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Results 1 through 20 out of 997

in category pharmacology and toxicology

 

1: Toxicity of JUUL Fluids and Aerosols Correlates Strongly with Nicotine and Some Flavor Chemical Concentrations

Esther E. Omaiye, Kevin J McWhirter et al.

26,442 downloads (posted 09 Dec 2018)

While JUUL electronic cigarettes (ECs) have captured the majority of the EC market with a large fraction of their sales going to adolescents, little is known about their cytotoxicity and potential effects on health. The purpose of this study was to determine flavor chemical and nicotine concentrations in the eight currently marketed pre-filled JUUL EC cartridges (pods) and to evaluate the cytotoxicity of the different variants (e.g., Cool Mint and Creme Brulee) using in vitro assays. Nicotine and flavor chemicals were analyzed using gas chromatography/mass spectrometry in pod fluid before and after vaping and in the corresponding aerosols. 59 flavor chemicals were identified in JUUL pod fluids, and three were >1 mg/mL. Duplicate pods were similar in flavor chemical composition and concentration. Nicotine concentrations (average 60.9 mg/mL) were significantly higher than any EC products we have analyzed previously. Transfer efficiency of individual flavor chemicals that were >1mg/mL and nicotine from the pod fluid into aerosols was generally 35 - 80%. All pod fluids were cytotoxic at a 1:10 dilution (10%) in the MTT and neutral red uptake assays when tested with BEAS-2B lung epithelial cells. Most aerosols were cytotoxic in these assays at concentrations >1%. The cytotoxicity of aerosols was highly correlated with nicotine and ethyl maltol concentrations and moderately to weakly correlated with total flavor chemical concentration and menthol concentration. Our study demonstrates that: (1) some JUUL flavor pods have high concentrations of flavor chemicals that may make them attractive to youth, and (2) the concentrations of nicotine and some flavor chemicals (e.g. ethyl maltol) are high enough to be cytotoxic in acute in vitro assays, emphasizing the need to determine if JUUL products will lead to adverse health effects with chronic use.

https://rxivist.org/papers/38247
https://doi.org/10.1101/490607

2: Fatal toxicity of chloroquine or hydroxychloroquine with metformin in mice

N.V Rajeshkumar, Shinichi Yabuuchi et al.

10,156 downloads (posted 04 Apr 2020)

Guided by the principle of primum non nocere (first do no harm), we report a cautionary note on the potential fatal toxicity of chloroquine (CQ) or hydroxychloroquine (HCQ) in combination with anti-diabetic drug metformin. We observed that the combination of CQ or HCQ and metformin, which were used in our studies as potential anti-cancer drugs, killed 30-40% of mice. While our observations in mice may not translate to toxicity in humans, the reports that CQ or HCQ has anti-COVID-19 activity, the use of CQ resulting in t...

https://rxivist.org/papers/78811
https://doi.org/10.1101/2020.03.31.018556

3: Nelfinavir was predicted to be a potential inhibitor of 2019 nCov main protease by an integrative approach combining homology modelling, molecular docking and binding free energy calculation

Zhijian Xu, Cheng Peng et al.

8,919 downloads (posted 28 Jan 2020)

2019-nCov has caused more than 80 deaths as of 27 January 2020 in China, and infection cases have been reported in more than 10 countries. However, there is no approved drug to treat the disease. 2019-nCov Mpro is a potential drug target to combat the virus. We built homology models based on SARS Mpro structures, and docked 1903 small molecule drugs to the models. Based on the docking score and the 3D similarity of the binding mode to the known Mpro ligands, 4 drugs were selected for binding free energy calculations. Bo...

https://rxivist.org/papers/72183
https://doi.org/10.1101/2020.01.27.921627

4: Garcinia cambogia extract removes calcium oxalate kidney stones in both genetic and non-genetic Drosophila models of nephrolithiasis

Qiuxia Fan, Xiaoming Feng et al.

