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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 125,186 papers from 537,576 authors.

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in category pharmacology and toxicology

1,084 results found. For more information, click each entry to expand.

921: Rearing medium dictates variability across replicates in untreated and arsenic challenged zebrafish larvae
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Posted 23 Aug 2020

Rearing medium dictates variability across replicates in untreated and arsenic challenged zebrafish larvae
119 downloads bioRxiv pharmacology and toxicology

Anjana Ramdas Nair, Patrice Delaney, Shashi Ranjan, Nouf Khan, Catherine Palmer, Kirsten C Sadler

Reproducibility and consistency are hallmarks of scientific integrity. Biological systems are inherently noisy, posing a challenge to reproducibility. This is particularly relevant to the field of environmental toxicology, where many unaccounted experimental parameters can have a marked influence on the biological response to exposure. Here, we extend the use of zebrafish as a robust toxicological model for studying the effects of inorganic arsenic (iAs) on liver biology. We observed that iAs toxicity in this system is not influenced by important parameters including genetic background, rearing container material or rearing volume but the dose response to iAs is influenced by the rearing medium. We compared mortality as a measure of iAs toxicity to embryos cultured in two standard rearing media: egg water made from dehydrated ocean salts dissolved in water and a defined embryo medium which is a pH adjusted, buffered salt solution. Larvae reared in egg water were more susceptible to iAs compared to those reared in embryo medium. This effect was independent of the pH differences between these solutions. These culture conditions did not cause any difference in the global hepatic transcriptome of control zebrafish. Further, no difference in the expression of genes involved in the unfolded protein response (UPR) in larvae exposed to iAs treatment or in a stress independent system to activate UPR genes by transgenic overexpression of activating transcription factor 6 (nAtf6) in hepatocytes was observed. However, the clutch-to-clutch variation in gene expression was significantly greater in larvae reared in egg water compared to those in embryo medium. These data demonstrate that egg water affects reproducibility across replicates in terms of gene expression and exacerbates iAs mediated toxic response. This highlights the importance of rigorous evaluation of experimental conditions to assure reproducibility. ### Competing Interest Statement The authors have declared no competing interest.

922: Discovery of isoplumbagin as a novel NQO1 substrate and anti-cancer quinone
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Posted 30 Apr 2020

Discovery of isoplumbagin as a novel NQO1 substrate and anti-cancer quinone
119 downloads bioRxiv pharmacology and toxicology

Yen-Chi Tsao, Yu-Jung Chang, Chun-Hsien Wang, Linyi Chen

Isoplumbagin (5-hydroxy-3-methyl-1,4-naphthoquinone), a naturally occurring quinone from Lawsonia inermis and Plumbago europaea, that has been reported to have anti-inflammatory and anti-microbial activity. Inflammation has long been implicated in cancer progression. In this study, we examined the anti-cancer effect of chemically-synthesized isoplumbagin. Our results revealed that isoplumbagin treatment suppressed cell viability and invasion of highly invasive oral squamous cell carcinoma (OSCC) OC3-IV2 cells, glioblastoma U87 cells, non-small cell lung carcinoma H1299 cells, prostate cancer PC3 cells, and cervical cancer Hela cells by using MTT and Boyden chamber assays. In vivo studies demonstrate the inhibitory effect of 2 mg/kg isoplumbagin on the growth of orthotopic xenograft tumors derived from OSCC cells. Mechanistically, isoplumbagin exerts its cytotoxic effect through acting as a substrate of NAD(P)H quinone dehydrogenase 1 (NQO1) to generate hydroquinone, which reverses mitochondrial fission phenotype, reduces mitochondrial complex IV activity and thus compromises mitochondrial function. Collectively, this work reveals an anti-cancer activity of isoplumbagin mainly through modulating mitochondrial dynamics and function. ### Competing Interest Statement The authors have declared no competing interest.

923: Prophylactic efficacy of riluzole against anxiety- and depressive-like behaviors in two rodent stress models
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Posted 07 Aug 2020

Prophylactic efficacy of riluzole against anxiety- and depressive-like behaviors in two rodent stress models
118 downloads bioRxiv pharmacology and toxicology

Corey Fee, Keith A Misquitta, Etienne Sibille, Robert M. Berman, Vladimir Coric, Gerard Sanacora, Mounira Banasr

