeted full scan to assist in identifying unknown/unexpected components. Results. During the pilot, 113 samples were submitted for analysis, with 88 (78%) containing the client expected substance. Fentanyl was detected in 45 of 59 expected fentanyl samples, and in 50 (44%) samples overall at a median concentration of 3.6% (w/w%). The synthetic precursor of fentanyl, 4-anilino-N-phenethyl-piperidine (4-ANPP), was found in 74.0% of all fentanyl samples at a median concentration of 2.2%, suggesting widespread poor manufacturing practices. Etizolam was detected in 10 submitted samples anticipated to be fentanyl at a median concentration of 2.5%. No clients submitting these samples expected etizolam or a benzodiazepine in their sample. In three instances, it was co-measured with fentanyl, and in seven cases it was detected alone. Discussion and Conclusions. The quantitative capabilities and low detection limits demonstrated by paper spray mass spectrometry offer distinct benefits over existing on-site drug checking methods and harm reduction services. This work was supported by the Natural Science and Engineering Research Council of Canada Discovery Grant Program funding (RGPIN-2016-05380), Vancouver Island University and the Health Canada Drug Checking Technology Challenge. This article was originally published as: Borden, S.A., Saatchi, A., Vandergrift, G.W., Palaty, J., Lysyshyn, M., & Gill, C.G. (2021). A new quantitative drug checking technology for harm reduction: Pilot study in Vancouver, Canada using paper spray mass spectrometry. Drug and Alcohol Review, 1-8. https://doi.org/10.1111/dar.13370 This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. https://viurrspace.ca/bitstream/handle/10613/24515/Gill2021.pdf?sequence=3

Early warning systems detect new psychoactive substances (NPS), while dedicated monitoring programs and routine drug and toxicology testing identify fluctuations in prevalence. We report the increasing prevalence of the synthetic cannabinoid receptor agonist (SCRA) ADB-BUTINACA (N-[1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-butyl-1H-indazole-3-carbox-amide). ADB-BUTINACA was first detected in a seizure in Sweden in 2019, and we report its detection in 13 routine Swedish forensic toxicology cases soon after. In January 2021, ADB-BUTINACA was detected in SCRA-infused papers seized in Scottish prisons and has rapidly increased in prevalence, being detected in 60.4% of the SCRA-infused papers tested between January and July 2021. In this work, ADB-BUTINACA was incubated with human hepatocytes (HHeps), and 21 metabolites were identified in vitro, 14 being detected in authentic case samples. The parent drug and metabolites B9 (mono-hydroxylation on the n-butyl tail) and B16 (mono-hydroxylation on the indazole ring) are recommended biomarkers in blood, while metabolites B4 (dihydrodiol formation on the indazole core), B9, and B16 are suitable biomarkers in urine. ADB-4en-PINACA (N-[1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-[pent-4-en-1-yl]-1H-indazole-3-carboxamide) was detected in Scottish prisons in December 2020, but, unlike ADB-BUTINACA, prevalence has remained low. ADB-4en-PINACA was incubated with HHeps, and 11 metabolites were identified. Metabolites E3 (dihydrodiol formed in the tail moiety) and E7 (hydroxylation on the linked/head group) are the most abundant metabolites in vitro and are suggested as urinary biomarkers. The in vitro potencies of ADB-BUTINACA (EC50, 11.5 nM and ADB-4en-PINACA (EC50, 11.6 nM) are similar to that of MDMB-4en-PINACA (EC50, 4.3 nM). A third tert-leucinamide SCRA, ADB-HEXINACA was also detected in prison samples and warrants further investigation. Funding Agencies|Linkopings Universitet; Dubai Police Force [2427681]; Leverhulme TrustLeverhulme Trust [RC-2015-01]; Scottish Prison Service [01865]; Linkoping University; VINNOVAVinnova [2019-03566]; European CommissionEuropean CommissionEuropean Commission Joint Research Centre [E! 113377]

In this study, different assortments of 2-arylquinolines and 2,6-diarylquinolines have been developed. Recently, we have developed a new series of 6,7-dimethoxy-4-alkoxy-2-arylquinolines as Topoisomerase I (TOP1) inhibitors with potent anticancer activity. Utilising the SAR outputs from this study, we tried to enhance anticancer and TOP1 inhibitory activities. Though target quinolines demonstrated potent antiproliferative effect, specifically against colorectal cancer DLD-1 and HCT-116, they showed weak TOP1 inhibition which may be attributable to their non-coplanarity. Thereafter, screening against kinase panel revealed their dual inhibitory activity against EGFR and FAK. Quinolines 6f, 6h, 6i, and 20f were the most potent EGFR inhibitors (IC50s = 25.39, 20.15, 22.36, and 24.81 nM, respectively). Meanwhile, quinolines 6f, 6h, 6i, 16d, and 20f exerted the best FAK inhibition (IC50s = 22.68, 14.25, 18.36, 17.36, and 15.36 nM, respectively). Finally, molecular modelling was employed to justify the promising EGFR/FAK inhibition. The study outcomes afforded the first reported quinolines with potent EGFR/FAK dual inhibition., Graphical Abstract

