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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 128,741 papers from 551,614 authors.

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in category pharmacology and toxicology

1,136 results found. For more information, click each entry to expand.

881: Electronic cigarettes induce mitochondrial DNA damage and trigger toll-like receptor 9-mediated atherosclerosis
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Posted 15 Aug 2020

Electronic cigarettes induce mitochondrial DNA damage and trigger toll-like receptor 9-mediated atherosclerosis
149 downloads bioRxiv pharmacology and toxicology

Jieliang Li, Do Luong Huynh, Moon-Shong Tang, Hannah Simborio, Jing Huang, Beata Kosmider, Michael B Steinberg, Le Thu Thi Le, Kien Pham, Chen Liu, He Wang

Objective: Both electronic cigarette (e-cig) use and toll-like receptor 9 (TLR9) activation have been implicated in promoting atherosclerosis. In this study we aimed to investigate the causative relationship of e-cig exposure on TLR9 activation and atherosclerosis development. Approach and Results: Eight-week-old ApoE-/- mice fed normal chow diet were exposed to e-cig vapor (ECV) for 2 h/day, 5 days/week for 16 weeks. We found that ECV exposure significantly induced atherosclerotic lesions as examined by Oil Red O staining of aortic root and greatly upregulated TLR9 expression in classical monocytes and in the atherosclerotic plaques, which the latter was corroborated by upregulated TLR9 expression in human femoral artery atherosclerotic plaques in e-cig smokers. Intriguingly, we found a significant increase of damaged mitochondria DNA level in the circulating blood of ECV exposed mice. Furthermore, administration of TLR9 antagonist prior to ECV exposure not only alleviated atherosclerotic lesion and the upregulation of TLR9 in plaques, but also attenuated the increase of plasma levels of inflammatory cytokines, reduced the accumulation of lipid and macrophages, and decreased the frequency of blood CCR2+ classical monocytes. Surprisingly, we found that the cytoplasmic mtDNA isolated from ECV extract-treated cells can greatly enhance the expression of TLR9 in reporter cells. Conclusion: E-cig induces mtDNA damage and the mtDNA in circulating blood stimulates the expression of TLR9, which elevate the expression of proinflammatory cytokines in monocyte/macrophage and consequently lead to atherosclerosis. Our results raise the possibility that intervention of TLR9 activation is a potential pharmacologic target of ECV-related inflammation and cardiovascular diseases. ### Competing Interest Statement The authors have declared no competing interest.

882: Application of the in vivo oxidative stress reporter Hmox1 as mechanistic biomarker of arsenic toxicity.
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Posted 20 Jun 2020

Application of the in vivo oxidative stress reporter Hmox1 as mechanistic biomarker of arsenic toxicity.
149 downloads bioRxiv pharmacology and toxicology

Francisco Inesta-Vaquera, Panida Navasumrit, Colin J. Henderson, Tanya G. Frangova, Tadashi Honda, Albena T. Dinkova-Kostova, Mathuros Ruchirawat, C. Roland Wolf

Inorganic arsenic (iAs) is a naturally occurring metalloid present in drinking water and polluted air exposing millions of people globally. Epidemiological studies have linked iAs exposure to the development of numerous diseases including cognitive impairment, cardiovascular failure and cancer. Despite intense research, an effective therapy for chronic arsenicosis has yet to be developed. Laboratory studies have been of great benefit in establishing the pathways involved in iAs toxicity and providing insights into its mechanism of action. However, the in vivo analysis of arsenic toxicity mechanisms has been difficult by the lack of reliable in vivo biomarkers of the effects of iAs. To resolve this issue we have applied the use of our recently developed stress reporter models to study iAs toxicity. The reporter mice Hmox1 (oxidative stress/inflammation; HOTT) and p21 (DNA damage) were exposed to iAs at acute and chronic, environmentally relevant, doses. We observed induction of the oxidative stress reporters in several cell types and tissues, which was largely dependent on the activation of transcription factor NRF2. We propose that our HOTT reporter model can be used as a surrogate biomarker of iAs-induced oxidative stress, and it constitutes a first-in-class platform to develop treatments in arsenicosis. Indeed, in a proof of concept experiment, the HOTT reporter mice were able to predict the therapeutic utility of the antioxidant N-acetyl cysteine in the prevention of iAs associated toxicity. ### Competing Interest Statement The authors have declared no competing interest.

