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Rxivist combines biology preprints from bioRxiv and medRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 118,598 papers from 511,573 authors.

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in category pharmacology and toxicology

1,014 results found. For more information, click each entry to expand.

961: Accelerated erythrocyte senescence causes dose-limiting anemia of antimalarial enolase inhibitors
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Posted 10 Oct 2020

Accelerated erythrocyte senescence causes dose-limiting anemia of antimalarial enolase inhibitors
77 downloads bioRxiv pharmacology and toxicology

Andrew J. Jezewski, Yu-Hsi Lin, Julie A. Reisz, Rachel Culp-Hill, Yasaman Barekatain, Victoria C. Yan, Angelo D'Alessandro, Florian L. Muller, Audrey R. Odom John

Glycolysis controls cellular energy, redox balance, and biosynthesis. Antiglycolytic therapies are being investigated for obesity, cancer, aging, autoimmunity, and microbial diseases. Interrupting glycolysis is highly valued as a therapeutic strategy, because glycolytic disruption is generally tolerated in mammals. Unfortunately, anemia is a key dose-limiting side effect of these inhibitors and presents a major caveat to development of antiglycolytic therapies. We developed specific inhibitors of enolase (a critical enzyme in glycolysis) and validated their metabolic and cellular effects on human erythrocytes. Enolase inhibition increases erythrocyte susceptibility to oxidative damage that induces rapid and premature erythrocyte senescence, rather than direct hemolysis. We apply our model of red cell toxicity to address questions regarding erythrocyte glycolytic disruption in the context of malaria pathogenesis. Our study provides a framework for understanding red blood cell homeostasis under normal and disease states and clarifies the importance of erythrocyte reductive capacity. ### Competing Interest Statement The authors have declared no competing interest.

962: Nicotine dosimetry and stability in Cambridge Filter PADs (CFPs) following different smoking regimen protocols and condition storage
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Posted 10 Sep 2020

Nicotine dosimetry and stability in Cambridge Filter PADs (CFPs) following different smoking regimen protocols and condition storage
77 downloads bioRxiv pharmacology and toxicology

Pietro Zuccarello, Sonja Rust, Massimo Caruso, Rosalia Emma, Roberta Pulvirenti, Claudia Favara, R. Polosa, Giovanni Li Volti, Margherita Ferrante

Despite the growing numbers of studies with cigarettes and other electronic nicotine delivery products (ENDs), there is no standard covering nicotine dosimetry and its stability in various matrix. The aim of the present study was to provide a protocol to normalize nicotine concentration adsorbed in Cambridge Filter PADs (CFPs) and their storage method. Smoke/vapor generated by a reference tobacco cigarette (1R6F) and ENDs with different exposure regimes (ISO, HCI and CRM81) was collected in CFPs. For each exposure, some CFPs were analyzed at time zero, whereas the others were stored under different conditions for nicotine assessment after 30 days. Principal Component Analysis (PCA) was also performed to establish the best parameter for nicotine normalization. PCA showed the best correlation between nicotine in CFPs and TPM. Our results showed differences between products and puffing regimes, but storage of CFPs at −80°C was always effective in maintaining the nicotine content. In conclusion, this study highlights that different exposure regimens and products can affect the preservation of nicotine titer in CFPs and samples storage at −80°C may prevent the loss of nicotine. These conditions are recommended and should be adopted for Inter-laboratory comparison studies on ENDs to ensure harmonization between participating laboratories. ### Competing Interest Statement In relation to his work in the area of tobacco control and respiratory diseases, Riccardo Polosa has received lecture fees and research funding from Pfizer, Inc., GlaxoSmithKline plc, CV Therapeutics, NeuroSearch A/S, Sandoz, MSD, Boehringer Ingelheim, Novartis, Duska Therapeutics, and Forest Laboratories. He has also served as a consultant for Pfizer, Inc., Global Health Alliance for treatment of tobacco dependence, CV Therapeutics, NeuroSearch A/S, Boehringer Ingelheim, Duska Therapeutics, Forest Laboratories, ECITA (Electronic Cigarette Industry Trade Association, in the UK), and Health Diplomat (consulting company that delivers solutions to global health problems with special emphasis on harm minimization). Lecture fees from a number of European EC industry and trade associations (including Federation Interprofessionnelle de la VAPE in France and Federazione Italiana Esercenti Svapo Elettronico in Italy) were directly donated to vaper advocacy no-profit organizations. He is currently Head of the European Technical Committee for standardization on Requirements and test methods for emissions of electronic cigarettes (CEN/TC 437; WG4). He is also founder of the Center of Excellence for the acceleration of Harm Reduction at the University of Catania (CoEHAR), which has received a grant from the Foundation for a Smoke Free World to support 8 independent investigator-initiated research projects on tobacco harm reduction, and scientific advisor for LIAF, Lega Italiana Anti Fumo (Italian acronym for Italian Anti-Smoking League). Prof. Li Volti is currently elected Director of the Center of Excellence for the acceleration of HArm Reduction. All the other authors declare no conflicts of interest.