Graphical abstract Hydroxychloroquine (HCQ) and favipiravir (FPV) are known to be effective antivirals, and there are reports about their use to fight the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) despite that these are not conclusive. The use of combined drugs is common in drug discovery, and thus, we investigated HCQ and FPV as a combined drug. The density functional theory method was used for the optimization of geometries, spectroscopic analysis and calculation of reactivity parameters. The quantum theory of atoms in molecules was applied to explain the nature of the hydrogen bonds and confirm the higher stability of the combined drug. We also evaluated the absorption, distribution, metabolism and excretion (ADME) parameters to assess their drug actions jointly using SwissADME. The preliminary findings of our theoretical study are promising for further investigations of more potent and selective antiviral drugs. Supplementary Information The online version contains supplementary material available at 10.1007/s11696-021-01946-8.

Introduction Several drugs of abuse (DOA) are capable of modulating neurohypophysial hormones, such as oxytocin (OT) and vasopressin (VP), potentially resulting in the development of psychological abnormalities, such as cognitive dysfunction, psychoses, and affective disorders. Efavirenz (EFV), widely used in Africa and globally to treat HIV, induces diverse neuropsychiatric side effects while its abuse has become a global concern. The actions of EFV may involve neurohypophysial system (NS) disruption like that of known DOA. This study investigated whether sub-chronic EFV exposure, at a previously-determined rewarding dose, alters peripheral OT and VP levels versus that of a control, ∆9-tetrahydrocannabinol (∆9-THC), methamphetamine (MA) and cocaine. Materials and methods To simulate the conditions under which reward-driven behavior had previously been established for EFV, male Sprague Dawley rats (n = 16/exposure) received intraperitoneal vehicle (control) or drug administration across an alternating sixteen-day dosing protocol. Control administration (saline/olive oil; 0.2 ml) occurred on odd-numbered and drug administration (EFV: 5 mg/kg, ∆9-THC: 0.75 mg/kg, MA: 1 mg/kg, or cocaine: 20 mg/kg) on even-numbered days followed by euthanasia, trunk blood collection and plasma extraction for neuropeptide assay. Effect of drug exposure on peripheral OT and VP levels was assessed versus controls and quantified using specific ELISA kits. Statistical significance was determined by Kruskal-Wallis ANOVA, with p, Highlights • Efavirenz alters rat plasma neuropeptide levels in a similar manner to illicit drugs. • Opposed to cocaine, methamphetamine reduces plasma vasopressin rather than oxytocin. • Efavirenz and ∆−9-tetrahydrocannabinol comparably affect peripheral neuropeptides. • Efavirenz reduces vasopressin more than oxytocin versus ∆−9-tetrahydrocannabinol.

Pancreatic cancer is an extremely malignant digestive tract tumor. With the increase of chemotherapeutic resistance of pancreatic cancer, clinical treatment is in a dilemma. Hence, it is pivotal to design an effective drug for treating individuals with pancreatic cancer. Fisetin extracted from vegetables, as well as fruits was explored to possess antioxidant, anti-cancer, anti-inflammatory along with anti-microbial properties. Nonetheless, there is limited research focusing on the utility of fisetin as an inhibitor of pancreatic cancer. Similarly, the mechanism through which Fisetin dampens pancreatic cancer remains unknown. This research work systematically evaluated the possible anti-cancer influences of fisetin in pancreatic cancer, as well as explored its responsible molecular mechanism. Our data revealed that fisetin obviously dampens pancreatic cancer progress in vitro along with in vivo dose-dependently. Furthermore, we established that fisetin repressed pancreatic cancer via explicitly targeting PI3K/AKT/mTOR signaling cascade and not the JAK2 cascade. Our data clarified that fisetin is a prospective anti-cancer drug for pancreatic cancer, as well as indicated the distinct molecular target of fisetin.

Nanoparticle deployment in drug delivery is contingent upon controlled drug loading and a desired release profile, with simultaneous biocompatibility and cellular targeting. Iron oxide nanoparticles (IONPs), being biocompatible, are used as drug carriers. However, to prevent aggregation of bare IONPs, they are coated with stabilizing agents. We hypothesize that, zwitterionic drugs like norfloxacin (NOR, a fluoroquinolone) can manifest dual functionality – nanoparticle stabilization and antibiotic activity, eliminating the need of a separate stabilizing agent. Since these drugs have different charges, depending on the surrounding pH, drug loading enhancement could be pH dependent. Hence, upon synthesizing IONPs, they were coated with NOR, either at pH 5 (predominantly as cationic, NOR+) or at pH 10 (predominantly as anionic, NOR−). We observed that, drug loading at pH 5 exceeded that at pH 10 by 4.7–5.7 times. Furthermore, only the former (pH 5 system) exhibited a desirable slower drug release profile, compared to the free drug. NOR-coated IONPs also enable a 22 times higher drug accumulation in macrophages, compared to identical extracellular concentrations of the free drug. Thus, lowering the drug coating pH to 5 imparts multiple benefits – improved IONP stability, enhanced drug coating, higher drug uptake in macrophages at reduced toxicity and slower drug release.