883: Effects of rhein on bile acid homeostasis in rats
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Posted 30 Jan 2020

Effects of rhein on bile acid homeostasis in rats
149 downloads bioRxiv pharmacology and toxicology

Zhong Xian, Jingzhuo Tian, Lianmei Wang, Yushi Zhang, Jiayin Han, Nuo Deng, Suyan Liu, Yong Zhao, Chunying Li, Yan Yi, Dunfang Wang, Jing Meng, Chen Pan, Aihua Liang

Rhein, the active ingredient of rhubarb, a medicinal and edible plant, is widely used in clinical practice. In this work, we investigated the alterations of 14 bile acids and hepatic transporters after rats were administered rhein for 5 consecutive weeks. There was no obvious injury to the liver and kidney, and there were no significant changes in biochemical indicators. However, 1,000 mg/kg rhein increased the liver total bile acid (TBA) levels, especially taurine-conjugated bile acids (t-CBAs), inhibited the expression of Farnesoid X receptor (FXR) and (bile salt export pump) BSEP mRNA, and upregulated the expression of (cholesterol 7-hydroxylase) CYP7A1 mRNA. Rhein close to the clinical dose reduced the amounts of TBAs, especially unconjugated bile acids (UCBAs), and elevated the expression of FXR and multidrug resistance-associated protein 3 (Mrp3) mRNA. These results denote that rhein is not toxic and is safe to use at a reasonable dose and timing.

884: Quantitative Analysis of Effects of a Single 60Co Gamma Ray Point Exposure on Time-Dependent Change in Locomotor Activity in Rats
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Posted 29 Nov 2019

Quantitative Analysis of Effects of a Single 60Co Gamma Ray Point Exposure on Time-Dependent Change in Locomotor Activity in Rats
148 downloads bioRxiv pharmacology and toxicology

Keiko Otani, Megu Ohtaki, Nariaki Fujimoto, Aisulu Saimova, Ynkar Kairkhanova, Darkhan Uzbekov, Nailya Chaizhunusova, Nulran Aukenov, Tolebay Rakhypbekov, Hitoshi Sato, Noriyuki Kawano, Masaharu Hoshi

Fatigue is one of the earliest nonspecific symptoms of radiation exposure in humans, but its etiology, mechanism, and dose dependency remain unexplained. Investigating initial behavioral changes caused by irradiation of animals might provide important information to aid understanding of early health effects of radiation exposure and clinical features of radiation injury. Although previous studies in rodents suggested that radiation exposure leads to reduced activity, detailed properties of the effects were unrevealed due to a lack of proper statistical analysis, which is needed to better elucidate details of changes in locomotor activity. Ten-week-old male Wistar rats were subjected to single point external whole-body irradiation with 60Co gamma rays at 0, 2.0, 3.5, and 5.0 Gy (4 rats per group). Infrared sensors were used to continuously record locomotor activity of each rat. Cumulative number of movements during the night was defined as “activity” for each day. A non-linear mixed effects model accounting for individual differences and daily fluctuation of activity was applied to analyze the rats’ longitudinal locomotor data. Despite a small number of animals per group, our statistical method successfully revealed characteristics of the changes in locomotor activity after radiation exposure, showing that 1) reduction in activity occurred immediately—and in a dose-dependent manner—after irradiation and 2) recovery to pre-irradiation levels required almost one week, with the same recovery rate in each dose group. In addition to improving our understanding of radiation effects on locomotor activity, this statistical framework should be useful to analyze other data with similar structure.

885: Sotagliflozin, a dual SGLT1/2 inhibitor, improves cardiac outcomes in a mouse model of early heart failure without diabetes
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Posted 15 Aug 2020

Sotagliflozin, a dual SGLT1/2 inhibitor, improves cardiac outcomes in a mouse model of early heart failure without diabetes
148 downloads bioRxiv pharmacology and toxicology

Sophia L Young, Lydia Ryan, Thomas P Mullins, Melanie Flint, Sarah E Steane, Sarah L Walton, Helle Bielefeldt-Ohmann, David A Carter, Melissa E Reichelt, Linda A Gallo

Aims: Selective SGLT2 inhibition reduces the risk of worsening heart failure and cardiovascular death in patients with existing heart failure, irrespective of diabetic status. We aimed to investigate the effects of dual SGLT1/2 inhibition, using sotagliflozin, on cardiac outcomes in non-diabetic and diabetic mice with cardiac pressure overload. Methods and Results: Five-week old male C57BL/6J mice were randomized to receive a high fat diet (HFD; 60% of calories from fat) to induce diabetes or remain on normal diet (ND) for 12 weeks. Transverse aortic constriction (TAC) was then employed to induce cardiac pressure-overload (50% increase in right:left carotid pressure versus sham surgery), resulting in features representative of heart failure with preserved ejection fraction. At five weeks into the dietary protocol, mice were treated for seven weeks by oral gavage once daily with sotagliflozin (10mg/kg body weight) or vehicle (0.1% tween 80). In ND non-diabetic mice, treatment with sotagliflozin attenuated cardiac hypertrophy and histological markers of cardiac fibrosis induced by TAC. These benefits were associated with profound diuresis and glucosuria, without shifts toward whole-body fatty acid utilisation nor increased cardiac ketolysis. In HFD diabetic mice, sotagliflozin did not attenuate cardiac injury induced by TAC. HFD mice had vacuolation of proximal tubular cells, associated with less profound diuresis and glucosuria, which may have compromised drug action and subsequent cardio-protection. Conclusion: We demonstrate the utility of dual SGLT1/2 inhibition in treating heart failure risk factors in the non-diabetic state. Its efficacy in high fat-induced diabetes with proximal tubular damage requires further study. ### Competing Interest Statement The authors have declared no competing interest.