963: Antifungal effects of PC945, a novel inhaled triazole, on Candida albicans-infected immunocompromised mice
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Posted 27 Jul 2020

Antifungal effects of PC945, a novel inhaled triazole, on Candida albicans-infected immunocompromised mice
77 downloads bioRxiv pharmacology and toxicology

Yuki Nishimoto, Kazuhiro Ito, Genki Kimura, Kirstie A. Lucas, Leah Daly, Pete Strong, Yasuo Kizawa

Although Candida spp. are frequently detected in fungal cultures of respiratory secretions, their presence is normally assumed to reflect benign colonization. However, there is growing evidence that Candida spp. are involved in the pathogenesis of respiratory diseases such as bronchiectasis and asthma.  The aim of this study is to investigate the in vitro and in vivo effects of a novel antifungal triazole, PC945, optimised for topical delivery, against C. albicans. In temporarily neutropenic, immunocompromised mice, C. albicans (529L [ATCC®MYA4901™] strain), inoculated intranasally, induced acute lung injury and death, associated with higher fungal burden and cytokine induction in the lung.  PC945 saline suspension, dosed intranasally once daily, starting one day post candida inoculation, dose-dependently (0.56 ~ 14 μg/mouse) improved survival rate and inhibited fungal load in the lung on Day 5 post inoculation. These effects by PC945 were 7 ~ 25-fold more potent than those of voriconazole, despite being of similar in vitro antifungal activity versus this strain. Furthermore, extended prophylaxis with low dose PC945 (0.56 μg/mouse) was found to inhibit fungal load more potently than the shorter treatment regimens, suggesting antifungal effects of PC945 accumulated on repeat dosing. In addition, antifungal susceptibility testing on 88 candida isolates (C. albicans, C. parapsilosis, C. tropicalis, C. lucitaniae, C. glabrata, C. guilliermondii) revealed that PC945 has potent effects on Candida species broadly. Thus, PC945 has the potential to be a novel topical therapy for the treatment of C. albicans pulmonary infection in humans.

964: The anti-mycobacterial activity of Artemisia annua L is based on deoxyartemisinin and artemisinic acid
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Posted 25 Oct 2020

The anti-mycobacterial activity of Artemisia annua L is based on deoxyartemisinin and artemisinic acid
77 downloads bioRxiv pharmacology and toxicology

Sumana Bhowmick, Rafael Baptista, David Fazakerley, Kezia Whatley, Karl F. Hoffmann, Jianying Shen, Luis A Mur

The discovery of antimalarial artemisinin from Artemisia annua L. is an example of how Traditional Chinese Medicine (TCM) may be exploited to meet a recognized need. In this study, we systemically investigated A. annua L. for its antimicrobial activity and assessed it as a source of bioactive natural products for anti-mycobacterial activity. We used a silica gel column to perform antimicrobial activity-guided purification of the A. annua leaf, whose identity was confirmed by rbcL DNA barcoding, and used UHPLC-HRMS and NMR to elucidate the structure of purified active compounds. The antimicrobial activity of crude extracts, isolated compounds and the control artemisinin (Apollo Scientific Ltd) was assessed against Escherichia coli , Pseudomonas aeruginosa , Staphylococcus aureus , methicillin-resistant Staphylococcus aureus (MRSA), Mycobacterium smegmatis strains by serial micro dilution method (31.25-1000 μg/mL). The isolated compounds were tested for synergistic effects against mycobacterium. Bioactive compounds were purified and identified as deoxyartemisinin and artemisinic acid. Artemisinic acid (MIC 250 μg/mL) was more effective in comparison to deoxyartemisinin (MIC 500 μg/mL) and artemisinin (MIC 1000 μg/mL) against M. smegmatis . We used a molecular docking approach to investigate the interactions between selected anti-mycobacterial compounds and proteins involved in vital physiological functions in M. tuberculosis , namely MtPks13 , MtPknB , MtPanK , MtKasA , MtInhA and MtDprE1 and found artemisinic acid showed docking scores superior to the control inhibiters for MtKasA , suggesting it to be a potential nick for further in vitro biological evaluation and anti-TB drug design. ### Competing Interest Statement The authors have declared no competing interest.

965: Pathway-extended gene expression signatures integrate novel biomarkers that improve predictions of patient responses to kinase inhibitors
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Posted 15 Nov 2020

Pathway-extended gene expression signatures integrate novel biomarkers that improve predictions of patient responses to kinase inhibitors
76 downloads bioRxiv pharmacology and toxicology

