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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

1,147 results found. For more information, click each entry to expand.

901: 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.

902: In vivo Evaluation and in silico Prediction of the Toxicity of Drepanoalpha Hard capsules
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Posted 04 Dec 2020

In vivo Evaluation and in silico Prediction of the Toxicity of Drepanoalpha Hard capsules
142 downloads bioRxiv pharmacology and toxicology

Benjamin Gbolo Zoawe, Jean-Paul Ngbolua Koto-te-Nyiwa, Damien Tshibangu Sha-Tshibey, Patrick Memvanga Bondo, Dorothee Tshilanda Dinangayi, Aristote Matondo, Jason Kilembe Thambwe, Bienvenu Lebwaze Masamba, Amandine Nachtergael, Pius Mpiana Tshimankinda, Pierre Duez

Drepanoalpha(R) hard capsules, a dry ethanolic extract (drug-extract ratio, 100/11) of a mixture of Justicia secunda Vahl and Moringa oleifera Lam dried leaves (1: 1, w/w) are used for the management of sickle cell disease in the Democratic Republic of Congo. Aim of the study: This phytomedicine safety was investigated by acute and sub-acute administration in Guinea pigs. Materials and methods: Healthy, male and nulliparous and non-pregnant female Guinea pigs were obtained from Laboratory of Animal Experimentation and Toxicology of the Department of Biology, Faculty of Sciences, University of Kinshasa. The animals were randomly selected, marked and divided into 2 groups of 5 animals each (3 males and 2 females) and 4 groups of 3 animals each for acute and sub-acute toxicity studies, respectively. The contents of hard capsules were dissolved in normal saline solution (NaCl 0.9 %). Animals received by gavage a single dose of 5000 mg/ kg of body weight (B.W.) of Drepanoalpha(R) hard capsules (acute toxicity) and 125 mg/ kg, 250 mg/ kg and 500 mg/ kg of B.W. twice daily for 28 days (sub-acute toxicity). Normal saline solution was used as control. Hematological, biochemical and histopathological analyses were performed and the behavior of the animals was observed after treatment. Results: The median lethal dose (LD50) is higher than 5000 mg/ kg of B.W., and the relative weights of vital organs (kidneys, liver and heart) collected from Guinea pigs at the end of treatment on D14 (acute toxicity) and D28 (sub-acute toxicity) has not undergone significant changes (p > 0.05). The results of haematological (red and white blood cells counts, haemoglobin, haematocrit) and biochemical (ALT, AST, albumin, total protein) tests did not show significant differences between control and test groups (=0.05 for acute toxicity), while the histopathological study revealed no damage to the various organs excised. Conclusion: The results indicate the safety of Drepanoalpha(R) hard capsules, confirming previous studies, in rats and Guinea pigs, based on aqueous decoction of its raw herbs mixtures and the corresponding lyophilizate. Keywords: Acute toxicity, Sub-acute toxicity, Drepanoalpha(R) hard capsules

903: 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

904: 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.

905: 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.

906: Anti-diabetic Potential of Aqueous Extract of Moringa oleifera, Ocimum gratissimum and Vernonia amygdalina in Alloxan-Induced Diabetic Rats
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Posted 10 Aug 2020

Anti-diabetic Potential of Aqueous Extract of Moringa oleifera, Ocimum gratissimum and Vernonia amygdalina in Alloxan-Induced Diabetic Rats
140 downloads bioRxiv pharmacology and toxicology