886: FGF21 Normalizes Plasma Glucose in Mouse Models of Type 1 Diabetes and Insulin Receptor Dysfunction
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Posted 05 Jan 2021

FGF21 Normalizes Plasma Glucose in Mouse Models of Type 1 Diabetes and Insulin Receptor Dysfunction
148 downloads bioRxiv pharmacology and toxicology

John L Diener, Sarah Mowbray, David Yowe, Jain Xu, Shari Caplan, Abhay Misra, Ankur Kapur, Waan-Jeng Huang, Jeffrey Shapiro, Xiaoling Ke, Xiaoping Wu, Avirup Bose, Darrell Panza, Min Chen, Valerie Beaulieu, Jiaping Gao

Fibroblast growth factor 21 (FGF21) is a member of the fibroblast growth factor (FGF) family of proteins. The biological activity of FGF21 was first shown to induce insulin independent glucose uptake in adipocytes through the GLUT1 transporter. Subsequently, it was shown to have effects on the liver to increase fatty acid oxidation. FGF21 treatment provides beneficial metabolic effects in both animal models and patients with obesity, type 2 diabetes mellitus (T2D) and/or fatty liver disease. In this paper, we revisited the original finding and found that insulin independent glucose uptake in adipocytes is preserved in the presence of an insulin receptor antagonist. Using a 40 kDa PEGylated (PEG) and half-life extended form of FGF21 (FGF21-PEG), we extended these in vitro results to two different mouse models of diabetes. FGF21-PEG normalized plasma glucose in streptozotocin-treated mice, a model of type 1 diabetes (T1D), without restoring pancreatic {beta}-cell function. FGF21-PEG also normalized plasma glucose levels and improved glucose tolerance in mice chronically treated with an insulin competitive insulin receptor antagonist, a model of autoimmune/Type-B insulin resistance. These data extend the pharmacological potential of FGF21 beyond the settings of T2D, fatty liver and obesity.

887: An in silico exploration of combining Interleukin-12 with Oxaliplatin to treat liver-metastatic colorectal cancer
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Posted 22 Jul 2019

An in silico exploration of combining Interleukin-12 with Oxaliplatin to treat liver-metastatic colorectal cancer
147 downloads bioRxiv pharmacology and toxicology

Qing Wang, Zhijun Wang, Yan Wu, David J. Klinke

Background: Combining anti-cancer therapies with orthogonal modes of action, such as direct cytotoxicity and immunostimulatory, hold promise for expanding clinical benefit to patients with metastatic disease. For instance, a chemotherapy agent Oxaliplatin (OXP) in combination with Interleukin-12 (IL-12) can eliminate pre-existing liver metastatic colorectal cancer and protect from relapse in a murine model. However, the underlying dynamics associated with the targeted biology and the combinatorial space consisting of possible dosage and timing of each therapy present challenges for optimizing treatment regimens. To address some of these challenges, we developed a predictive simulation platform for optimizing dose and timing of the combination therapy involving Mifepristone-induced IL-12 and chemotherapy agent OXP. Methods: A multi-scale mathematical model comprised of impulsive ordinary differential equations was developed to describe the interaction between the immune system and tumor cells in response to the combined IL-12 and OXP therapy. An ensemble of model parameters were calibrated to published experimental data using a genetic algorithm and used represent three different phenotypes: responders, partial-responders, and non-responders. Results: The multi-scale model captures tumor growth patterns of the three phenotypic responses observed in mice in response to the combination therapy against a tumor re-challenge and was used to explore changing the dose and timing of the mixed immune-chemotherapy on tumor growth subjected to a tumor re-challenge in mice. An increased ratio of CD8+ T effectors to regulatory T cells during and after treatment was key to improve tumor control in the responder cohort. Sensitivity analysis indicates that combined OXP and IL-12 therapy worked more efficiently in responders by increased priming of T cells, enhanced CD8+ T cell-mediated killing, and functional inhibition of regulatory T cells. In a virtual cohort that mimics non-responders and partial-responders, simulations show that an increased dose of OXP alone would improve the response. In addition, enhanced IL-12 expression alone or an increased number of treatment cycles of the mixed immune-chemotherapy can barely improve tumor control for non-responders and partial responders. Conclusions: Overall, this study illustrates how mechanistic models can be used for in silico screening of the optimal therapeutic dose and timing in combined cancer treatment strategies.