Ashis J. Bagchee-Clark, Eliseos J Mucaki, Tyson Whitehead, Peter K Rogan

Cancer chemotherapy responses have been related to multiple pharmacogenetic biomarkers, often for the same drug. This study utilizes machine learning to derive multi-gene expression signatures that predict individual patient responses to specific tyrosine kinase inhibitors, including erlotinib, gefitinib, sorafenib, sunitinib, lapatinib and imatinib. Support Vector Machine learning was used to train mathematical models that distinguished sensitivity from resistance to these drugs using a novel systems biology-based approach. This began with expression of genes previously implicated in specific drug responses, then expanded to evaluate genes whose products were related through biochemical pathways and interactions. Optimal pathway-extended support vector machines predicted responses in patients at accuracies of 70% (imatinib), 71% (lapatinib), 83% (sunitinib), 83% (erlotinib), 88% (sorafenib) and 91% (gefitinib). These best performing pathway-extended models demonstrated improved balance predicting both sensitive and resistant patient categories, with many of these genes having a known role in cancer etiology. Ensemble machine learning-based averaging of multiple pathway-extended models derived for an individual drug increased accuracy to >70% for erlotinib, gefitinib, lapatinib, and sorafenib. Through incorporation of novel cancer biomarkers, machine learning-based pathway-extended signatures display strong efficacy predicting both sensitive and resistant patient responses to chemotherapy. ### Competing Interest Statement Peter K. Rogan is a co-founder of CytoGnomix, which hosts a chemotherapy response calculator for prediction of response to the gene signatures described in this study. A patent application has been submitted describing the contents of this manuscript.

966: Morphological plasticity in Chlamydomonas reinhardtii and acclimation to micropollutant stress
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Posted 31 Aug 2020

Morphological plasticity in Chlamydomonas reinhardtii and acclimation to micropollutant stress
75 downloads bioRxiv pharmacology and toxicology

Giulia Cheloni, Vera I. Slaveykova

Phytoplankton are characterized by a great phenotypic plasticity and amazing morphological variability, both playing a primary role in the acclimation to changing environments. However, there is a knowledge gap concerning the role of algal morphological plasticity in stress responses and acclimation to micropollutants. The present study aims examining the palmelloid colony formation of the green alga Chlamydomonas reinhardtii upon micropollutants exposure. Cells were exposed to four micropollutants (MPs) with different modes of action (copper, cadmium, PFOS and paraquat) for a duration of 72h. Effects of MPs on palmelloid formation, growth and physiological traits (chlorophyll fluorescence, membrane integrity and oxidative stress) were monitored via flow cytometry and fluorescence microscopy. Palmelloid formation was observed upon treatment with the four micropollutants. Number of palmelloid colonies and their size were dependent on MP concentration and exposure duration. Cells reverted to their unicellular lifestyle when colonies were harvested and inoculated in fresh medium indicating that palmelloid formation is a plastic response to micropollutants. No physiological effects of these compounds were observed in cells forming palmelloids and palmelloid colonies accumulated lower Cd concentration than unicellular C. reinhardtii suggesting that colony formation protects the cells form MPs exposure. The results show that colony formation in Chlamydomonas reinhardtii is a stress response strategy activated to face sub-lethal micropollutant concentrations. HIGHLIGHTS ### Competing Interest Statement The authors have declared no competing interest. * FCM : flow cytometry MP : micropollutant PFOS : Perfluorooctanesulfonic acid

967: A vapor exposure method for delivering heroin alters nociception, body temperature and spontaneous activity in female and male rats
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Posted 04 Sep 2020

A vapor exposure method for delivering heroin alters nociception, body temperature and spontaneous activity in female and male rats
75 downloads bioRxiv pharmacology and toxicology

Arnold Gutierrez, Kevin M Creehan, Michael A. Taffe

Background The ongoing crisis related to non-medical use of opioids makes it of continued importance to understand the risk factors for opioid addiction, the behavioral and neurobiological consequences of opioid exposure and to seek potential avenues for therapy. Pre-clinical rodent models have been critical to advancing understanding of opioid consequences for decades, but have been mostly limited to drug delivery by injection or by oral dosing. Inhalation, a significant route for many human users, has not been as well-established. Method We adapted an e-cigarette based exposure system, previously shown efficacious for delivery of other drugs to rats, to deliver heroin vapor. Effects in vivo were assessed in male and female Sprague-Dawley rats using a warm-water assay for anti-nociception and an implanted radiotelemetry system for evaluating changes in body temperature and spontaneous activity rate. Results Inhalation of vapor created by heroin 100 mg/mL in the propylene glycol (PG) vehicle significantly slowed tail-withdrawal from a 52°C water bath, bi-phasically altered activity, and increased temperature in male and female rats. Inhalation of heroin 50 mg/mL for 15 minutes produced significant effects, as the lower bound on efficacy, whereas inhalation of heroin 100 mg/mL for 30 minutes produced robust effects across all endpoints and groups. Conclusions This work shows that e-cigarette devices deliver psychoactive doses of heroin to rats, using concentrations of ∼50-100 mg/mL and inhalation durations of 15-30 minutes. This technique may be useful to assess the health consequences of inhaled heroin and other opioid drugs. ### Competing Interest Statement The authors have declared no competing interest.