Purpose To build a physiologically based pharmacokinetic (PBPK) model of the clinical OATP1B1/OATP1B3/BCRP victim drug rosuvastatin for the investigation and prediction of its transporter-mediated drug-drug interactions (DDIs). Methods The Rosuvastatin model was developed using the open-source PBPK software PK-Sim®, following a middle-out approach. 42 clinical studies (dosing range 0.002–80.0 mg), providing rosuvastatin plasma, urine and feces data, positron emission tomography (PET) measurements of tissue concentrations and 7 different rosuvastatin DDI studies with rifampicin, gemfibrozil and probenecid as the perpetrator drugs, were included to build and qualify the model. Results The carefully developed and thoroughly evaluated model adequately describes the analyzed clinical data, including blood, liver, feces and urine measurements. The processes implemented to describe the rosuvastatin pharmacokinetics and DDIs are active uptake by OATP2B1, OATP1B1/OATP1B3 and OAT3, active efflux by BCRP and Pgp, metabolism by CYP2C9 and passive glomerular filtration. The available clinical rifampicin, gemfibrozil and probenecid DDI studies were modeled using in vitro inhibition constants without adjustments. The good prediction of DDIs was demonstrated by simulated rosuvastatin plasma profiles, DDI AUClast ratios (AUClast during DDI/AUClast without co-administration) and DDI Cmax ratios (Cmax during DDI/Cmax without co-administration), with all simulated DDI ratios within 1.6-fold of the observed values. Conclusions A whole-body PBPK model of rosuvastatin was built and qualified for the prediction of rosuvastatin pharmacokinetics and transporter-mediated DDIs. The model is freely available in the Open Systems Pharmacology model repository, to support future investigations of rosuvastatin pharmacokinetics, rosuvastatin therapy and DDI studies during model-informed drug discovery and development (MID3).

Coated microneedles (MNs) are widely used for delivering biopharmaceuticals. In this study, a novel gel encapsulated coated MNs (GEC-MNs) was developed. The water-soluble drug coating was encapsulated with sodium alginate (SA) in situ complexation gel. The manufacturing process of GEC-MNs was optimized for mass production. Compared to the water-soluble coated MNs (72.02% ± 11.49%), the drug delivery efficiency of the optimized GEC-MNs (88.42% ± 6.72%) was steadily increased, and this improvement was investigated through in vitro drug release. The sustained-release of BSA was observed in vitro permeation through the skin. The rhIFNα-1b GEC-MNs was confirmed to achieve biosafety and 6-month storage stability. Pharmacokinetics of rhIFNα-1b in GEC-MNs showed a linearly dose-dependent relationship. The AUC of rhIFNα-1b in GEC-MNs (4.51 ng/ml·h) was bioequivalent to the intradermal (ID) injection (5.36 ng/ml·h) and significantly higher than water-soluble coated MNs (3.12 ng/ml·h). The rhIFNα-1b elimination half-life of GEC-MNs, soluble coated MNs, and ID injection was 18.16, 1.44, and 2.53 h, respectively. The complexation-based GEC-MNs have proved to be more efficient, stable, and achieve the sustained-release of water-soluble drug in coating MNs, constituting a high value to biopharmaceutical., Graphical abstract In the coated microneedle produced by the layer-by-layer coating method, the water-soluble drug-containing coating is encapsulated by the complexation-based gel (GEC-MNs). After GEC-MNs are applied to the skin, the release rate of the drug is reduced by the outer layer of the gel. The pharmacokinetic results of rh-IFNα-1b showed that compared with intradermal injection and water-soluble coated microneedles, the sustained release was achieved in GEC-MNs.Image, graphical abstract

There is growing empirical evidence that certain types of chemotherapy and phototherapy trigger immunogenic cell death and enhance the therapeutic anticancer efficacy of genetic immunotherapy. However, the main challenge is spatiotemporally co-delivering different drugs to maximize the therapeutic index of the combination therapy. In this study, a drug delivery system (HTCP-Au/shPD-L1/DOX) was designed with a polysaccharide-wrapped shell and a condensed DNA core. To construct the HTCP-Au vector, dodecyl side chains with a polyethylenimine (PEI) head were grafted onto hyaluronic acid, and AuNPs were grafted via Au-S bonds. During drug loading, PEI arrested shRNA plasmid DNA targeting programmed cell death ligand 1 (shPD-L1) via electrostatic interactions. It also formed a PEI-DNA core that was automatically enclosed when aliphatic hydrocarbons pulled the hyaluronic acid backbone. A hydrophobic interlayer consisting of dodecyl bridge chains between the PEI-DNA core and the hyaluronic acid shell was required to accommodate hydrophobic doxorubicin. In vitro and in vivo assays demonstrated that this core-shell drug delivery system could efficiently load and transport three different drugs and effectively target tumors. Moreover, it could activate the immune system, thereby providing promising therapeutic efficacy against tumor growth and metastasis., Graphical abstract HTCP-Au/shPD-L1/DOX was composed of gold nanoparticles (AuNPs)-modified hyaluronic acid shell, shPD-L1 plasmid core compressed by cationic polyethyleneimine and doxorubicin (DOX) encapsulated in hydrophobic layer. It could target to tumor cells by the CD44 receptor which is over-expressed in tumor microenvironment, followed by drug releasing responsively at 808 nm laser and the low pH in lysosome. Then the PD-L1 gene silencing induced by shPD-L1 and immunogenic cell death effect triggered by DOX and AuNPs will eliminate the tumor synergisticallyImage, graphical abstract