888: Metabolic Reprogramming by In Utero Maternal Benzene Exposure
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Posted 12 Oct 2020

Metabolic Reprogramming by In Utero Maternal Benzene Exposure
146 downloads bioRxiv pharmacology and toxicology

Lisa Koshko, Lucas K. Debarba, Mikaela Sacla, Juliana M.B. de Lima, Olesya Didyuk, Patrick Fakhoury, Marianna Sadagurski

Environmental chemicals play a significant role in the development of metabolic disorders, especially when exposure occurs early in life. We have recently demonstrated that benzene exposure, at concentrations relevant to a cigarette smoke, induces a severe metabolic imbalance in a sex-specific manner affecting male but not female mice. However, the roles of benzene in the development of aberrant metabolic outcomes following gestational exposure, remain largely unexplored. In this study, we exposed pregnant C57BL/6JB dams to benzene at 50 ppm or filtered air for 5 days/week (6h/day from gestational day 1 to birth) and studied male and female offspring metabolic phenotypes in their adult life. While no changes in body weight or body composition were observed between groups, 4-month-old male and female offspring exhibited reduced parameters of energy homeostasis (VO2, VCO2, and heat production). However, only male offspring from benzene-exposed dams were glucose intolerant and insulin resistant at this age. By six months of age, both male and female offspring displayed glucose and insulin intolerance, associated with elevated expression of hepatic gluconeogenesis and inflammatory genes. Additionally, this effect was accompanied by elevated insulin secretion and increased beta-cell mass only in male offspring. Thus, gestational benzene exposure can reprogram offspring for increased susceptibility to the metabolic imbalance in adulthood with differential sensitivity between sexes. ### Competing Interest Statement The authors have declared no competing interest.

889: Reconstituted Mining Effluent Reduces Neuronal Proliferation in the Developing Brain and Slows Growth of Body and Facial Features in Wild-Caught Wood Frog Tadpoles.
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Posted 30 Jan 2020

Reconstituted Mining Effluent Reduces Neuronal Proliferation in the Developing Brain and Slows Growth of Body and Facial Features in Wild-Caught Wood Frog Tadpoles.
145 downloads bioRxiv pharmacology and toxicology

Hannah G. Sturgeon, Jeremy P Kitchen, Lara I. Dahora, Sara E Sweeten, Christopher K. Thompson

Mining, whether current or inactive, generally increases salt concentrations in catchment watersheds due to precipitation on and through exposed rock surfaces. Practices like mountaintop removal mining have exacerbated this issue, with measurements of salt concentrations in nearby catchment systems well above normal levels. Nevertheless, the impact of the ionic composition of mining effluent on aquatic animal health is not well understood. This is a particularly important issue in Appalachia because it is home to an enormous diversity of organisms, including a huge array of amphibians that live in streams that receive mining effluent from operating and abandoned mines. To investigate this issue, we examined the effects of reconstituted mining effluent on the development of wild-caught wood frog (Lithobates sylvaticus) tadpoles. We collected day-old fertilized eggs from a creek near Blacksburg, VA in early March, 2018 and raised them to hatch. Tadpoles were then assigned to either sulfate or chloride-based reconstituted mining effluent diluted to six different conductivities (100 μS/cm - 2,400 μS/cm). After 7 or 14 days of treatment, tadpoles were euthanized and fixed in paraformaldehyde. We imaged the heads and bodies of tadpoles for morphometric analysis before dissecting out brains and immunostaining them for phospho-histone H3, which labels dividing progenitor cells in the brain. We found that sulfate-based reconstituted mining effluent significantly lowered progenitor cell division at 1200 μS/cm at Day 7 and at 600 μS/cm at Day 14 relative to control. Chloride-based reconstituted mining effluent was less impactful, with no significant differences observed at Day 7 and significantly lowered progenitor cell division at 2400 μS/cm at Day 14. In addition, both treatments slowed growth of some head morphological features, including head size and interocular distance. Chloride treatment slowed growth of body length at Day 14 at 600 μS/cm, whereas sulfate-based reconstituted mining effluent had no effect on body length. These data show that sulfate-based mining effluent has a substantial impact on aspects of neural development, whereas chloride-based reconstituted mining effluent had less effect. In contrast, chloride-based reconstituted mining effluent had a much greater impact than sulfate on body morphology and growth. These experiments demonstrate that the chemical composition of salts in mining effluent can have divergent effects on the development of amphibians.