Background: Chronic stress-related illnesses, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD), share symptomatology, including anxiety, anhedonia, and helplessness. Across disorders, neurotoxic dysregulated glutamate (Glu) signaling may underlie symptom emergence. Current first-line antidepressant drugs (ADs), which do not directly target Glu signaling, fail to provide adequate benefit for many patients and are associated with high relapse rates. Riluzole modulates glutamatergic neurotransmission by increasing metabolic cycling and modulating signal transduction. Clinical studies exploring riluzole efficacy in stress-related disorders have provided varied results. However, the utility of riluzole for treating specific symptom dimensions or as a prophylactic treatment has not been comprehensively assessed. Methods: We investigated whether chronic prophylactic riluzole (12-15/kg/day p.o.) could prevent the emergence of behavioral deficits induced by unpredictable chronic mild stress (UCMS) in mice. We assessed i) anxiety-like behavior using the elevated-plus maze, open field test, and novelty-suppressed feeding, ii) mixed anxiety/anhedonia-like behavior in the novelty-induced hypophagia test and, iii) anhedonia-like behavior using the sucrose consumption test. Z-scoring summarized changes across tests measuring similar outcomes. In a separate learned helplessness (LH) cohort, we investigated whether chronic preventative riluzole treatment could block the development of helplessness-like behavior. Results: UCMS induced an elevation in anxiety-, anhedonia-like behavior, and overall behavioral emotionality that was blocked by prophylactic riluzole. In the LH cohort, preventative riluzole blocked the development of helplessness-like behavior. Conclusion: This study supports the utility of riluzole as a prophylactic medication, and potential relapse-preventing treatment targeting anhedonia, anxiety, and helplessness symptoms associated with stress-related disorders. ### Competing Interest Statement G.S. has received consulting fees from Allergan, Alkermes, AstraZeneca, Avanier, Axsome Therapeutics, Pharmaceuticals, Biohaven Pharmaceuticals, Bristol-Myers Squibb, Clexio Biosciences, EMA Wellness, Epiodyne, Intra-Cellular Therapies, Janssen, Lundbeck, Merck & Co., Minerva pharmaceuticals, Navitor, Neurocrine biosciences, NeruoRx, Novartis, Noven Pharmaceuticals, Otsuka, Perception Neuroscience, Praxis Therapeutics, Sage Pharmaceuticals, Servier Pharmaceuticals, Taisho Pharmaceuticals, Teva, Valeant, and Vistagen therapeutics over the last 36 months. He has also received additional research contracts from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Hoffman La-Roche, Merck & Co., and Usona over the last 36 months. Free medication was provided to GS for an NIH-sponsored study by Sanofi-Aventis. In addition, he holds shares in BioHaven Pharmaceuticals Holding Company and is a co-inventor on a patent Glutamate agents in the treatment of mental disorders (Patent number: 8778979), and a U.S. Provisional Patent Application No. 047162-7177P1 (00754) filed on August 20, 2018 by Yale University Office of Cooperative Research OCR 7451 US01. RMB and VC are employees and stockholders of Biohaven Pharmaceuticals. R.M.B. and V.C. are employees of Biohaven Pharmaceuticals.

924: Chronic Developmental Lead Exposure increases μ-Opiate Receptor Levels in the Adolescent Rat Brain
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Posted 20 Apr 2020

Chronic Developmental Lead Exposure increases μ-Opiate Receptor Levels in the Adolescent Rat Brain
118 downloads bioRxiv pharmacology and toxicology

Damaris Albores-Garcia, Jennifer L McGlothan, Zoran Bursac, Tomás R Guilarte

Opioid use and abuse has reached epidemic proportion in the United States resulting in a significant number of deaths due to overdose. While environmental factors are implicated in opioid addiction, less is known about the role of exposure to environmental pollutants on the brain opioid system. Human and preclinical studies have suggested an association between childhood lead (Pb2+) intoxication and proclivity to substance abuse and delinquent behavior. Opioid receptors are involved in the biological effects of opioids and other drugs of abuse. In this study, we examine the effect of chronic developmental Pb2+ exposure on m-opioid receptor (MOR) levels in the rat brain using [3H]-D-Ala2-MePhe4-Gly-ol5 enkephalin ([3H]-DAMGO) quantitative receptor autoradiography. Our results indicate that chronic developmental Pb2+ exposure increases the levels of [3H]-DAMGO specific binding to MOR in several limbic regions of the brain in male and female rats during the pre-adolescence (PN14) and early-adolescence (PN28) period. These changes were less pronounced in late-adolescence (PN50) and adult (PN120) animals. Our findings are important because the pre-adolescence and early adolescence period is a time in which there is higher engagement in reward and drug-seeking behaviors in humans. In summary, we show that chronic exposure to Pb2+ an ubiquitous and well-known environmental contaminant and neurotoxicant, alters MOR levels in brain regions associated with addiction circuits in the adolescent period with important implications to opioid drug use and abuse. ### Competing Interest Statement The authors have declared no competing interest.

925: Amorphous solid dispersions and the confounding effect of nanoparticles in in vitro dissolution and in vivo testing: Niclosamide as a case of study
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Posted 22 Dec 2020

Amorphous solid dispersions and the confounding effect of nanoparticles in in vitro dissolution and in vivo testing: Niclosamide as a case of study
117 downloads bioRxiv pharmacology and toxicology