Because of the scale of the novel coronavirus (COVID-19) pandemic and the swift transmission of this highly contagious respiratory virus, repurposing existing drugs has become an urgent treatment approach. The objective of our study is to unravel the binding mechanism of the Food and Drug Administration (FDA)-approved dexamethasone (Dex) and boceprevir (Boc) drugs with selected COVID-19 protein targets SARS-CoV-2 spike protein C-terminal domain (spike-CTD), main protease (Mpro), and interleukin-6 (IL-6). Another objective is to analyze the effects of binding Dex and Boc drugs on the interactions of viral spike protein to human angiotensin-converting enzyme 2 (hACE2). Molecular docking and one-microsecond-long molecular dynamics simulations of each of the six protein–drug complexes along with steered molecular dynamics (SMD) and umbrella sampling (US) methods have revealed the binding mode interactions and the physicochemical stability of the three targeted proteins with two drugs. Results have shown that both drugs bind strongly with the three protein targets through hydrogen bonding and hydrophobic interactions. A major finding from this study is how the binding of the drugs with viral spike protein affects its interactions at the binding interface with hACE2 protein. Simulations of drug-bound spike-CTD with hACE2 show that due to the presence of a drug at the binding interface of spike-CTD, hACE2 is being blocked from making putative interactions with viral protein at such interface. These important findings regarding the binding affinity and stability of the two FDA-approved drugs with the main targets of COVID-19 along with the effect of drugs on hACE2 interactions would contribute to COVID-19 drug discovery and development. Supplementary Information The online version contains supplementary material available at 10.1007/s11696-021-01843-0.

There are several antibody therapeutics in preclinical and clinical development, industry-wide, for the treatment of central nervous system (CNS) disorders. Due to the limited permeability of antibodies across brain barriers, the quantitative understanding of antibody exposure in the CNS is important for the design of antibody drug characteristics and determining appropriate dosing regimens. We have developed a minimal physiologically-based pharmacokinetic (mPBPK) model of the brain for antibody therapeutics, which was reduced from an existing multi-species platform brain PBPK model. All non-brain compartments were combined into a single tissue compartment and cerebral spinal fluid (CSF) compartments were combined into a single CSF compartment. The mPBPK model contains 16 differential equations, compared to 100 in the original PBPK model, and improved simulation speed approximately 11-fold. Area under the curve ratios for minimal versus full PBPK models were close to 1 across species for both brain and plasma compartments, which indicates the reduced model simulations are similar to those of the original model. The minimal model retained detailed physiological processes of the brain while not significantly affecting model predictability, which supports the law of parsimony in the context of balancing model complexity with added predictive power. The minimal model has a variety of applications for supporting the preclinical development of antibody therapeutics and can be expanded to include target information for evaluating target engagement to inform clinical dose selection. Supplementary Information The online version contains supplementary material available at 10.1007/s10928-021-09776-7.

Aims Flavonoids and related compounds, such as quercetin‐based antiviral drug Gene‐Eden‐VIR/Novirin, inhibit the protease of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). The alkylated chalcones isolated from Angelica keiskei inhibit SARS‐CoV proteases. In this study, we aimed to compare the anti‐SARS CoV‐2 activities of both newly synthesized chalcone derivatives and these two drugs. Methods Determination of the potent antiviral activity of newly synthesized chalcone derivatives against SARS‐CoV‐2 by calculating the RT‐PCR cycling threshold (Ct ) values. Results Antiviral activities of the compounds varied because of being dose dependent. Compound 6, 7, 9, and 16 were highly effective against SARS‐CoV‐2 at the concentration of 1.60 µg/mL. Structure‐based virtual screening was carried out against the most important druggable SARS‐CoV‐2 targets, viral RNA‐dependent RNA polymerase, to identify putative inhibitors that could facilitate the development of potential anti‐coronavirus disease‐2019 drug candidates. Conclusions Computational analyses identified eight compounds inhibiting each target, with binding affinity scores ranging from −4.370 to −2.748 kcal/mol along with their toxicological, ADME, and drug‐like properties.