890: C. elegans pharyngeal pumping provides a whole organism bio-assay to investigate anti-cholinesterase intoxication and antidotes
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Posted 04 Jun 2020

C. elegans pharyngeal pumping provides a whole organism bio-assay to investigate anti-cholinesterase intoxication and antidotes
144 downloads bioRxiv pharmacology and toxicology

Patricia G. Izquierdo, Vincent O’Connor, Christopher Green, Lindy Holden-Dye, John Tattersall

Inhibition of acetylcholinesterase by either organophosphates or carbamates causes anti-cholinesterase poisoning. This arises through a wide range of neurotoxic effects triggered by the overstimulation of the cholinergic receptors at synapses and neuromuscular junctions. Without intervention, this poisoning can lead to profound toxic effects, including death, and the incomplete efficacy of the current treatments, particularly for oxime-insensitive agents, provokes the need to find better antidotes. Here we show how the non-parasitic nematode Caenorhabditis elegans offers an excellent tool for investigating the acetylcholinesterase intoxication. The C. elegans neuromuscular junctions show a high degree of molecular and functional conservation with the cholinergic transmission that operates in the autonomic, central and neuromuscular synapses in mammals. In fact, the anti-cholinesterase intoxication of the worm's body wall neuromuscular junction has been unprecedented in understanding molecular determinants of cholinergic function in nematodes and other organisms. We extend the use of the model organism's feeding behaviour as a tool to investigate carbamate and organophosphate mode of action. We show that inhibition of the cholinergic-dependent rhythmic pumping of the pharyngeal muscle correlates with the inhibition of the acetylcholinesterase activity caused by aldicarb, paraoxons and DFP exposure. Further, this bio-assay allows one to address oxime dependent reversal of cholinesterase inhibition in the context of whole organism recovery. Interestingly, the recovery of the pharyngeal function after such anti-cholinesterase poisoning represents a sensitive and easily quantifiable phenotype that is indicative of the spontaneous recovery or irreversible modification of the worm acetylcholinesterase after inhibition. These observations highlight the pharynx of C. elegans as a new tractable approach to explore anti-cholinesterase intoxication and recovery with the potential to resolve critical genetic determinants of these neurotoxins' mode of action. ### Competing Interest Statement The authors have declared no competing interest.

891: Youthful and age-related matreotypes predict drugs promoting longevity
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Posted 27 Jan 2021

Youthful and age-related matreotypes predict drugs promoting longevity
144 downloads bioRxiv pharmacology and toxicology

Cyril Statzer, Elisabeth Jongsma, Sean X Liu, Alexander Dakhovnik, Franziska Wandrey, Pavlo Mozharovskyi, Fred Zuelli, Collin Y Ewald

The identification and validation of drugs that promote health during aging ('geroprotectors') is key to the retardation or prevention of chronic age-related diseases. Here we found that most of the established pro-longevity compounds shown to extend lifespan in model organisms also alter extracellular matrix gene expression (i.e., matrisome) in human cell lines. To harness this novel observation, we used age-stratified human transcriptomes to define the age-related matreotype, which represents the matrisome gene expression pattern associated with age. Using a 'youthful' matreotype, we screened in silico for geroprotective drug candidates. To validate drug candidates, we developed a novel tool using prolonged collagen expression as a non-invasive and in-vivo surrogate marker for C. elegans longevity. With this reporter, we were able to eliminate false positive drug candidates and determine the appropriate dose for extending the lifespan of C. elegans. We improved drug uptake for one of our predicted compounds, genistein, and reconciled previous contradictory reports of its effects on longevity. We identified and validated new compounds, tretinoin, chondroitin sulfate, and hyaluronic acid, for their ability to restore age-related decline of collagen homeostasis and increase lifespan. Thus, our innovative drug screening approach - employing extracellular matrix homeostasis - facilitates the discovery of pharmacological interventions promoting healthy aging.

892: Trans-channel fluorescence learning improves high-content screening for Alzheimer's disease therapeutics
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Posted 09 Jan 2021

Trans-channel fluorescence learning improves high-content screening for Alzheimer's disease therapeutics
143 downloads bioRxiv pharmacology and toxicology

Daniel R. Wong, Jay Conrad, Noah Johnson, Jacob I Ayers, Annelies Laeremans, Joanne C. Lee, Jisoo Lee, Stanley B. Prusiner, Sourav Bandyopadhyay, Atul J. Butte, Nick A. Paras, Michael J. Keiser

In microscopy-based drug screens, fluorescent markers carry critical information on how compounds affect different biological processes. However, practical considerations may hinder the use of certain fluorescent markers. Here, we present a deep learning method for overcoming this limitation. We accurately generated predicted fluorescent signals from other related markers, and validated this new machine learning (ML) method on two biologically distinct datasets. We used the ML method to improve the selection of potentially efficacious therapeutic compounds for Alzheimers disease (AD) from high-content high-throughput screening (HCS). The ML method identified novel compounds that effectively blocked tau aggregation, which would have been missed by traditional screening approaches unguided by ML. The ML method also improved triaging efficiency of compound rankings over a current in-house screening approach. We reproduced this ML method on a biologically independent cancer-based dataset, demonstrating its generalizability. The approach is disease-agnostic, and applicable across fluorescence microscopy datasets.