A. L. Ayobami, E. A. Kade, K. A. Oladimeji, Kehinde Sowunmi, K. Gurpreet

The incidence of diabetes mellitus (DM) is increasing globally and it is a major source of concern. This study was undertaken to assess the antidiabetic effect of the aqueous extract of Moringa oleifera, Ocimum gratissimum and Vernonia amygdalina. Sixty adult Wistar rats with body weight of 120-150 g were randomly assigned to groups of five rats each (n=12). Groups 1 served as normal control; Groups 2-5 were diabetic groups; group 2 served as negative control; group 3-5 received 100, 200 and 400 mg/kg of triherbal formula respectively. The body weight (BW) and fasting blood glucose level (FBSL) of the rats were monitored weekly. At the end of the experiment, all the rats were anaesthetized intraperitoneally (I.P) and blood samples were collected by cardiac puncture for biochemical analysis. There was an increase in the BW of the control group and varying doses of tri-herbal formation. It caused 88.0% decrease in FBSL; 371.7%, 386.6% and 296.0% with respect to 100, 200 and 400 mg/kg. Sub-chronic study of the effect of the extract showed a significant increase (P<0.05) in packed cell volume (PCV), white blood counts in rat induced diabetes. The histological studies showed that the diabetic rats with the architecture of the pancreas distorted, was restored to normal by the extract. Its LD50 was found to be greater than 1000 mg/kg indicating its safety in rats. This study has shown that triherbal formula has hypoglycemic and haematogical effects. ### Competing Interest Statement The authors have declared no competing interest.

907: Hydrogen Peroxide Levels in Freshly Brewed Coffee and the Effects of Storage
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Posted 10 Aug 2020

Hydrogen Peroxide Levels in Freshly Brewed Coffee and the Effects of Storage
140 downloads bioRxiv pharmacology and toxicology

Sannihith N. Uppu, Bianca K. London

One of the world's most consumed beverages, coffee has its origins as early as the 15th century Ethiopia. Although there are studies on caffeine and other components of coffee such as cafestol and kahweol, up until recently knowledge of the presence of hydrogen peroxide (H2O2) in coffee was confined to the scientific community and some informed public. It is a general belief that H2O2 is formed only after long periods of storage or with certain roasting practices. The present study is focused on dispelling the myths of H2O2 in coffee. We first measured H2O2 in freshly brewed coffee from different companies using the ferrous oxidation-xylenol orange binding (FOX) assay. Following this, we examined the time-dependent accumulation of H2O2 and its changes with temperature. Further, H2O2 was estimated in coffee obtained from several local vendors. Contrary to the general belief that the accumulation of H2O2 is an aging phenomenon of coffee, we found this toxicant even in freshly brewed coffee. This was true for all brands tested, and the H2O2 content increased upon storage. The highest increase was seen in coffee stored on the hot plate compared to the ones kept at room temperature (22-25 °C) or in the cold (0-4 °C).The H2O2 content of coffee from different vendors ranged between 0.29 and 0.82 mM, which is 5- to 20-fold higher than the typical H2O2 concentrations at which significant cytotoxic effects have been reported for assay systems using the human Fanconi deficient (PD20 FANCD2−/−) fibroblasts and other cell types. Our findings are deemed to shine new light on the probable toxic effects of a commonly consumed beverage like coffee, and the time and temperature dependent variations of keeping. While there are documented benefits of consumption of coffee, the possible H2O2-medicated toxic effects are critical and should be considered. Future studies are warranted to delineate the contribution of H2O2 in the healthy wellbeing of individuals who consume coffee extensively. ### Competing Interest Statement The authors have declared no competing interest.

908: Magnesium Sulfate Attenuates Lethality and Oxidative Damage Induced by Different Models of Hypoxia in Mice
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Posted 26 May 2020

Magnesium Sulfate Attenuates Lethality and Oxidative Damage Induced by Different Models of Hypoxia in Mice
140 downloads bioRxiv pharmacology and toxicology

Hamidreza Mohammadi, Amir Shamshirian, Shafagh Eslami, Danial Shamshirian, Mohammad Ali Ebrahimzadeh