968: EP3 signaling is decoupled from regulation of glucose-stimulated insulin secretion in β-cells compensating for obesity and insulin resistance
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Posted 11 Jul 2020

EP3 signaling is decoupled from regulation of glucose-stimulated insulin secretion in β-cells compensating for obesity and insulin resistance
74 downloads bioRxiv pharmacology and toxicology

Michael D. Schaid, Jeffrey M. Harrington, Grant M. Kelly, Sophia M. Sdao, Matthew J. Merrins, Michelle E. Kimple

Of the β-cell signaling pathways altered by non-diabetic obesity and insulin resistance, some are adaptive while others actively contribute to β-cell failure and demise. Cytoplasmic calcium (Ca2+) and cyclic AMP (cAMP), which control the timing and amplitude of insulin secretion, are two important signaling intermediates that can be controlled by stimulatory and inhibitory G protein-coupled receptors. Previous work has shown the importance of the cAMP-inhibitory EP3 receptor in the beta-cell dysfunction of type 2 diabetes. To examine alterations in β-cell cAMP during diabetes progression we utilized a β-cell specific cAMP biosensor in tandem with islet Ca2+ recordings and insulin secretion assays. Three groups of C57BL/6J mice were used as a model of the progression from metabolic health to type 2 diabetes: wildtype, normoglycemic LeptinOb, and hyperglycemic LeptinOb. Here, we report robust increases in β-cell cAMP and insulin secretion responses in normoglycemic Leptinob mice as compared to wild-type: an effect that was lost in islets from hyperglycemic Leptinob mice, despite elevated Ca2+ duty cycle. Yet, the correlation of EP3 expression and activity to reduce cAMP levels and Ca2+ duty cycle with reduced insulin secretion only held true in hyperglycemic LeptinOb mice. Our results suggest alterations in beta-cell EP3 signaling may be both adaptive and maladaptive and define β-cell EP3 signaling as much more nuanced than previously understood. ### Competing Interest Statement The authors have declared no competing interest.

969: Effects of gypenosides on enteroendocrine L-cell function and GLP-1 secretion
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Posted 07 Sep 2020

Effects of gypenosides on enteroendocrine L-cell function and GLP-1 secretion
74 downloads bioRxiv pharmacology and toxicology

Chinmai Patibandla, Erin Campbell, Xinhua Shu, Angus M Shaw, Sharron Dolan, Steven Patterson

Glucagon-like peptide 1 (GLP-1) is an incretin hormone produced in gut L-cells, which regulates postprandial glucose-dependent insulin secretion, also known as the incretin effect. GLP-1 secretion may be reduced in type 2 diabetes mellitus, impacting on glycaemic regulation. Thus, methods to enhance endogenous GLP-1 secretion by use of natural GLP-1 secretagogues may improve glucose control in diabetes. Gypenosides (GYP) extracted from the plant Gynostemma Pentaphyllum (Jiaogulan) are known for their glucose-lowering effects both in vitro and in vivo , although their effect on GLP-1 secretion is unknown. Our results showed that GYP enhanced cell viability and significantly upregulated antioxidant gene Nrf2, Cat and Ho-1 expression. GYP did not affect glucokinase expression but downregulated proglucagon gene expression over 24h, although, cellular GLP-1 content was unchanged. Prohormone convertase 1 (Pcsk1) gene expression was unchanged by GYP over 24h, although protein levels were significantly downregulated, while prohormone convertase 2 (Pcsk2) mRNA and protein levels were significantly upregulated. Acute exposure to gypenosides enhanced calcium uptake and GLP-1 release from GLUTag cells both at low and high glucose concentrations. These results suggest that anti-diabetic properties of gypenosides are partly linked to their ability to stimulate GLP-1 secretion. Gypenosides enhance antioxidant gene expression and may protect L-cells from excess oxidative stress. ### Competing Interest Statement The authors have declared no competing interest. * GLP-1 : Glucagon-like peptide-1 GYP : Gypenosides T2DM : Type 2 diabetes mellitus Ncx : Sodium/Calcium exchange channel Sglt1 : Sodium/glucose cotransporter 1 Gcg : Glucagon Gck : Glucokinase Pc1 : Prohormone convertase-1 Pc2 : Prohormone convertase-2 Nrf2 : Nuclear factor erythroid 2-related factor 2 NFkb1 : Nuclear factor Kappa b1 Cat : Catalase Ho-1 : Heme oxygenase-1 MTT : 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

970: A novel and potent thrombolytic fusion protein consisting of anti-insoluble fibrin antibody and mutated urokinase
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Posted 08 Sep 2020

A novel and potent thrombolytic fusion protein consisting of anti-insoluble fibrin antibody and mutated urokinase
73 downloads bioRxiv pharmacology and toxicology