893: Predicting the activation of the androgen receptor by mixtures of ligands using Generalized Concentration Addition
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Posted 03 May 2020

Predicting the activation of the androgen receptor by mixtures of ligands using Generalized Concentration Addition
143 downloads bioRxiv pharmacology and toxicology

JJ Schlezinger, Wendy Heiger-Bernays, Thomas F Webster

Concentration/dose addition (CA) is widely used for compounds that act by similar mechanisms. But CA cannot make predictions for mixtures of full and partial agonists for effect levels above that of the least efficacious component. As partial agonists are common, we developed Generalized Concentration Addition (GCA), which has been successfully applied to systems in which ligands compete for a single binding site. Here, we applied a pharmacodynamic model for a system with two binding sites, the androgen receptor (AR). AR acts according to the classic homodimer activation model: each cytoplasmic AR protein binds ligand, undergoes a conformational change that relieves inhibition of dimerization, and binds to DNA response elements as a dimer. We generated individual dose-response data for full (dihydroxytestosterone, BMS564929) and partial (TFM-4AS-1) agonists and a competitive antagonist (MDV3100) using reporter data generated in the MDA-kb2 cell line. We used the Schild method to estimate the binding affinity of AR for MDV3100. Data for individual compounds fit the AR pharmacodynamic model well. The partial agonist had agonistic effects at low effect levels and antagonistic effects at high levels, as predicted by pharmacological theory. The GCA model fit the empirical mixtures data, full/full agonist, full/partial agonist and full agonist/antagonist, as well or better than relative potency factors (a special case of CA) or effect summation. The ability of generalized concentration addition to predict the activity of mixtures of different types of androgen receptor ligands is important as a number of environmental compounds act as partial AR agonists or antagonists. ### Competing Interest Statement The authors have declared no competing interest.

894: Stability of extemporaneously compounded amiloride nasal spray
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Posted 16 Apr 2020

Stability of extemporaneously compounded amiloride nasal spray
143 downloads bioRxiv pharmacology and toxicology

Venkata K. Yellepeddi, Casey Sayre, Anna Burrows, Kevin Watt, Simon Davies, John Strauss, Marco Battaglia

Anxiety disorders (AD) are the most common mental illnesses affecting an estimated 40 million adults in the United States. Amiloride, a diuretic agent, has shown efficacy in treating AD in preclinical models by inhibiting the acid-sensing ion channels (ASIC). By delivering amiloride via nasal route, rapid onset of action can be achieved due to direct “nose-to-brain” access. Therefore, this study reports the formulation, physical, chemical, and microbiological stability of an extemporaneously prepared amiloride 2 mg/mL nasal spray. The amiloride nasal spray was prepared by adding 100 mg of amiloride hydrochloride to 50 mL of sterile water for injection in a sterile reagent bottle. A stability-indicating high-performance liquid chromatography (HPLC) method was developed and validated. Forced-degradation studies were performed to confirm the ability of the HPLC method to identify the degradation products from amiloride distinctively. The physical stability of the amiloride nasal spray was assessed by pH, clarity, and viscosity assessments. For chemical stability studies, samples of nasal sprays stored at room temperature were collected at time-points 0, 3 hr., 24 hr., and 7 days and were assayed in triplicate using the stability-indicating HPLC method. Microbiological stability of the nasal spray solution was evaluated for up to 7 days based on the sterility test outlined in United States Pharmacopoeia (USP) chapter 71. The stability-indicting HPLC method identified the degradation products of amiloride without interference from amiloride. All tested solutions retained over 90% of the initial amiloride concentration for the 7-day study period. There were no changes in color, pH, and viscosity in any sample. The nasal spray solutions were sterile for up to 7 days in all samples tested. An extemporaneously prepared nasal spray solution of amiloride hydrochloride (2 mg/mL) was physically, chemically, and microbiologically stable for 7 days when stored at room temperature.