6,767 downloads (posted 27 Nov 2018)

Kidney stone formers with family history have a high rate of stone recurrence after kidney stone removal surgery and there is no effective medication available for treatment. Here, we show that Garcinia cambogia extract (GCE) efficiently removes calcium oxalate kidney stones from Malpighian tubules in both genetic and non-genetic Drosophila models of nephrolithiasis, and hydroxycitrate -a major component of GCE, directly dissolves calcium oxalate stones in Drosophila Malpighian tubules ex vivo. Our study discovers a pot...

https://rxivist.org/papers/37355
https://doi.org/10.1101/477570

5: Therapeutic Drugs Targeting 2019-nCoV Main Protease by High-Throughput Screening

Yan Li, Jinyong Zhang et al.

6,406 downloads (posted 29 Jan 2020)

2019 Novel Coronavirus (2019-nCoV) is a virus identified as the cause of the outbreak of pneumonia first detected in Wuhan, China. Investigations on the transmissibility, severity, and other features associated with this virus are ongoing. Currently, there is no vaccine or therapeutic antibody to prevent the infection, and more time is required to develop an effective immune strategy against the pathogen. In contrast, specific inhibitors targeting the key protease involved in replication and proliferation of the virus a...

https://rxivist.org/papers/72266
https://doi.org/10.1101/2020.01.28.922922

6: LSD impairs working memory, executive functions, and cognitive flexibility, but not risk-based decision making

Thomas Pokorny, Patricia Duerler et al.

5,090 downloads (posted 28 Jan 2019)

Psychiatric and neurodegenerative illnesses are characterized by cognitive impairments, in particular deficits in working memory, decision making, and executive functions including cognitive flexibility. However, the neuropharmacology of these cognitive functions is poorly understood. The serotonin (5-HT) 2A receptor might be a promising candidate for the modulation of cognitive processes. However, pharmacological studies investigating the role of this receptor system in humans are rare. Recent evidence demonstrates tha...

https://rxivist.org/papers/42627
https://doi.org/10.1101/532234

7: Novel Natural Product Discovery from Marine Sponges and their Obligate Symbiotic Organisms

Regina R. Monaco, Rena F. Quinlan

5,014 downloads (posted 24 May 2014)

Abstract: Discovery of novel natural products is an accepted method for the elucidation of pharmacologically active molecules and drug leads. Best known sources for such discovery have been terrestrial plants and microbes, accounting for about 85% of the approved natural products in pharmaceutical use (1), and about 60% of approved pharmaceuticals and new drug applications annually (2). Discovery in the marine environment has lagged due to the difficulty of exploration in this ecological niche. Exploration began in earn...

https://rxivist.org/papers/27732
https://doi.org/10.1101/005454

8: AI-aided design of novel targeted covalent inhibitors against SARS-CoV-2

Bowen Tang, Fengming He et al.

4,515 downloads (posted 08 Mar 2020)

The focused drug repurposing of known approved drugs (such as lopinavir/ritonavir) has been reported failed for curing SARS-CoV-2 infected patients. It is urgent to generate new chemical entities against this virus. As a key enzyme in the life-cycle of coronavirus, the 3C-like main protease (3CLpro or Mpro) is the most attractive for antiviral drug design. Based on a recently solved structure (PDB ID: 6LU7), we developed a novel advanced deep Q-learning network with the fragment-based drug design (ADQN-FBDD) for generat...

https://rxivist.org/papers/76198
https://doi.org/10.1101/2020.03.03.972133

9: Iota carrageenan and xylitol inhibit SARS-CoV-2 in Vero cell culture

Julio Cesar Vega, Shruti Bansal et al.

3,593 downloads (posted 21 Aug 2020)

COVID-19 (coronavirus disease 2019) is a pandemic caused by SARS-CoV-2 (severe acute respiratory syndrome-coronavirus 2) infection affecting millions of persons around the world. There is an urgent unmet need to provide an easy-to-produce, affordable medicine to prevent transmission and provide early treatment for this disease. The nasal cavity and the rhinopharynx are the sites of initial replication of SARS-CoV-2. Therefore, a nasal spray may be a suitable dosage form for this purpose. The main objective of our study ...

https://rxivist.org/papers/95182
https://doi.org/10.1101/2020.08.19.225854

10: Scutellaria baicalensis extract and baicalein inhibit replication of SARS-CoV-2 and its 3C-like protease in vitro

Hongbo Liu, Fei Ye et al.