Shingo Hanaoka, Shinji Saijou, Yasuhiro Matsumura

Because the risk of thromboembolism increases with age, as well as due to infectious diseases, safer and more effective thrombolytic agents are in greater demand. Tissue plasminogen activator (tPA) is currently used clinically because it has higher binding specificity for insoluble fibrin (IF) than urokinase (UK), but even pro-tPA has catalytic activity in places other than IF. Meanwhile, UK has the advantage that it is specifically activated on IF, but it only binds IF weakly. Unlike the anti-IF monoclonal antibody (mAb) established in the past, our anti-IF mAb recognizes a pit structure formed only in IF. Here, we developed a new mAb against the pit, 1101, that does not affect coagulation or fibrinolysis, and prepared a fusion protein of UK with humanized 1101 Fab to transport UK selectively to IF. In IF-containing lesions, UK is cleaved by plasmin at two sites, Lys158/Ile159 and Lys135/Lys136. Cleavage of the former leads to activation of UK; however, because activated UK is linked by S-S bonds before and after cleavage, it is not released from the fusion. Cleavage at the latter site causes UK to leave the fusion protein; hence, we mutated Lys135/Lys136 to Gly135/Gly136 to prevent release of UK. This engineered UK-antibody fusion, AMU1114, significantly decreased the systemic side effects of UK in vivo . In a mouse thrombus formation experiment, the vascular patency rate was 0% (0/10) in the control, 50% (5/10) in the tPA, and 90% (9/10) in the AMU1114 treatment group. These data support future clinical development of AMU1114. ### Competing Interest Statement Y.M. is co-founder, shareholder, and Board Member of RIN Institute, Inc., a venture company spun out from the National Cancer Center, Japan. S.H. and S.S. are employees of RIN Institute, Inc.

971: Discovery of a Novel, Selective and Short-Acting Skeletal Myosin II Inhibitor
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Posted 29 Jul 2020

Discovery of a Novel, Selective and Short-Acting Skeletal Myosin II Inhibitor
73 downloads bioRxiv pharmacology and toxicology

Laszlo Radnai, Matthew Surman, Madalyn Hafenbreidel, Erica J Young, Rebecca F Stremel, Li Lin, Paolo Pasetto, Xiaomin Jin, Mackenzie Geedy, Joni-Rae Partridge, Aagam Patel, Michael Conlon, James R. Sellers, Michael D Cameron, Gavin Rumbaugh, Patrick R Griffin, Theodore M. Kamenecka, Courtney A. Miller

Myosin IIs, actin-based motors that utilize the chemical energy of ATP to generate force, have potential as therapeutic targets. Their heavy chains differentiate the family into muscle (skeletal [SkMII], cardiac, smooth) and nonmuscle myosin IIs. Despite therapeutic potential for muscle disorders, no SkMII-specific inhibitor has been reported and characterized. Here we present the discovery, synthesis and characterization of 'skeletostatins', novel derivatives of the pan-myosin II inhibitor blebbistatin, with selectivity within the myosin IIs for SkMII. In addition, the skeletostatins bear improved potency, solubility and photostability, without cytotoxicity. Based on its optimal in vitro profile, Skeletostatin 1's in vivo tolerability, efficacy and pharmacokinetics were determined. Skeletostatin 1 was well-tolerated in mice, impaired motor performance, and had an excellent muscle to plasma ratio. Skeletostatins are useful probes for basic research and a strong starting point for drug development. ### Competing Interest Statement The authors have declared no competing interest.

972: Accelerated tissue repair through cell proliferative effect by a size controlled aqueous based Fullerene C60 nanoformulation
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Posted 03 Jul 2020

Accelerated tissue repair through cell proliferative effect by a size controlled aqueous based Fullerene C60 nanoformulation
73 downloads bioRxiv pharmacology and toxicology

Nabodita Sinha, Avinash Y. Gahane, Ashwani Kumar Thakur

We have developed Fullerene-C60 nanoformulations containing discrete sized nanoparticles by dispersing the concentration range of Fullerene. Small-sized particles are cytotoxic while larger ones are cell proliferative. The cell proliferative property is used for tissue repair in cellular and animal wound models. ### Competing Interest Statement The authors have declared no competing interest.

973: PDE1 inhibition modulates Cav1.2 channel to stimulate cardiomyocyte contraction
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Posted 05 Nov 2020

PDE1 inhibition modulates Cav1.2 channel to stimulate cardiomyocyte contraction
73 downloads bioRxiv pharmacology and toxicology

Grace K Muller, Joy Song, Vivek Jani, Yuejin Wu, Mark E. Anderson, David A Kass

Rationale: Cyclic adenosine monophosphate (cAMP) activation of protein kinase A (PKA) stimulates excitation-contraction coupling, increasing cardiac contractility. This is clinically leveraged by beta-adrenergic stimulation (β-ARs) or phosphodiesterase-3 inhibition (PDE3i), though both approaches are limited by arrhythmia and chronic myocardial toxicity. Phosphodiesterase-1 inhibition (PDE1i) also augments cAMP and was recently shown in rabbit cardiomyocytes to augment contraction independent of β-AR stimulation or blockade, and with less intracellular calcium rise than β-ARs or PDE3i. Early testing of PDE1 inhibition in humans with neuro-degenerative disease and dilated heart failure has commenced. Yet, the molecular mechanisms for PDE1i inotropic effects remain largely unknown. Objective: Define the mechanism(s) whereby PDE1i increases contractility. Methods and Results: Primary guinea pig myocytes which express the cAMP-hydrolyzing PDE1C isoform found in larger mammals and humans were studied. The potent, selective PDE1i (ITI-214) did not alter cell shortening or Ca2+ transients under resting conditions whereas both increased with β-ARs or PDE3i. However, PDE1i enhanced shortening with less Ca2+ rise in a PKA-dependent manner when combined with low-dose adenylate cyclase stimulation (Forskolin). Unlike PDE3i, PDE1i did not augment β-AR responses. Whereas β-ARs reduced myofilament Ca2+ sensitivity and increased sarcoplasmic reticular Ca2+ content in conjunction with greater phosphorylation of troponin I, myosin binding protein C, and phospholamban, PDE1i did none of this. However, PDE1i increased Cav1.2 channel conductance similar to PDE3i in a PKA-dependent manner. Myocyte shortening and peak Ca2+ transients were more sensitive to Cav1.2 blockade with nitrendipine combined with PDE1i versus PDE3i. Lastly, PDE1i was found to be far less arrythmogenic than PDE3i. Conclusions: PDE1i enhances contractility by a PKA-dependent increase in Cav1.2 conductance without concomitant myofilament desensitization. The result is less rise in intracellular Ca2+ and arrhythmia compared to β-ARs and/or PDE3i. PDE1i could be a novel positive inotrope for failing hearts without the toxicities of β-ARs and PDE3i. ### Competing Interest Statement Dr. David Kass is a consultant with Intracellular Therapies Inc., manufacturer of ITI-214 that is used in this study.