Miguel O. Jara, Zachary N. Warnken, Robert O. Williams

We developed an amorphous solid dispersion (ASD) of the poorly water-soluble molecule niclosamide that achieved more than a 2-fold increase in bioavailability. Notably, this niclosamide ASD formulation increased the apparent drug solubility about 60-fold relative to the crystalline material due to the generation of nanoparticles. Niclosamide is a weakly acidic drug, BCS class II, and a poor glass former with low bioavailability in vivo. Hot-melt extrusion is a high-throughput manufacturing method commonly used in the development of ASDs for increasing the apparent solubility and bioavailability of poorly water-soluble compounds. We utilized the polymer polyvinylpyrrolidone-vinyl acetate (PVP-VA) to manufacture niclosamide ASDs by extrusion. Samples were analyzed based on their microscopic and macroscopic behavior and their intermolecular interactions, using DSC, XRD, NMR, FTIR, and DLS. The niclosamide ASD generated nanoparticles with a mean particle size of about 100 nm in FaSSIF media. In a side-by-side diffusion test, these nanoparticles produced a 4-fold increase in niclosamide diffusion. We successfully manufactured amorphous extrudates of the poor glass former niclosamide that showed remarkable in vitro dissolution and diffusion performance. These in vitro tests were translated to a rat model that also showed an increase in oral bioavailability. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

926: The kallikrein-kinin system is falling into pieces: bradykinin fragments are biological active peptides
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Posted 14 Sep 2020

The kallikrein-kinin system is falling into pieces: bradykinin fragments are biological active peptides
117 downloads bioRxiv pharmacology and toxicology

Igor Maciel Souza-Silva, Cristiane Amorim de Paula, Robson Augusto Souza Santos, Vívian Louise Soares de Oliveira, Isabella Domingos da Rocha, Maísa Mota Antunes, Lídia Pereira Barbosa Cordeiro, Vanessa Pereira Teixeira, Sérgio Ricardo Aluotto Scalzo Júnior, Flávio Almeida Amaral, Jarbas Magalhães Resende, Marco Antônio Peliky Fontes, Gustavo Batista Menezes, Silvia Guatimosim, Thiago Verano-Braga

Background and purpose Bradykinin [BK-(1-9)] is an endogenous peptide involved in many physiological and pathological processes, such as cardiovascular homeostasis and inflammation. The central dogma of the kallikrein-kinin system is that BK-(1-9) fragments are biologically inactive. In this manuscript, we proposed to test whether these fragments were indeed inactive. Experimental Approach Nitric oxide (NO) was quantified in human, mouse and rat cells loaded with DAF-FM after stimulation with BK-(1-9), BK-(1-7), BK-(1-5) and BK-(1-3). We used adult male rat aortic ring preparation to test vascular reactivity mediated by BK-(1-9) fragments. Changes in blood pressure and heart rate was measured in conscious adult male rats by intraarterial catheter method. Key results BK-(1-9) induced NO production in all cell types tested by B2 receptor activation. BK-(1-7), BK-(1-5) and BK-(1-3) also induced NO production in all tested cell types but this response was independent of the activation of B1 receptor and/or B2 receptor. BK-(1-7), BK-(1-5) or BK-(1-3) induced only vasorelaxant effect and in a concentration-dependent fashion. Vasorelaxant effects for BK-(1-7), BK-(1-5) or BK-(1-3) were independent of the kinin receptors. Different administration routes ( i.e ., intravenous or intra-arterial) did not affect the observed hypotension induced by BK-(1-7), BK-(1-5) or BK-(1-3). Importantly, these observations diverged from the BK-(1-9) results, highlighting that indeed the BK-(1-9) fragments do not seem to act via the classical kinin receptors. Conclusions and implications In conclusion, BK-(1-7), BK-(1-5) and BK-(1-3) are biologically active components of the kallikrein-kinin system. Importantly, observed pathophysiological outcomes of these peptides are independent of B1R and/or B2R activation. ### Competing Interest Statement The authors have declared no competing interest.

927: Methylation-directed Acetylation of Histone H3 Regulates Developmental Sensitivity to Histone Deacetylase Inhibition
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Posted 24 Jul 2020

Methylation-directed Acetylation of Histone H3 Regulates Developmental Sensitivity to Histone Deacetylase Inhibition
117 downloads bioRxiv pharmacology and toxicology

Li-Yao Huang, Duen-Wei Hsu, Catherine Pears

Background: Treatment of cells with hydroxamate-based lysine deacetylase inhibitors (KDACis) such as Trichostatin A (TSA) can induce biological effects such as differentiation or apoptosis of cancer cells, and a number of related compounds have been approved for clinical use. TSA treatment induces rapid initial acetylation of histone 3 (H3) proteins which are already modified by tri-methylation on lysine 4 (H3K4me3) while acetylation of bulk histones, lacking this mark, is delayed. Sgf29, a subunit of the SAGA acetyltransferase complex, interacts with H3K4me3 via a tandem tudor domain (TTD) and has been proposed to target the acetyltransferase activity to H3K4me3. However the importance of acetylation of this pool of H3 in the biological consequences of KDACi treatment is not known. Results: We investigated the role of H3K4me3-directed acetylation in the mechanism of action of TSA on inhibiting development of the eukaryotic social amoeba Dictyostelium discoideum. Loss of H3K4me3 in strains with mutations in the gene encoding Set1 or the histone proteins confers resistance to TSA-induced inhibition of development and delays accumulation of histone acetylation on H3K9 and K14. A candidate orthologue of Sgf29 in Dictyostelium has been identified which specifically recognizes the H3K4me3 modification via its tandem Tudor domain (TTD). Disruption of the gene encoding Sgf29 delayed accumulation of H3K9Ac, abolished targeted H3K4me3-directed H3Ac and led to developmental resistance to TSA, which is dependent on a functional TTD. TSA resistance also results from overexpression of Sgf29. Conclusion: Preferential acetylation of H3K4me3 histones, regulated by Sgf29 via its TTD, is important in developmental sensitivity to TSA. Levels of H3K4me3 or Sgf29 will provide useful biomarkers for sensitivity to this class of chemotherapeutic drug. ### Competing Interest Statement The authors have declared no competing interest.