3,517 downloads (posted 12 Apr 2020)

COVID-19 has become a global pandemic that threatens millions of people worldwide. There is an urgent call for developing effective drugs against the virus (SARS-CoV-2) causing this disease. The main protease of SARS-CoV-2, 3C-like protease (3CLpro), is highly conserved across coronaviruses and is essential for the maturation process of viral polyprotein. Scutellariae radix (Huangqin in Chinese), the root of Scutellaria baicalensis has been widely used in traditional Chinese medicine to treat viral infection related sym...

https://rxivist.org/papers/79639
https://doi.org/10.1101/2020.04.10.035824

11: Human ACE2 peptide mimics block SARS-CoV-2 Pulmonary Cells Infection

Philippe Karoyan, Vincent Vieillard et al.

3,487 downloads (posted 24 Aug 2020)

In the light of the recent accumulated knowledge on SARS-CoV-2 and its mode of human cells invasion, the binding of viral spike glycoprotein to human Angiotensin Converting Enzyme 2 (hACE2) receptor plays a central role in cell entry. We designed a series of peptides mimicking the N-terminal helix of hACE2 protein which contains most of the contacting residues at the binding site and have a high helical folding propensity in aqueous solution. Our best peptide mimics bind to the virus spike protein with high affinity and...

https://rxivist.org/papers/95509
https://doi.org/10.1101/2020.08.24.264077

12: Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease

Chunlong Ma, Michael D. Sacco et al.

3,486 downloads (posted 20 Apr 2020)

A novel coronavirus SARS-CoV-2, also called novel coronavirus 2019 (nCoV-19), started to circulate among humans around December 2019, and it is now widespread as a global pandemic. The disease caused by SARS-CoV-2 virus is called COVID-19, which is highly contagious and has an overall mortality rate of 6.96% as of May 4, 2020. There is no vaccine or antiviral available for SARS-CoV-2. In this study, we report our discovery of inhibitors targeting the SARS-CoV-2 main protease (Mpro). Using the FRET-based enzymatic assay,...

https://rxivist.org/papers/80546
https://doi.org/10.1101/2020.04.20.051581

13: Nucleotide Analogues as Inhibitors of SARS-CoV Polymerase

Jingyue Ju, Xiaoxu Li et al.

3,482 downloads (posted 14 Mar 2020)

SARS-CoV-2, a member of the coronavirus family, has caused a global public health emergency. Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously reasoned that the FDA-approved heptatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) should inhibit coronaviruses, including SARS-CoV-2. Here, using model polymerase extension experiments, we demonstrate that the activated triphosphate form of Sofosbuvir is incorporated by low-fideli...

https://rxivist.org/papers/76745
https://doi.org/10.1101/2020.03.12.989186

14: Nucleotide Analogues as Inhibitors of Viral Polymerases

Jingyue Ju, Shiv Kumar et al.

3,441 downloads (posted 31 Jan 2020)

Coronaviruses such as the newly discovered virus from Wuhan, China, 2019-nCoV, and the viruses that cause SARS and MERS, have resulted in regional and global public health emergencies. Based on our molecular insight that the hepatitis C virus and the coronavirus use a similar viral genome replication mechanism, we reasoned that the FDA-approved drug EPCLUSA (Sofosbuvir/Velpatasvir) for the treatment of hepatitis C will also inhibit the above coronaviruses, including 2019-nCoV. To develop broad spectrum anti-viral agents...

https://rxivist.org/papers/72576
https://doi.org/10.1101/2020.01.30.927574

15: Triphosphates of the Two Components in DESCOVY and TRUVADA are Inhibitors of the SARS-CoV-2 Polymerase

Steffen Jockusch, Chuanjuan Tao et al.