974: Modulation of Recombinant Human T-type calcium Channels by Δ9-tetrahydrocannabinolic acid in vitro
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Posted 11 Oct 2020

Modulation of Recombinant Human T-type calcium Channels by Δ9-tetrahydrocannabinolic acid in vitro
72 downloads bioRxiv pharmacology and toxicology

Somayeh Mirlohi, Chris Bladen, Marina Santiago, Mark Connor

Introduction: Low voltage-activated T-type calcium channels (T-type I Ca), CaV3.1, CaV3.2, and CaV3.3 are opened by small depolarizations from the resting membrane potential in many cells and have been associated with neurological disorders including absence epilepsy and pain. Δ9-tetrahydrocannabinol (THC) is the principal psychoactive compound in Cannabis and also directly modulates T-type I Ca , however, there is no information about functional activity of most phytocannabinoids on T-type I Ca, including Δ9-tetrahydrocannabinol acid (THCA), the natural non-psychoactive precursor of THC. The aim of this work was to characterize THCA effects on T-type I Ca . Materials and Methods: We used HEK293 Flp-In-TREx cells stably expressing CaV3.1, 3.2 or 3.3. Whole-cell patch clamp recordings were made to investigate cannabinoid modulation of I Ca . Results: THCA and THC inhibited the peak current amplitude CaV3.1 with a pEC50s of 6.0 ± 0.7 and 5.6 ± 0.4, respectively. 1 μM THCA or THC produced a significant negative shift in half activation and inactivation of CaV3.1 and both drugs prolonged CaV3.1 deactivation kinetics. THCA (10 μM) inhibited CaV3.2 by 53% ± 4 and both THCA and THC produced a substantial negative shift in the voltage for half inactivation and modest negative shift in half activation of CaV3.2. THC prolonged the deactivation time of CaV3.2 while THCA did not. THCA inhibited the peak current of CaV3.3 by 43% ± 2 (10μM) but did not notably affect CaV3.3 channel activation or inactivation, however, THC caused significant hyperpolarizing shift in CaV3.3 steady state inactivation. Discussion: THCA modulated T-type I Ca currents in vitro, with significant modulation of kinetics and voltage dependence at low μM concentrations. This study suggests that THCA may have potential for therapeutic use in pain and epilepsy via T-type channel modulation without the unwanted psychoactive effects associated with THC ### Competing Interest Statement The authors have declared no competing interest.

975: Adverse drug reactions associated with the use of biological agents
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Posted 24 Sep 2020

Adverse drug reactions associated with the use of biological agents
72 downloads bioRxiv pharmacology and toxicology

Jorge Enrique Machado-Alba, Anyi Liliana Jiménez-Morales, Yulieth Carolina Moran-Yela, Ilsa Yadira Parrado-Fajardo, Luis Fernando Valladales-Restrepo

Introduction Biotech drugs open new possibilities to treat diseases for which drug therapy is limited, but they may be associated with serious adverse drug reactions (ADRs). Objective To identify the ADRs associated with the use of biotech drugs in Colombia. Methods This was a retrospective study of ADR reports from 2014 to 2019, contained in the database of the pharmacovigilance program of Audifarma SA. The ADRs, groups of associated drugs, and affected organs were classified. Results A total of 5,415 reports of ADRs associated with biotech drugs were identified in 78 Colombian cities. A total of 76.1% of the cases corresponded to women. The majority were classified as type A (55.0%) and B (28.9%), and 16.7% were serious cases. The respiratory tract was the most commonly affected organ system (16.8%), followed by the skin and adnexa (15.6%). Antineoplastic and immunomodulatory drugs accounted for 70.6% of the reports, and the drugs related to the greatest number of ADRs were adalimumab (12.2%) and etanercept (11.6%). Conclusions There has been an incremental increase in the reporting of ADRs associated with the use of biotech drugs in the pharmacovigilance program, related to the strengthening and appropriation of the patient safety culture and improvement in the quality of the generated information. It is important to empower physicians and entire health teams to ensure the traceability of ADRs and to perform interdisciplinary interventions derived from pharmacovigilance at the individual and population levels.