928: Cardiac toxicity predictions: Safety pharmacologists correlate with the CiPA model
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Posted 12 Jun 2020

Cardiac toxicity predictions: Safety pharmacologists correlate with the CiPA model
117 downloads bioRxiv pharmacology and toxicology

Hitesh B. Mistry, Jaimit Parikh

There has been a lot of interest and publicity regarding the use of a complex biophysical model within drug development for predicting the TdeP risk of new compounds. Throughout the development of the complex model numerous groups have shown that a simple linear mechanistic model explains the predictive behaviour of complex mechanistic models. That is the input-output relationship is almost linear even when complex kinetic assays are used. We hypothesized that given this linear relationship that scientist would be able to predict the outcome of the biophysical model. The objective of this pilot study was to assess the feasibility of such an analysis but also assess the initial degree of correlation. A set of 15 compounds with diverse ion-channel blocking against 4 ion-channel currents, IKr, ICaL, INa and INaL, was generated. Safety pharmacologists across numerous companies were approached and asked to categorize the TdeP risk of these compounds using only the % block depicted via a bar chart into one of 3 categories: Risk, No-risk or Unsure. 12 scientists participated in the study, of which 11 correlated strongly with the model (11 person ROC AUC range: 0.86-1, 7 scientists had a value >0.9). The combined prediction of all scientists also correlated strongly with the model. These results highlight that the linear input-output relationship can indeed be predicted by the scientist. A future study exploring the degree of correlation with a wider group of scientists and wider set of compounds would be required to get a more precise estimate of the correlation. We hope this initial exploratory study will encourage the community to pursue this idea. ### Competing Interest Statement The authors have declared no competing interest.

929: Annexin a2 as a target protein for chlorogenic acid in human lung cancer A549 cells
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Posted 12 Jun 2020

Annexin a2 as a target protein for chlorogenic acid in human lung cancer A549 cells
116 downloads bioRxiv pharmacology and toxicology

Lei Wang, Hongwu Du, Peng Chen

Chlorogenic acid, an important active component of coffee with anti-tumor activities, has been found for many years. However, the lack of understanding about its target proteins greatly limits the exploration of its anti-tumor molecular mechanism and clinical application. Here, in vitro and animal experiments showed that chlorogenic acid had a significant inhibitory effect on the proliferation of A549 cells. Using the spontaneous fluorescence characteristic of chlorogenic acid to screen the target proteins cleverly to avoid the problem of chemical modification increasing false positive, we identify and verify annexin A2 (ANXA2) as a covalent binding target of chlorogenic acid in A549 cells. Then, we discover that chlorogenic acid as an inhibitor of the binding of ANXA2 to p50 subunit inhibited the expression of downstream anti-apoptotic genes cIAP1 and cIAP2 of NF-κB signaling pathway in A549 cells in vitro and vivo. Moreover, we find chlorogenic acid hindered the binding of ANXA2 and actin maybe involved in the impediment of tumor cell cycle and migration. Thus, this work demonstrates that chlorogenic acid, as a binding ligand of ANXA2, decrease the expression of NF-κB downstream anti-apoptotic genes, inhibiting the proliferation of A549 cells in vivo and vitro. ### Competing Interest Statement The authors have declared no competing interest.

930: Automated identification of multinucleated germ cells with U-Net
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Posted 20 Feb 2020

Automated identification of multinucleated germ cells with U-Net
116 downloads bioRxiv pharmacology and toxicology

Samuel Bell, Andras Zsom, Justin Conley, Daniel Spade

Phthalic acid esters (phthalates) are male reproductive toxicants, which exert their most potent toxicity during a critical window of sensitivity in fetal development. In the fetal rat, exposure to phthalates reduces testosterone biosynthesis, alters the development of seminiferous cords and other male reproductive tissues, and induces the formation of abnormal multinucleated germ cells (MNGs). Identification of MNGs is a time-intensive process, and it requires specialized training to identify MNGs in histological sections. As a result, MNGs are not routinely quantified in phthalate toxicity experiments. In order to speed up and standardize this process, we have developed an improved method for automated detection of MNGs. Using hand-labeled histological section images with human-identified MNGs, we trained a convolutional neural network with a U-Net architecture to identify MNGs on unlabeled images. With unseen hand-labeled images not used in model training, we assessed the performance of the model, using five different configurations of the data. On average, the model reached near human accuracy, and in the best model, it exceeded it. The use of automated image analysis will allow data on this histopathological endpoint to be more readily collected for analysis of phthalate toxicity. Our trained model application code is available for download at github.com/brown-ccv/mngcount.