3,392 downloads (posted 05 Apr 2020)

SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 pandemic. We previously demonstrated that four nucleotide analogues (specifically, the active triphosphate forms of Sofosbuvir, Alovudine, AZT and Tenofovir alafenamide) inhibit the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). Tenofovir and emtricitabine are the two components in DESCOVY and TRUVADA, the two FDA-approved medications for use as pre-exposure prophylaxis (PrEP) to prevent HIV infection. This is a preventative method ...

https://rxivist.org/papers/79001
https://doi.org/10.1101/2020.04.03.022939

16: Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase

Minchen Chien, Thomas K. Anderson et al.

3,141 downloads (posted 20 Mar 2020)

SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 pandemic. Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously demonstrated that three nucleotide analogues inhibit the SARS-CoV RNA-dependent RNA polymerase (RdRp). Here, using polymerase extension experiments, we have demonstrated that the active triphosphate form of Sofosbuvir (a key component of the FDA approved hepatitis C drug EPCL...

https://rxivist.org/papers/77406
https://doi.org/10.1101/2020.03.18.997585

17: A New Big-Data Paradigm For Target Identification And Drug Discovery

Neel S. Madhukar, Prashant K. Khade et al.

3,081 downloads (posted 07 May 2017)

Drug target identification is one of the most important aspects of pre-clinical development yet it is also among the most complex, labor-intensive, and costly. This represents a major issue, as lack of proper target identification can be detrimental in determining the clinical application of a bioactive small molecule. To improve target identification, we developed BANDIT, a novel paradigm that integrates multiple data types within a Bayesian machine-learning framework to predict the targets and mechanisms for small mol...

https://rxivist.org/papers/27684
https://doi.org/10.1101/134973

18: Enhancing Intracellular Accumulation and Target Engagement of PROTACs with Reversible Covalent Chemistry

Wen-Hao Guo, Xiaoli Qi et al.

3,009 downloads (posted 30 Dec 2019)

Current efforts in the proteolysis targeting chimera (PROTAC) field mostly focus on choosing an appropriate E3 ligase for the target protein, improving the binding affinities towards the target protein and the E3 ligase, and optimizing the PROTAC linker. However, due to the large molecular weights of PROTACs, their cellular uptake remains an issue. Through comparing how different warhead chemistry, reversible noncovalent (RNC), reversible covalent (RC), and irreversible covalent (IRC) binders, affects the degradation of...

https://rxivist.org/papers/69920
https://doi.org/10.1101/2019.12.30.873588

19: Discovery of a Novel Inhibitor of Coronavirus 3CL Protease as a Clinical Candidate for the Potential Treatment of COVID-19

Britton Boras, Rhys M. Jones et al.

2,968 downloads (posted 13 Sep 2020)

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential to the viral life cycle across a broad spectrum of coronaviruses with no close human analogs. The designed phosphate prodrug PF-07304814 is metabolized to PF-00835321 which is a potent inhibitor in vitro of the coronavirus family 3CL pro, with selectivity over human host protease targets. Furthermore, PF-00835231 exhibits potent in vitro antiviral activity against SARS-CoV-2 as a single agent...

https://rxivist.org/papers/99457
https://doi.org/10.1101/2020.09.12.293498

20: Traffic-derived particulate matter and angiotensin-converting enzyme 2 expression in human airway epithelial cells

L Miyashita, G Foley et al.

2,774 downloads (posted 15 May 2020)

Background: The mechanism for the association between traffic-derived particulate matter less than 10 microns (PM10) and cases of COVID-19 disease reported in epidemiological studies is unknown. To infect cells, the spike protein of SARS-CoV-2 interacts with angiotensin-converting enzyme 2 (ACE2) on host airway cells. Increased ACE2 expression in lower airway cells in active smokers, suggests a potential mechanism whereby PM10 increases vulnerability to COVID-19 disease. Objective: To assess the effect of traffic-derive...

https://rxivist.org/papers/83644
https://doi.org/10.1101/2020.05.15.097501