976: Cycle network model of Prostaglandin H Synthase-1
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Posted 12 Aug 2020

Cycle network model of Prostaglandin H Synthase-1
71 downloads bioRxiv pharmacology and toxicology

Alexey Goltsov, Maciej Swat, Kirill Peskov, Yuri Kosinsky

The kinetic model of Prostaglandin H Synthase-1 (PGHS-1) was developed to investigate its complex network kinetics and non-steroidal anti-inflammatory drugs (NSAIDs) efficacy in different in vitro and in vivo conditions. To correctly describe the complex mechanism of PGHS-1 catalysis, we developed a microscopic approach to modelling of intricate network dynamics of 35 intraenzyme reactions among 24 intermediate states of the enzyme. The developed model quantitatively describes interconnection between cyclooxygenase and peroxidase enzyme activities; substrate (arachidonic acid, AA) and reducing cosubstrate competitive consumption; enzyme self-inactivation; autocatalytic role of AA; enzyme activation threshold, and synthesis of intermediate PGG2 and final PGH2 products under wide experimental conditions. In the paper we provided the detailed description of the enzyme catalytic cycle, model calibration based on a series of in vitro kinetic data and model validation using experimental data on the regulatory properties of PGHS-1. The validated model of PGHS-1 with a unified set of kinetic parameters is applicable for in silico screening and prediction of the inhibition effects of NSAIDs and their combination on the balance of pro-thrombotic (thromboxane) and anti-thrombotic (prostacyclin) prostaglandin biosynthesis in platelets and endothelial cells expressing PGHS-1. ### Competing Interest Statement The authors have declared no competing interest.

977: The possible anti-inflammatory activity of macrolide antibiotics in some animal models
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Posted 21 Oct 2020

The possible anti-inflammatory activity of macrolide antibiotics in some animal models
71 downloads bioRxiv pharmacology and toxicology

Mohamed Hamed, Esmail Abdelmonem, Mahmoud Zayed, Sameh Shaban, Iman El Khashab, Soheir Abu-El-Azm

Recently, there has been increasing evidence on the use of macrolide antibiotic in treatment of chronic inflammatory disease through mechanisms of distinct from their antibacterial activity. The key desired effect lies somewhere between these two therapeutic potentials and has not been identified yet. The aim of the present study was to evaluate the anti-inflammatory activity of azithromycin in formaldehyde induced arthritis and carrageenan induced air pouch in albino rats incomparable to meloxicam. Results of Formaldehyde induced arthritis revealed that pre-treatment of animals with either azithromycin (10,20,40) mg/kg or meloxicam (4mg/kg) I.P with single daily dose 1 hour before formaldehyde for 15 days produce significant reduction in Paw weight (9) (p<0.05), the percentage inhibition was 32.76%, 34.3%, 40.1% and 29.3% respectively. Histopathological study showed that Formaldehyde produced marked inflammatory cell infiltration, congestion of blood vessels and soft tissue edema which were attenuated by azithromycin in dose dependent manner. The radiological study revealed that azithromycin attenuate soft tissue oedema, periarticular bone resorption, narrowing of joint spaces and joint deformities induced by formaldehyde. This effect was marked with 40mg/kg azithromycin pre-treatment. In carrageenan induced air pouch, results demonstrate that group of animals pre-treated with azithromycin (10, 20 and 40 mg/kg/day) or meloxicam (4mg/kg) for 6 days significantly attenuated the mean increase in TLC in air pouch exudate with percentage of inhibition by 59.3%, 6.3%, 77.4% and 67.7% respectively. In conclusion, the present work showed that azithromycin has anti-inflammatory activity in the models tested and suggests that it can exert therapeutics effects independent of its anti-bacterial activity. Also, the anti-inflammatory effect of azithromycin 40mg/kg was potent and even comparable to that of meloxicam 4mg/kg. ### Competing Interest Statement The authors have declared no competing interest.

978: Prohibitin protects against cigarette smoke extract-induced cell apoptosis in cultured human pulmonary microvascular endothelial cells
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Posted 01 May 2020

Prohibitin protects against cigarette smoke extract-induced cell apoptosis in cultured human pulmonary microvascular endothelial cells
70 downloads bioRxiv pharmacology and toxicology

Yating Peng, Zijing Zhou, Aiyuan Zhou, JiaXi Duan, Hong Peng, Ruoyun Ouyang, Yan Chen, Ping Chen

Prohibitin is an evolutionarily conserved and ubiquitously expressed protein in eukaryocyte. It mediate many important roles in cell survival, apoptosis, autophagy and senescence. In the present study, we aimed to explore the role of prohibitin in cigarette smoke extract (CSE)-induced apoptosis of human pulmonary microvascular endothelial cells (HPMECs). For this purpose, HPMECs were trasfected with prohibitin and challenged with CSE. Our results showed that CSE exposure inhibited prohibitin expression in a dose-dependent manner in HPMECs. Overexpression of prohibitin could protect cell from CSE-induced injury by inhibiting CSE-induced cell apoptosis, inhibiting reactive oxygen species (ROS) production, increase mitochondrial membrane potential, increase the content of mitochondrial transcription factor A (mtTFA), IKKα/β phosphorylation and IκB-α degradation. CSE decreases prohibitin expression in endothelial cells and restoration of prohibitin expression in these cells can protect against the deleterious effects of CSE on mitochondrial and cells. We identified prohibitin is a novel regulator of endothelial cell apoptosis and survival in the context of cigarette smoke exposure.