895: Bisphenol-S and Bisphenol-F alter mouse pancreatic β-cell ion channel expression and activity and insulin release through an estrogen receptor ERβ mediated pathway
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Posted 01 Oct 2020

Bisphenol-S and Bisphenol-F alter mouse pancreatic β-cell ion channel expression and activity and insulin release through an estrogen receptor ERβ mediated pathway
143 downloads bioRxiv pharmacology and toxicology

Laura Marroqui, Juan Martinez-Pinna, Manuel Castellano-Muñoz, Reinaldo S. dos Santos, Regla M. Medina-Gali, Sergi Soriano, Ivan Quesada, Jan-Ake Gustafsson, José A. Encinar, Angel Nadal

Bisphenol-S (BPS) and Bisphenol-F (BPF) are current Bisphenol-A (BPA) substitutes. Here we used pancreatic β-cells from wild type (WT) and estrogen receptor β (ERβ) knockout (BERKO) mice to investigate the effects of BPS and BPF on insulin secretion, and the expression and activity of ion channels involved in β-cell function. BPS or BPF rapidly increased insulin release and diminished ATP-sensitive K+ (KATP) channel activity. Similarly, 48 h treatment with BPS or BPF enhanced insulin release and decreased the expression of several ion channel subunits in β-cells from WT mice, yet no effects were observed in cells from BERKO mice. PaPE-1, a ligand designed to preferentially trigger extranuclear-initiated ER pathways, mimicked the effects of bisphenols, suggesting the involvement of extranuclear-initiated ERβ pathways. Molecular dynamics simulations indicated differences in ERβ ligand-binding domain dimer stabilization and solvation free energy among different bisphenols and PaPE-1. Our data suggest a mode of action involving ERβ whose activation alters three key cellular events in β-cell, namely ion channel expression and activity, and insulin release. These results may help to improve the hazard identification of bisphenols. ### Competing Interest Statement The authors have declared no competing interest.

896: Preserved efficacy and reduced toxicity with intermittent linezolid dosing in combination with bedaquiline and pretomanid in a murine TB model
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Posted 12 Jun 2020

Preserved efficacy and reduced toxicity with intermittent linezolid dosing in combination with bedaquiline and pretomanid in a murine TB model
142 downloads bioRxiv pharmacology and toxicology

Kristina M. Bigelow, Rokeya Tasneen, Yong S. Chang, Kelly E Dooley, Eric Nuermberger

The novel regimen of bedaquiline, pretomanid, and linezolid (BPaL) is highly effective against drug resistant tuberculosis, but linezolid toxicities are frequent. We hypothesized that, for a similar total weekly cumulative dose, thrice-weekly administration of linezolid would preserve efficacy while reducing toxicity compared to daily dosing, in the context of the BPaL regimen. Using C3HeB/FeJ and BALB/c mouse models of tuberculosis disease, thrice-weekly linezolid dosing was compared to daily dosing, with intermittent dosing introduced (a) from treatment initiation or (b) following an initial period of daily dosing. In all animals, BPa was dosed daily throughout treatment. Blood counts were used to assess hematologic toxicity. Following unexpected findings of apparent antagonism, we conducted additional experiments to investigate strain-to-strain differences in the contribution of linezolid to regimen efficacy comparing each 1- and 2-drug component to the BPaL regimen in BALB/c mice infected with Mycobacterium tuberculosis H37Rv or HN878. Giving linezolid daily for 1-2 months achieved the greatest efficacy, but following that, results were similar if the drug was stopped, dosed thrice-weekly, or continued daily. Erythrocyte counts were lower with daily than thrice-weekly dosing. Linezolid had additive effects with BPa against M. tuberculosis H37Rv but antagonistic effects with BPa against M. tuberculosis HN878. However, overall efficacy of BPaL was high and similar against both strains.

897: 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
142 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

898: Isoprenylcysteine carboxylmethyltransferase based therapy for Hutchinson Gilford progeria syndrome
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Posted 24 Jul 2020

Isoprenylcysteine carboxylmethyltransferase based therapy for Hutchinson Gilford progeria syndrome
141 downloads bioRxiv pharmacology and toxicology

Beatriz Marcos-Ramiro, Ana Gil-Ordóñez, Nagore I. Marín-Ramos, Francisco J. Ortega-Nogales, Moisés Balabasquer, Pilar Gonzalo, Loïc Rolas, Anna Barkaway, Sussan Nourshargh, Vicente Andrés, Mar Martín-Fontecha, María L. López-Rodríguez, Silvia Ortega-Gutiérrez

Progerin is a mutant prelamin A variant that causes Hutchinson Gilford progeria syndrome (HGPS, progeria), a rare genetic disease characterized by premature aging and death in childhood. Although several therapeutic approaches have been explored in experimental models, clinical trials have shown very limited benefits in HGPS patients. Here, we describe the development of UCM-13207, a new potent inhibitor of isoprenylcysteine carboxylmethyltransferase (ICMT) that reduces progerin nuclear accumulation and ameliorates the typical alterations in progeroid human and mouse cells. UCM-13207 also improves phenotypic anomalies and extends lifespan in progerin-expressing LmnaG609G/G609G mice. These results support the potential use of UCM-13207 as a new treatment for progeria. ### Competing Interest Statement The authors have declared no competing interest.