931: Epigenetic compound screening uncovers small molecules for re-activation of latent HIV-1
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Posted 24 Aug 2020

Epigenetic compound screening uncovers small molecules for re-activation of latent HIV-1
115 downloads bioRxiv pharmacology and toxicology

Ariane Zutz, Lin Chen, Franziska Sippl, Christian Schölz

During infection with the human immunodeficiency virus type 1 (HIV-1), latent reservoirs are established, which circumvent full eradication of the virus by antiretroviral therapy (ART) and are the source for viral rebound after cessation of therapy. As these reservoirs are phenotypically undistinguishable from infected cells, current strategies aim to reactivate these reservoirs, followed by pharmaceutical and immunological destruction of the cells. Here, we employed a simple and convenient cell-based reporter system, which enables sample handling under biosafety level (BSL)-1 conditions, to screen for compounds that were able to reactivate latent HIV-1. The assay showed a high dynamic signal range and reproducibility with an average Z-factor of 0.77, classifying the system as robust. The assay was used for high-throughput screening (HTS) of an epigenetic compound library in combination with titration and cell-toxicity studies and revealed several potential new latency reversing agents (LRAs). Further validation in well-known latency model systems verified earlier studies and identified two novel compounds with very high reactivation efficiency and low toxicity. Both drugs, namely N-hydroxy-4-(2-[(2-hydroxyethyl)(phenyl)amino]-2-oxoethyl)benzamide (HPOB) and 2',3'-difluoro-[1,1'-biphenyl]-4-carboxylic acid, 2-butylhydrazide (SR-4370), showed comparable performances to other already known LRAs, did not activate CD4+ T-cells or caused changes in the composition of PBMCs as shown by flow cytometry analyses. Both compounds may represent an effective new treatment possibility for revocation of latency in HIV-1 infected individuals.

932: Improving drug safety predictions by reducing poor analytical practices
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Posted 28 Sep 2020

Improving drug safety predictions by reducing poor analytical practices
115 downloads bioRxiv pharmacology and toxicology

Stanley E. Lazic, Dominic Williams

Predicting the safety of a drug from preclinical data is a major challenge in drug discovery, and progressing an unsafe compound into the clinic puts patients at risk and wastes resources. In drug safety pharmacology and related fields, methods and analytical decisions known to provide poor predictions are common and include creating arbitrary thresholds, binning continuous values, giving all assays equal weight, and multiple reuse of information. In addition, the metrics used to evaluate models often omit important criteria and models' performance on new data are often not assessed rigorously. Prediction models with these problems are unlikely to perform well, and published models suffer from many of these issues. We describe these problems in detail, demonstrate their negative consequences, and propose simple solutions that are standard in other disciplines where predictive modelling is used. ### Competing Interest Statement The authors have declared no competing interest.

933: Gastrointestinal absorption of pimozide is enhanced by inhibition of P-glycoprotein
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Posted 16 Apr 2020

Gastrointestinal absorption of pimozide is enhanced by inhibition of P-glycoprotein
114 downloads bioRxiv pharmacology and toxicology

Hiroki Morishita, Kozue Okawa, Misaki Ishii, Kenta Mizoi, Hiroshi Arakawa, Kentaro Yano, Takuo Ogihara

Following the death due to cardiac arrest of a patient taking pimozide, sertraline and aripiprazole antipsychotic/antidepressant combination therapy, a role of drug-drug interaction was suggested. Here, we investigated P-glycoprotein (P-gp)-mediated interaction among the three drugs using in vitro methods. Sertraline or aripiprazole significantly increased the permeability of pimozide in Caco-2 cell monolayers. ATPase assay indicated that pimozide is a P-gp substrate, and might act as a P-gp inhibitor at higher concentrations. The values of the kinetic parameters of carrier-mediated efflux, calculated from the concentration dependence of pimozide efflux from LLC-GA5-COL150 cells expressing human P-gp, were as follows: maximum transport rate (J max ) = 84.9 ± 8.9 pmol/min/mg protein, half-saturation concentration (K t ) = 10.6 ± 4.7 μM, first-order rate constant (k d ) = 0.67 ± 0.14 pmol/min/mg protein. Further, the efflux ratio of pimozide in LLC-GA5-COL150 cells was significantly decreased in the presence of sertraline or aripiprazole. These results indicate that pimozide is a substrate of P-gp, and its efflux is inhibited by sertraline and aripiprazole. Thus, P-gp inhibition by sertraline and/or aripiprazole may alter the gastrointestinal permeability of co-administered pimozide, resulting in an increased blood concentration of pimozide, which may increase the likelihood of pimozide's known life-threatening side effect of QT prolongation.