Aims Hydroxychloroquine (HCQ) is using as a repurposed drug in considerable proportion of COVID‐19 patients. However, being a substrate of cytochrome P450 (CYP) enzymes of CYP3A4/5, CYP2C8 and CYP2D6, the safety and efficacy of this drug may be affected by the coadministration of respective CYP inhibitors, substrates or inducer drugs. It was aimed to identify potential clinically significant drug‐drug interaction (DDI) pairs of HCQ. Methods Inhibitors, substrates and inducer drugs lists of CYP enzymes of interest from international well‐recognised evidence‐based drug interaction resources were used to identify potential clinically significant pharmacokinetic DDI pairs of HCQ. Results Among 329 identified interacting drugs that predicted to cause clinically significant DDIs of HCQ, 45 (13.7%), 43 (13.1%) and 123 (37.4%) unique DDI pairs were identified from the FDA, Stockley's and Flockhart lists, respectively. Of interest, 55 (16.7%) DDI pairs were recognised by all three resources. At least, 29 (8.8%) severe DDI pairs were identified predicted to cause severe toxicity of HCQ in patients with COVID‐19. When comparing these interactions with Liverpool DDI lists, it was found that out of 423 total interactions, 238 (56.3%) and 94 (22.2%) unique DDI pairs were identified from all three resources and Liverpool DDI lists, respectively. Of interest, only three (0.7%) DDI pairs were recognised by both the three international resources and Liverpool DDI lists of HCQ. Conclusion Using HCQ has clinical debate whether it should or should not continue in COVID‐19 patients, however, potential clinically significant DDIs identified in this study may optimise safety or efficacy of HCQ in considerable proportion of patients.

Motivation Large-scale screenings of cancer cell lines with detailed molecular profiles against libraries of pharmacological compounds are currently being performed in order to gain a better understanding of the genetic component of drug response and to enhance our ability to recommend therapies given a patient's molecular profile. These comprehensive screens differ from the clinical setting in which (i) medical records only contain the response of a patient to very few drugs, (ii) drugs are recommended by doctors based on their expert judgment and (iii) selecting the most promising therapy is often more important than accurately predicting the sensitivity to all potential drugs. Current regression models for drug sensitivity prediction fail to account for these three properties. Results We present a machine learning approach, named Kernelized Rank Learning (KRL), that ranks drugs based on their predicted effect per cell line (patient), circumventing the difficult problem of precisely predicting the sensitivity to the given drug. Our approach outperforms several state-of-the-art predictors in drug recommendation, particularly if the training dataset is sparse, and generalizes to patient data. Our work phrases personalized drug recommendation as a new type of machine learning problem with translational potential to the clinic. Availability and implementation The Python implementation of KRL and scripts for running our experiments are available at https://github.com/BorgwardtLab/Kernelized-Rank-Learning. Supplementary information Supplementary data are available at Bioinformatics online., Bioinformatics, 34 (16), ISSN:1367-4803, ISSN:1460-2059

Graphical abstract A novel coronavirus known as severe acute respiratory syndrome is rapidly spreading worldwide. The international health authorities are putting all their efforts on quick diagnosis and placing the patients in quarantine. Although different vaccines have come for quick use as prophylactics, drug repurposing seems to be of paramount importance because of inefficient therapeutic options and clinical trial limitations. Here, we used structure-based drug designing approach to find and check the efficacy of the possible drug that can inhibit coronavirus main protease which is involved in polypeptide processing to functional protein. We performed virtual screening, molecular docking and molecular dynamics simulations of the FDA-approved drugs against the main protease of SARS-CoV-2. Using well-defined computational methods, we identified amprenavir, cefoperazone, riboflavin, diosmin, nadide and troxerutin approved for human therapeutic uses, as COVID-19 main protease inhibitors. These drugs bind to the SARS-CoV-2 main protease conserved residues of substrate-binding pocket and formed a remarkable number of non-covalent interactions. We have found diosmin as an inhibitor which binds covalently to the COVID-19 main protease. This study provides enough evidences for therapeutic use of these drugs in controlling COVID-19 after experimental validation and clinical demonstration. Supplementary Information The online version contains supplementary material available at 10.1007/s00894-021-04923-w.