899: Renoprotective and haemodynamic effects of adiponectin and peroxisome proliferator-activated receptor agonist, pioglitazone, in renal vasculature of diabetic Spontaneously hypertensive rats
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Posted 17 Feb 2020

Renoprotective and haemodynamic effects of adiponectin and peroxisome proliferator-activated receptor agonist, pioglitazone, in renal vasculature of diabetic Spontaneously hypertensive rats
141 downloads bioRxiv pharmacology and toxicology

Sheryar Afzal, Munavvar Abdul Sattar, Edward James Johns, Olorunfemi. A. Eseyin

Pioglitazone, a therapeutic drug for diabetes, possesses full PPAR-γ agonist activity and increase circulating adiponectin plasma concentration. Plasma adiponectin concentration decreases in hypertensive patients with renal dysfunctions. Present study investigated the reno-protective, altered excretory functions and renal haemodynamic responses to adrenergic agonists and ANG II following separate and combined therapy with pioglitazone in diabetic model of hypertensive rats. Pioglitazone was given orally [10mg/kg/day] for 28 days and adiponectin intraperitoneally [2.5µg/kg/day] for last 7 days. Groups of SHR received either pioglitazone or adiponectin in combination. A group of Wistar Kyoto rats [WKY] served as normotensive controls, whereas streptozotocin administered SHRs served as diabetic hypertensive rats. Metabolic data and plasma samples were taken on day 0, 8, 21 and 28. In acute studies, the renal vasoconstrictor actions of Angiotensin II [ANGII], noradrenaline [NA], phenylephrine [PE] and methoxamine [ME] were determined. Diabetic SHRs control had a higher basal mean arterial blood pressure than the WKY, lower RCBP and plasma adiponectin, higher creatinine clearance and urinary sodium excretion compared to WKY [all P<0.05] which were normalized by the individual drug treatments and to greater degree following combined treatment. Responses to intra-renal administration of NA, PE, ME and ANGII were larger in diabetic SHR than WKY and SHRs [P<0.05]. Adiponectin significantly blunted responses to NA, PE, ME and ANG II in diabetic treated SHRs by 40%, whereas the pioglitazone combined therapy with adiponectin further attenuated the responses to adrenergic agonists by 65%. [all P <0.05]. These findings suggest that adiponectin possesses renoprotective effects and improves renal haemodynamics through adiponectin receptors and PPAR-γ in diabetic SHRs, suggesting that synergism exists between adiponectin and pioglitazone. A cross-talk relationship also supposed to exists between adiponectin receptors, PPAR-γ and alpha adrenoceptors in renal vasculature of diabetic SHRs.

900: Antibiotic concentrations in the sinonasal secretions and tissue in CRS patients after oral therapy: a randomized trial
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Posted 18 Jun 2020

Antibiotic concentrations in the sinonasal secretions and tissue in CRS patients after oral therapy: a randomized trial
140 downloads bioRxiv pharmacology and toxicology

Joey Siu, Lilian Klingler, Yi Wang, Cheung-Tak Hung, Soo Hee Jeong, Susan Smith, Malcolm Tingle, Brett Wagner Mackenzie, Kristi Biswas, Richard Douglas

Background: Despite the widespread prescription of antibiotics for patients with chronic rhinosinusitis (CRS), the extent to which drug distribution to the sinonasal mucosa influences their efficacy remains largely undefined. Methods: Thirty subjects undergoing functional endoscopic sinus surgery (FESS) for bilateral CRS were randomized to one of three groups: 1) doxycycline (100 mg daily for seven days) 2) roxithromycin (300 mg daily for seven days) and 3) control (no antibiotics given). Drug levels were measured using liquid chromatography-tandem mass spectrometry in sinonasal secretions, sinonasal tissues and serum at steady state. Nasal endoscopy (Modified Lund-Kennedy) and Gastrointestinal Symptom Rating Scale (GSRS) scores were recorded. Results: Antibiotic concentrations in the nasal secretions were significantly lower compared to those in the serum and tissue (mean mucus/serum ratio at steady state = 0.16 and 0.37 for doxycycline and roxithromycin respectively; p<0.01). A short course of antibiotic intake did not correlate with any difference in clinical outcomes except where slightly higher GSRS scores were reported in the roxithromycin group (p=0.04). Conclusions: Although the efficacy of doxycycline and roxithromycin in sinonasal mucus in vivo cannot be predicted solely from reported minimum inhibitory concentrations, given the added complication of bacterial biofilm antimicrobial tolerance, these results suggest that low mucosal penetration of antibiotics may be one of the factors contributing to the limited efficacy of these agents in the treatment of CRS.

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