934: Structural requirements for dihydrobenzoxazepinone anthelmintics: actions against medically important and model parasites - Trichuris muris, Brugia malayi, Heligmosomoides polygyrus and Schistosoma mansoni
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Posted 18 Nov 2020

Structural requirements for dihydrobenzoxazepinone anthelmintics: actions against medically important and model parasites - Trichuris muris, Brugia malayi, Heligmosomoides polygyrus and Schistosoma mansoni
114 downloads bioRxiv pharmacology and toxicology

Frederick A Partridge, Carole JR Bataille, Ruth Forman, Amy E Marriott, Josephine Forde-Thomas, Cécile Häberli, Ria L Dinsdale, James D. B. O’Sullivan, Nicky J Willis, Graham M. Wynne, Helen Whiteland, John Archer, Andrew Steven, Jennifer Keiser, Joseph D Turner, Karl F Hoffmann, Mark J Taylor, Kathryn J. Else, Angela J Russell, David B Sattelle

Nine hundred million people are infected with the soil-transmitted helminths Ascaris lumbricoides (roundworm), hookworm, and Trichuris trichiura (whipworm). However, low single-dose cure rates of the benzimidazole drugs, the mainstay of preventative chemotherapy for whipworm, together with parasite drug resistance, mean that current approaches may not be able to eliminate morbidity from Trichuriasis. We are seeking to develop new anthelmintic drugs specifically with activity against whipworm as a priority, and previously identified a hit series of dihydrobenzoxazepinone (DHB) compounds that block motility of ex vivo Trichuris muris. Here we report a systematic investigation of the structure-activity relationship of the anthelmintic activity of DHB compounds. We synthesised 47 analogues, which allowed us to define features of the molecules essential for anthelmintic action, as well as broadening the chemotype by identification of dihydrobenzoquinolinones (DBQ) with anthelmintic activity. We investigated the activity of these compounds against other parasitic nematodes, identifying DHB compounds with activity against Brugia malayi and Heligmosomoides polygyrus. We also demonstrated activity of DHB compounds against the trematode Schistosoma mansoni, a parasite that causes schistosomiasis. These results demonstrate the potential of DHB and DBQ compounds for further development as broad-spectrum anthelmintics. Author summaryAround a billion people are infected by the soil transmitted helminths Ascaris, hookworm and whipworm. In the case of whipworm, the benzimidazole drugs, which are distributed to school children in affected areas, have low cure rates. This means that finding an improved treatment for whipworm is a priority. We previously identified five DHB compounds in a screen for new compounds active against whipworm. Here we systematically dissect these molecules, making 47 modified versions of the compounds. This allowed us to define the features of these compounds that are important for activity against whipworm. We also demonstrate activity of DHB compounds against other parasitic nematodes, and against Schistosoma mansoni, a trematode parasite. These results show the potential for further development of DHB compounds as broad-spectrum anthelmintics.

935: Alleviatory effects of Danshen, Salvianolic acid A and Salvianolic acid B on PC12 neuronal cells and Drosophila melanogaster model of Alzheimer's disease.
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Posted 14 May 2020

Alleviatory effects of Danshen, Salvianolic acid A and Salvianolic acid B on PC12 neuronal cells and Drosophila melanogaster model of Alzheimer's disease.
114 downloads bioRxiv pharmacology and toxicology

Florence Hui Ping Tan, Andrew Chung Jie Ting, Nazalan Najimudin, Nobumoto Watanabe, Ghows Azzam

Alzheimer's disease (AD) is the most common form of neurodegenerative disorder worldwide. Its pathogenesis involves the hallmark aggregation of amyloid-beta (Aβ). Of all the Aβ oligomers formed in the brain, Aβ42 has been found to be the most toxic and aggressive. Despite this, the mechanism behind this disease remains elusive. With the ability to utilize various genetic manipulations, Drosophila melanogaster is ideal in analysing not only cellular characteristics, but also physiological and behavioural traits of human neurodegenerative diseases. Danshen water extract (DWE), obtained from the root of Salvia miltiorrhiza Bunge, was found to have a vast array of beneficial properties. In this study, DWE, and its major components, Salvianolic acid A (SalA) and Salvianolic acid B (SalB) were tested for their abilities to ameliorate Aβ42's effects. DWE, SalA and SalB were confirmed to be able to reduce fibrillation of Aβ42. As Aβ42 causes neurodegeneration on neurons, DWE, SalA and SalB were tested on Aβ42-treated PC12 neuronal cells and were shown to increase cell viability. DWE and its components were then tested on the Drosophila melanogaster AD model and their rescue effects were further characterized. When human Aβ42 was expressed, the Drosophila exhibited degenerated eye structures known as the rough eye phenotype (REP), reduced lifespan and deteriorated locomotor ability. Administration of DWE, SalA and SalB partially reverted the REP, increased the age of AD Drosophila and improved most of the mobility of AD Drosophila . In conclusion, DWE and its components may have therapeutic potential for AD patients and possibly other forms of brain diseases. ### Competing Interest Statement The authors have declared no competing interest.