Background Spontaneous reporting systems (SRSs) have been increasingly established to collect adverse drug events for fostering adverse drug reaction (ADR) detection and analysis research. SRS data contain personal information, and so their publication requires data anonymization to prevent the disclosure of individuals’ privacy. We have previously proposed a privacy model called MS(k, θ*)-bounding and the associated MS-Anonymization algorithm to fulfill the anonymization of SRS data. In the real world, the SRS data usually are released periodically (eg, FDA Adverse Event Reporting System [FAERS]) to accommodate newly collected adverse drug events. Different anonymized releases of SRS data available to the attacker may thwart our single-release-focus method, that is, MS(k, θ*)-bounding. Objective We investigate the privacy threat caused by periodical releases of SRS data and propose anonymization methods to prevent the disclosure of personal privacy information while maintaining the utility of published data. Methods We identify potential attacks on periodical releases of SRS data, namely, BFL-attacks, mainly caused by follow-up cases. We present a new privacy model called PPMS(k, θ*)-bounding, and propose the associated PPMS-Anonymization algorithm and 2 improvements: PPMS+-Anonymization and PPMS++-Anonymization. Empirical evaluations were performed using 32 selected FAERS quarter data sets from 2004Q1 to 2011Q4. The performance of the proposed versions of PPMS-Anonymization was inspected against MS-Anonymization from some aspects, including data distortion, measured by normalized information loss; privacy risk of anonymized data, measured by dangerous identity ratio and dangerous sensitivity ratio; and data utility, measured by the bias of signal counting and strength (proportional reporting ratio). Results The best version of PPMS-Anonymization, PPMS++-Anonymization, achieves nearly the same quality as MS-Anonymization in both privacy protection and data utility. Overall, PPMS++-Anonymization ensures zero privacy risk on record and attribute linkage, and exhibits 51%-78% and 59%-82% improvements on information loss over PPMS+-Anonymization and PPMS-Anonymization, respectively, and significantly reduces the bias of ADR signal. Conclusions The proposed PPMS(k, θ*)-bounding model and PPMS-Anonymization algorithm are effective in anonymizing SRS data sets in the periodical data publishing scenario, preventing the series of releases from disclosing personal sensitive information caused by BFL-attacks while maintaining the data utility for ADR signal detection.

Cancer is a multifactorial disease with a convoluted genesis and progression. The emergence of multidrug resistance to presently be offered drug and relapse is by far, the most critical concern to tackle this deteriorating disease. Henceforth, there is undeniably an inflated necessity for safe, promising, and less harmful new anticancer drugs. Natural compounds from various sources like plants, animals, and microorganisms have occupied a center stage in drug discovery due to their tremendous chemical diversity and potential as therapeutic agents. Endophytic microbes are symbiotically associated with plants and have been proven to produce novel or analogues of host bioactive metabolites exhibiting a variety of biological activities including anticancer activity. This review emphasizes on structurally diverse unprecedented anticancer natural compounds that have been reported exclusively from endophytic fungi from 2016 to 2020. It covers chemical nature of metabolites, its fungal source associated with terrestrial, as well as marine plants and anticancer activity based on their cytotoxicity profile against various cancer cell lines. Many of these fungal metabolites with promising anticancer activity can be used as lead molecules for in silico experiments and deserve special attention from scientists for further in vitro and clinical research., Graphical abstract Image 1, Highlights • Endophytic fungi are the gold mine for natural chemotherapeutic agents. • The present study sheds light on novel cytotoxic fungal metabolites. • Future aspects of endophytic metabolites have been precisely discussed. • Library for the 3D structures of reviewed compounds will be provided on request.

The ongoing pandemic, COVID-19 (SARS-CoV-2), has afflicted millions of people around the world, necessitating that the scientific community work, diligently and promptly, on suitable medicaments. Although vaccination programs have been run globally, the new variants of COVID-19 make it difficult to restrict the spread of the virus by vaccination alone. The combination of vaccination with anti-viral drug formulation is an ideal strategy for tackling the current pandemic situation. Drugs approved by the United States Food and Drug Administration (FDA), such as Remdesivir, have been found to be of little or no benefit. On the other hand, re-purposing of FDA-approved drugs, such as niclosamide (NIC), has offered promise but its applicability is limited due to its poor aqueous solubility and, therefore, low bioavailability. With advanced nano-pharmaceutical approaches, re-purposing this drug in a suitable drug-carrier for a better outcome may be possible. In the current study, an attempt was made to explore the loading of NIC into exfoliated layered double hydroxide nanoparticles (X-LDH NPs); prepared NIC-X-LDH NPs were further modified with eudragit S100 (ES100), an enteric coating polymer, to make the final product, ES100-NIC-X-LDH NPs, to improve absorption by the gastro/intestinal tract (GIT). Furthermore, Tween 60 was added as a coating on ES100-NIC-X-LDH NPs, not just to enhance its in vitro and in vivo stability, but also to enhance its mucoadhesive property, and to obtain, ultimately, better in vivo pharmacokinetic (PK) parameters upon oral administration. Release of NIC from Tween 60-ES100-NIC-X-LDH NPs was found to be greater under gastro/intestinal solution within a shorter period of time than the uncoated samples. The in vivo analysis revealed that Tween 60-ES100-NIC-X-LDH NPs were able to maintain a therapeutically relevant NIC plasma concentration in terms of PK parameters compared to the commercially available Yomesan®, proving that the new formulation might prove to be an effective oral drug-delivery system to deal with the SARS-CoV-2 viral infections. Further studies are required to ensure their safety and anti-viral efficacy. Supplementary Information The online version contains supplementary material available at 10.1007/s42860-021-00153-6.