979: Estimating daily intakes of manganese due to breast milk, infant formulas, or young child nutritional beverages in the United States and France: Comparison to sufficiency and toxicity thresholds
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Posted 11 Jun 2020

Estimating daily intakes of manganese due to breast milk, infant formulas, or young child nutritional beverages in the United States and France: Comparison to sufficiency and toxicity thresholds
70 downloads bioRxiv pharmacology and toxicology

Erika J. Mitchell, Seth H. Frisbie, Stéphane Roudeau, Asuncion Carmona, Richard Ortega

Background: Although manganese (Mn) is an essential nutrient, recent research has revealed that excess Mn in early childhood may have adverse effects on neurodevelopment. Methods: We estimated daily total Mn intake due to breast milk at average body weights by reviewing reported concentrations of breast milk Mn and measurements of body weight and breast milk intake at 3 weeks, 4.25 months, 7 months, and 18 months. We compared these figures to the Mn content measured in 44 infant, follow-up, and toddler formulas purchased in the United States and France. We calculated Mn content of formula products made with ultra-trace elemental analysis grade water (0 μg Mn/L) and with water containing 250 μg Mn/L, a concentration which is relatively high but less than the World Health Organization Health-based value of 400 μg Mn/L or the United States Environmental Protection Agency Health Advisory of 350 μg Mn/L. Results: Estimated mean daily Mn intake from breast milk ranged from 1.2 μg Mn/kg/day (3 weeks) to 0.16 μg Mn/kg/day (18 months), with the highest intakes at the youngest age stage we considered, 3 weeks. Estimated daily Mn intake from formula products reconstituted with 0 μg Mn/L water ranged from 130 μg Mn/kg/day (3 weeks) to 4.8 μg Mn/kg/day (18 months) with the highest intakes at 3 weeks. Formula products provided 28 to 520 times greater than the mean daily intake of Mn from breast milk for the 4 age stages that we considered. Estimated daily Mn intake from formula products reconstituted with water containing 250 μg Mn/L ranged from 12 μg Mn/kg/day to 170 μg Mn/kg/day, which exceeds the United States Environmental Protection Agency Reference Dose of 140 μg Mn/kg/day for adults. Conclusions: Mn deficiency is highly unlikely with exclusive breast milk or infant formula feeding, but established tolerable daily intake levels for Mn may be surpassed by some of these products when following labeled instructions. ### Competing Interest Statement The authors have declared no competing interest.

980: JQ-1 ameliorates schistosomiasis liver fibrosis by suppressing JAK2 and STAT3 activation
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Posted 04 Aug 2020

JQ-1 ameliorates schistosomiasis liver fibrosis by suppressing JAK2 and STAT3 activation
70 downloads bioRxiv pharmacology and toxicology

Han Ding, Jiaming Tian, Xuhan Yang, Yongsheng Ji, Saeed El-Ashram, Xin Hou, Cuiping Ren, Jijia Shen, Fengchun Liu

Schistosomiasis is a serious parasitic infection caused by Schistosoma . The parasite deposits eggs in the host liver, causing inflammation that activates hepatic stellate cells (HSCs), which leads to liver fibrosis. Currently, there is no effective therapy for liver fibrosis; thus, treatments are urgently needed. Therefore, in the present study, mice infected with Schistosoma japonicum were treated with JQ-1, a small-molecule bromodomain inhibitor with reliable anti-tumor and anti-inflammatory activities. The fibrotic area of the liver measured by computer-assisted morphometric analysis and the expression levels of the cytoskeletal protein alpha smooth muscle actin (α-SMA) and of collagen assessed by quantitative PCR and immunohistochemistry were significantly decreased in the liver following JQ-1 treatment compared with vehicle-treated controls. Total RNA was extracted from the liver of JQ-1–treated Schistosoma- infected mice for RNA- sequencing analysis. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that JQ-1 affected biological processes and the expression of cellular components known to play key roles in HSC transdifferentiation into myofibroblasts. In vitro treatment with JQ-1 of JS-1 cells, a mouse HSC line, indicated that JQ-1 significantly inhibited JS-1 proliferation but had no effect on JS-1 activity, senescence, or apoptosis. Western blot results showed that JQ-1 inhibited the expression of phosphorylated JAK2 and phosphorylated STAT3 without altering expression levels of these non-phosphorylated proteins. Taken together, these findings suggested that JQ-1 treatment ameliorated S. japonicum egg–induced liver fibrosis, at least in part, by suppressing HSC activation and proliferation through the inhibition of JAK2/STAT3 signaling. These results lay a foundation for the development of novel approaches to treat and control liver fibrosis caused by S. japonicum .

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