936: Sodium Diethyldithiocarbamate antiparasitic activity against different Trypanosoma cruzi strains: Insights of its biological activity
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Posted 06 Jul 2020

Sodium Diethyldithiocarbamate antiparasitic activity against different Trypanosoma cruzi strains: Insights of its biological activity
114 downloads bioRxiv pharmacology and toxicology

Johny Wysllas de Freitas Oliveira, Taffarel Melo Torres, Cláudia Jassica Gonçalves Moreno, Bruno Amorim-Carmo, Igor Zumba Damasceno, Ana Katarina Menezes Cruz Soares, Jefferson da Silva Barbosa, Hugo Alexandre Oliveira Rocha, Marcelo Sousa Silva

Background . Chagas disease is caused by the protozoan Trypanosoma cruzi , a neglected tropical disease that affects thousands of people, mainly in Latin America. The drugs currently used in therapy are toxic and have therapeutic limitations during treatment. In addition, the genetic diversity of T. cruzi represents an important variable and challenge with regard to the pathogenesis of the infection, the epidemiological profile of the cases, and the therapeutic control of the infection. Sodium diethyldithiocarbamate (DETC) is a compound of high pharmacological versatility acting as metal chelators and producing reactive oxygen species. Thus, the objective of this work is to characterize the antiparasitic action of DETC against different strains and evolutionary forms of T. cruzi, as well as the characterization of the mechanism of antiparasitic action.  Methodology/Principal findings.   The different strains and evolutionary forms of T. cruzi were grown in LIT medium. To evaluate the antiparasitic activity of DETC, the evolutionary forms epimastigote and trypomastigote of T. cruzi were used by resazurin reduction methods and by counting under optical microscopy. Different response patterns were obtained between the strains and an IC 50 of DETC ranging from 9.44 ± 3,181µM to 60.49 ± 7.62 µM. Cell cytotoxicity against cell lines 3T3 and RAW and evaluated by MTT, demonstrated that DETC in high concentration (2222 µM) reduces around 60% the cell capacity of MTT reduction. The antiparasitic activity of DETC has been demonstrated through damage caused in the mitochondria of T. cruzi, a reduction of up to 80% in the mitochondrial potential of the parasites, as well as through damage caused in the membrane of the parasite. Conclusion. In this study we can conclude that DETC has antiparasitic activity against different genotypes and evolutionary forms of T. cruzi , representing a promising molecule as a drug for the treatment of Chagas disease.

937: Application of Generalized Concentration Addition to Predict Mixture Effects of Glucocorticoid Receptor Ligands
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Posted 26 May 2020

Application of Generalized Concentration Addition to Predict Mixture Effects of Glucocorticoid Receptor Ligands
114 downloads bioRxiv pharmacology and toxicology

Rosemarie de la Rosa, JJ Schlezinger, Martyn T. Smith, Thomas F Webster

Environmental exposures often occur in complex mixtures and at low concentrations. Generalized concentration addition (GCA) is a method used to estimate the joint effect of receptor ligands that vary in efficacy. GCA models have been successfully applied to mixtures of aryl hydrocarbon receptor (AhR) and peroxisome proliferator-activated receptor gamma (PPARγ) ligands, each of which can be modeled as a receptor with a single binding site. Here, we evaluated whether GCA could be applied to homodimer nuclear receptors, which have two binding sites, to predict the combined effect of full glucocorticoid receptor (GR) agonists with partial agonists. We measured transcriptional activation of GR using a cell-based bioassay. Individual dose response curves for dexamethasone (full agonist), prednisolone (full agonist), and medroxyprogesterone 17-acetate (partial agonist) were generated and applied in three additivity models, GCA, effect summation (ES), and relative potency factor (RPF), to generate response surfaces. GCA and RPF yielded adequate predictions of the experimental data for two full agonists. However, GCA fit experimental data significantly better than ES and RPF for all other binary mixtures. This work extends the application of GCA to homodimer nuclear receptors and improves prediction accuracy of mixture effects of GR agonists. ### Competing Interest Statement The authors have declared no competing interest.

938: Membrane-tethered peptides derived from intracellular loops 2 and 3 of the urotensin II receptor act as allosteric biased ligands
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Posted 24 Nov 2020

Membrane-tethered peptides derived from intracellular loops 2 and 3 of the urotensin II receptor act as allosteric biased ligands
113 downloads bioRxiv pharmacology and toxicology

Hassan Nassour, Tuan Anh Hoang, Ryan D Martin, Juliana C.C. Dallagnol, Etienne Billard, Myriam Létourneau, Ettore Novellino, Alfonso Carotenuto, Bruce G. Allen, Jason C Tanny, Alain Fournier, Terence E. Hébert, David Chatenet