The scientific community has been releasing whole genomic sequences of SARS-CoV-2 to facilitate the investigation of molecular features and evolutionary history. We retrieved 36 genomes of 18 prevalent countries of Asia, Europe and America for genomic diversity and mutational analysis. Besides, we studied mutations in the RBD regions of Spike (S) proteins to analyze the drug efficiency against these mutations. In this research, phylogenenetic analysis, evolutionary modeling, substitution pattern analysis, molecular docking, dynamics simulation, etc. were performed. The genomic sequences showed >99% similarity with the reference sequence of China.TN93 + G was predicted as a best nucleotide substitution model. It was revealed that effective transition from the co-existing SARS genome to the SARS-CoV-2 and a noticeable positive selection in the SARS-CoV-2 genomes occurred. Moreover, three mutations in RBD domain, Val/ Phe367, Val/ Leu 382 and Ala/ Val522, were discovered in the genomes from Netherland, Bangladesh and the USA, respectively. Molecular docking and dynamics study showed RBD with mutation Val/Leu382 had the lowest binding affinity with remdesivir. In conclusion, the SARS-CoV-2 genomes are similar, but multiple degrees of transitions and transversions occurred. The mutations cause a significant conformational change, which are needed to be investigated during drug and vaccine development.

Introduction For more than two decades several initiatives have emerged to increase recruitment of paediatric patients in drug trials. While trials of newly approved drugs have successfully included paediatric patients in their drug development plan, the collection of safety and efficacy data in paediatric patients treated with off-patent drugs poses a major challenge. Aim This paper aims to draw attention to problems and solutions across countries in investigator-initiated trials with off-patent drugs and recommendations for improvement. Discussion Off-patent drugs represent a particular challenge when they are included in a paediatric trial; these trials are frequently investigator-initiated and have limited resources, off-patent drugs are used in clinical settings and the trial protocol must accommodate e.g. flexible dosing and specimen sampling schedules, off-patent drugs typically exist in few formulations and concentrations which necessitates special or imported formulations. Paediatric trials are in some countries confined by e.g. consent from both parents, regardless of whether the Investigational Medicinal Product (IMP) is a well-known drug or a new experimental drug. Conclusion Facilitation of research in off-patent drugs can improve evidence-based and safe treatment for the paediatric population. The following supportive initiatives are recommended: Harmonised regulatory change that improves the consent process in low risk trials to prevent inadequate recruitment. Pharmaceutical expertise should be prioritized to secure the best choice of IMP and supply. Constant focus on flexibility in design to accommodate a multifaceted paediatric population and ensure that trial protocols fit in well with routine clinical care and family life.

Highlights • Adults reporting past 5-year non-oral prescription stimulant NMU were studied. • Non-oral NMU preferences were snorting (59%) injecting (4%) or smoking (1%). • Polysubstance use was reported by 79.1% of the sample. • Route of administration and motivation for prescription stimulant NMU were related. • Prescription stimulant oral and intranasal NMU was to enhance performance. • Prescription stimulant intravenous and smoking NMU was to get high., Objective Increased prescription stimulant nonmedical use (NMU) is part of a growing polysubstance use landscape. The purpose of the present study was to characterize prescription stimulant NMU among adults reporting past 5-year non-oral prescription stimulant NMU. Methods Adults who reported non-oral prescription stimulant NMU within the last 5 years were recruited by banner ads placed on the Reddit website between February and September 2019. Types of prescription stimulants used, routes of administration, preferred routes of administration, motivations for prescription stimulant NMU, concurrent substances used simultaneously during prescription stimulant NMU, illicit substances used and factors impacting prescription stimulant NMU were queried. Results Respondents (n = 225) were male (86.2%), non-Hispanic (92.4%), white (78.2%), between 18 and 24 (48.0%) or 25–34 (43.1%) years with some amount of college education (81.3%). Most reported lifetime intranasal (93.8%) or oral use (85.2%). Prescription stimulants were diverted: 64.5% reported the prescription stimulants were given to them by a family or a friend and 10.5% reported that they had stolen these medications from a family or friend. Preferred route of administration was oral use (70.2%). Motivations to use were stratified by route of administration: intranasal (55.6%) or oral (63.0%) use was primarily endorsed as an attempt to enhance performance at work or at school; use by injection (57.1%) or smoking (62.5%) was primarily endorsed to get high. Most of the sample reported concurrent drug use (79.1%) including tobacco (57.3%), marijuana (52.0%), caffeine (47.6%) or alcohol (41.8%), among others. When excluding licit substances, 30.7% reported using 1 illicit substance concurrently with prescription stimulants and 25.3% reported using 2 or more illicit substances concurrently with prescription stimulants. Whether participants would undertake prescription stimulant NMU was determined by their work/school schedules or the location of the NMU (48.9%) whereas the route of administration employed was primarily influenced by the desired feeling or effect (56.9%). Conclusions Adults reporting lifetime non-oral prescription stimulant NMU engage in substantial risky behaviors that in addition to alternate routes of administration include polysubstance use, diversion and concurrent substance use.