Over the last decade, the urotensinergic system has garnered significant attention as a promising new target for the treatment of various cardiovascular diseases and also cancer. Significant investment toward the development of clinically relevant UT ligands for therapeutic intervention has been made but have met little to no success to date. The UT system, which has yet to be effectively targeted, therefore remains to be therapeutically exploited. The discovery of allosteric sites that allow modulation of receptor activity will increase the searchable chemical space against a disease-relevant target. Pepducins and other lipidated peptides have been used as both mechanistic probes and potential therapeutics. Therefore, pepducins derived from the human urotensin II receptor might represent unique tools to generate signaling bias and study UT signaling networks. Two hUT-derived pepducins, derived from the second and the third intracellular loop of UT, respectively, have been synthesized and pharmacologically characterized. Our results demonstrated that hUT-Pep2 and [Trp1, Leu2]hUT-Pep3 acted as biased ago-allosteric modulators, triggered ERK1/2 phosphorylation and to a lesser extent, IP1 production, stimulated cell proliferation yet were devoid of contractile activity. Interestingly, both hUT-derived pepducins were able to modulate hUII- and URP-mediated contraction albeit to different extents. These new derivatives represent unique tools to reveal the intricacies of hUT signaling and also a novel avenue to design allosteric ligands selectively targeting UT signaling that could prove to be useful for the treatment of hUT-associated diseases.

939: Vanilloids Hamper Caenorhabditis elegans Response to Noxious Heat
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Posted 11 Sep 2020

Vanilloids Hamper Caenorhabditis elegans Response to Noxious Heat
113 downloads bioRxiv pharmacology and toxicology

Bruno Nkambeu, Jennifer Ben Salem, Francis Beaudry

Eugenol, a known vanilloid, was frequently used in dentistry as a local analgesic in addition, antibacterial and neuroprotective effects were also reported. Eugenol, capsaicin and many vanilloids are interacting with the transient receptor potential vanilloid 1 (TRPV1) in mammals and are activated by noxious heat. The pharmacological manipulation of the TRPV1 has been shown to have therapeutic value. Caenorhabditis elegans (C. elegans) express TRPV orthologs (e.g. OCR-2, OSM-9) and it is a commonly used animal model system to study nociception as it displays a well-defined and reproducible nocifensive behavior. After exposition to vanilloid solutions, C. elegans wild type (N2) and mutants were placed on petri dishes divided in quadrants for heat stimulation. Thermal avoidance index was used to phenotype each tested C. elegans experimental groups. The results showed that eugenol, vanillin and zingerone can hamper nocifensive response of C. elegans to noxious heat (32C - 35C) following a sustained exposition. Also, the effect was reversed 6h post exposition. Furthermore, eugenol and vanillin did not target specifically the OCR-2 or OSM-9 but zingerone did specifically target the OCR-2 similarly to capsaicin. Further structural and physicochemical analyses were performed. Key parameters for quantitative structure-property relationships (QSPR), quantitative structure-activity relationships (QSAR) and frontier orbital analyses suggest similarities and dissimilarities amongst the tested vanilloids and capsaicin in accordance with the relative anti-nociceptive effects observed. ### Competing Interest Statement The authors have declared no competing interest.

940: Antimicrobial efficacy of neem and liquorice with chlorhexidine on Streptococcus sanguis, Streptococcus mutans, Lactobacillus and Actinomyces naeslundii – An In Vitro Study
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Posted 26 Sep 2020

Antimicrobial efficacy of neem and liquorice with chlorhexidine on Streptococcus sanguis, Streptococcus mutans, Lactobacillus and Actinomyces naeslundii – An In Vitro Study
113 downloads bioRxiv pharmacology and toxicology

Saad M Alqahtani

The study was to formulate 2% neem and 2% liquorice mouthwashes and to compare the antimicrobial efficacy of these mouthwashes with the standard 0.2% chlorhexidine mouthwash. Alcoholic solution was prepared and added to neem mixture and liquorice mixture separately and made up to a volume of 16000 ml with purified water. Nine dilutions of each drug were done with Brain heart infusion broth (BHI) for MIC. Culture suspension was added in each serially diluted tube of 200 μl. The tubes were incubated for 24 hours and observed for turbidity. Minimum inhibitory concentration (MIC) of 2% neem, 2% liquorice and 0.2% chlorhexidine against Lactobacillus, Actinomyces naeslundii, Streptococcus sanguis, Streptococcus mutans is determined by serial dilution analysis. Streptococcus mutans shows sensitivity to all three mouthwashes at a concentration starting from 0.2 μg/ml. Lactobacillus shows sensitivity to neem and chlorhexidine mouthwashes at a concentration starting from 1.6 μg/ml, whereas liquorice is effective at a concentration starting from 3.125 μg/ml. Streptococcus sanguis shows sensitivity to chlorhexidine and liquorice mouthwashes at a concentration starting from 25 μg/ml, whereas it shows sensitivity to neem at a concentration starting from 50 μg/ml. Actinomyces naeslundii shows sensitivity to chlorhexidine and neem mouthwashes at a concentration starting from 1.6 μg/ml, whereas it shows sensitivity to liquorice at a concentration starting from 3.125μg/ml. Analysis showed an inhibition of all the four strains by the mouthwashes. The MIC for the studied mouthwashes was found to be similar to that of 0.2% chlorhexidine.

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