Background Over the past decade, U.S. FDA has approved 10 opioid analgesics in abuse-deterrent formulations (ADFs). ADFs are intended to reduce abuse of a prescription opioid through manipulation of the product to use one or more routes of abuse. Although it is critically needed for evaluation of the abuse deterrent properties of an opioid product, the relationship between systemic exposure and likelihood of abuse of the opioid has not been fully characterized. To fill the current knowledge gap, we have evaluated the association of subjective measures predictive of abuse potential (e.g., scores of “drug liking,” “take drug again”), which are referred to as ‘pharmacodynamic (PD)’ responses for measuring abuse potential, with systemic exposure of the opioid using the data from all the clinical abuse potential trials submitted to FDA in support of the approval of innovator ADFs. Methods Extensive pharmacokinetic (PK) and subjective response data from 11 clinical abuse potential trials in recreational opioid users following oral and nasal administration of intact and manipulated oxycodone, hydrocodone and morphine products from the FDA internal database were utilized for the present analysis. This retrospective study used data collected from January 11th, 2010 until March 25th, 2015. The potential relationship between PK metrics, especially those for early exposure measures, and the subjective measures of drug liking and take drug again as PD metrics of abuse potential were explored using linear and logistic regression analyses. Heterogeneity analysis was conducted to assess study-to-study variation and multi-level logistic regression analysis was used to affirm the identified PK-PD relationship based on pooled data. Findings Following oral and nasal administration of intact and manipulated opioids, the maximum visual analogue scale (VAS) for Drug Liking was generally achieved no later than the time to peak plasma drug concentration. Both heterogeneity analysis and multi-level logistic regression indicated insignificant inter study variability for the evaluated PK-PD relationships. Duration of Drug Liking response (i.e., VAS ≥ 65) lasted for 2 to 4 h after drug administration. The early portion of the systemic area under the plasma concentration-time curve (AUC), e.g., partial AUCs in the first 3 h and 4 h were found to be associated with abuse potential measures including maximum Drug Liking VAS and maximum Taking Drug Again VAS. Neither a formulation factor (e.g., immediate-release vs. extended-release, intact vs. manipulated) nor a route of administration was identified as a significant factor together with early partial AUCs to predict the probability of maximum Drug Liking or maximum Take Drug Again responses being greater than or equal to 65. Interpretation Our assessment indicates that the measure of early systemic drug exposure of opioids is the best predictor of the abuse potential response in recreational opioid users following oral or nasal administration of a single dose of an intact or manipulated abuse deterrent opioids. Our findings support FDA's recommendation of comparative PK studies with early partial AUCs as a supportive PK metric for the assessment of abuse deterrent properties of generic opioid drug products in the general and product-specific guidance's of ADFs. Funding The study was partially funded by Fiscal Year 2017 Critical Path of the Center for Drug Evaluation and Research at the U.S. Food and Drug Administration.

Background Neutralizing monoclonal antibody (MAB) therapies may benefit patients with mild to moderate COVID-19 at high risk for progressing to severe COVID-19 or hospitalization. Studies documenting approaches to deliver MAB infusions and demonstrating their efficacy are lacking. Objective We describe our experience and the outcomes of almost 3000 patients who received MAB infusion therapy at Northwell Health, a large integrated health care system in New York. Methods This is a descriptive study of adult patients who received MAB therapy between November 20, 2020, to January 31, 2021, and a retrospective cohort survival analysis comparing patients who received MAB therapy prior to admission versus those who did not. A multivariable Cox model with inverse probability weighting according to the propensity score including covariates (sociodemographic, comorbidities, and presenting vital signs) was used. The primary outcome was in-hospital mortality; additional evaluations included emergency department use and hospitalization within 28 days of a positive COVID-19 test for patients who received MAB therapy. Results During the study period, 2818 adult patients received MAB infusion. Following therapy and within 28 days of a COVID-19 test, 123 (4.4%) patients presented to the emergency department and were released, and 145 (5.1%) patients were hospitalized. These 145 patients were compared with 200 controls who were eligible for but did not receive MAB therapy and were hospitalized. In the MAB group, 16 (11%) patients met the primary outcome of in-hospital mortality, versus 21 (10.5%) in the control group. In an unadjusted Cox model, the hazard ratio (HR) for time to in-hospital mortality for the MAB group was 1.38 (95% CI 0.696-2.719). Models adjusting for demographics (HR 1.1, 95% CI 0.53-2.23), demographics and Charlson Comorbidity Index (HR 1.22, 95% CI 0.573-2.59), and with inverse probability weighting according to propensity scores (HR 1.19, 95% CI 0.619-2.29) did not demonstrate significance. The hospitalization rate was 4.4% for patients who received MAB therapy within 0 to 4 days, 5% within 5 to 7 days, and 6.1% in ≥8 days of symptom onset (P=.15). Conclusions Establishing the capability to provide neutralizing MAB infusion therapy requires substantial planning and coordination. Although this therapy may be an important treatment option for early mild to moderate COVID-19 in patients who are at high risk, further investigations are needed to define the optimal timing of MAB treatment to reduce hospitalization and mortality.