Mg2+ is an important cation in our body. It is an essential co-factor for many enzymes. Despite many works, nothing is known about the protective effects of MgSO4 against hypoxia-induced lethality and oxidative damage in brain mitochondria. In this study, antihypoxic and antioxidative activities of MgSO4 were evaluated by three experimental models of induced-hypoxia (asphyctic, haemic, and circulatory) in mice. Mitochondria protective effects of MgSO4 were evaluated in mice brain after induction of different models of hypoxia. Antihypoxic activity was especially pronounced in asphyctic hypoxia where MgSO4 at dose 600 mg/kg showed the same activity as phenytoin which used as a positive control (P< 0.001). In the haemic model, MgSO4 at all used doses significantly prolonged latency of death. In circulatory hypoxia, MgSO4 (600 mg/kg) doubles the survival time. MgSO4 significantly decreased Lipid peroxidation, protein carbonyl, and improved mitochondrial function and glutathione content in brain mitochondria compared to control groups. The results obtained in this study showed that MgSO4 administration has protective effects against lethality induced by different models of hypoxia and improves brain mitochondria oxidative damage. ### Competing Interest Statement The authors have declared no competing interest.

909: Interleukin-22 mediated renal metabolic reprogramming via PFKFB3 to treat kidney injury
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Posted 05 Aug 2020

Interleukin-22 mediated renal metabolic reprogramming via PFKFB3 to treat kidney injury
139 downloads bioRxiv pharmacology and toxicology

Wei Chen, Yilan Shen, Jiajun Fan, Xian Zeng, Xuyao Zhang, Jingyun Luan, Jinghui Zhang, Si Fang, Xiaobin Mei, Dianwen Ju

Kidney damage initiates the deteriorating metabolic states in tubule cells that lead to the development of end-stage renal disease (ESTD). Interleukin 22 (IL-22) is an effective therapeutic antidote for kidney injury via promoting kidney recovery, but little is known about the underlying molecular mechanisms. Here we first provide evidence that IL-22 attenuates kidney injury via metabolic reprogramming of renal tubular epithelial cells (TECs). Specifically, our data suggest that IL-22 regulates mitochondrial function and glycolysis in damaged TECs. Further observations indicate that IL-22 alleviates the accumulation of mitochondrial reactive oxygen species (ROS) and dysfunctional mitochondria via the induction of AMPK/AKT signaling and PFBFK3 activities. In mice, amelioration of kidney injury and necrosis and improvement of kidney functions via regulation of these metabolism relevant signaling and mitochondrial fitness of recombinant IL-22 are certificated in cisplatin induced kidney damage and diabetic nephropathy (DN) animal models. Taken together, our findings unravel new mechanistic insights into protective effects of IL-22 on kidney and highlight the therapeutic opportunities of IL-22 and the involved metabolic regulators in various kidney diseases.

910: Exposure to a mixture of BMAA and MCLR synergistically modulates behavior in larval zebrafish while exacerbating molecular changes related to neurodegeneration.
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Posted 15 Jul 2020

Exposure to a mixture of BMAA and MCLR synergistically modulates behavior in larval zebrafish while exacerbating molecular changes related to neurodegeneration.
139 downloads bioRxiv pharmacology and toxicology

Rubia M Martin, Michael S Bereman, Kurt C. Marsden

Exposure to toxins produced by cyanobacteria (i.e., cyanotoxins) is an emerging health concern due to their increased occurrence and previous associations with neurodegenerative disease including amyotrophic lateral sclerosis (ALS). The objective of this study was to evaluate the neurotoxic effects of a mixture of two co-occurring cyanotoxins, β-methylamino-L-alanine (BMAA) and microcystin leucine and arginine (MCLR), using the larval zebrafish model. We combined high-throughput behavior-based toxicity assays with discovery proteomic techniques to identify behavioral and molecular changes following 6 days of exposure. While neither toxin caused mortality, morphological defects, or altered general locomotor behavior in zebrafish larvae, both toxins increased acoustic startle sensitivity in a dose-dependent manner by at least 40% (p<0.0001). Furthermore, startle sensitivity was enhanced by an additional 40% in larvae exposed to the BMAA/MCLR mixture relative to those exposed to the individual toxins. Supporting these behavioral results, our proteomic analysis revealed a 4-fold increase in the number of differentially expressed proteins (DEPs) in the mixture-exposed group. Additionally, prediction analysis reveals activation and/or inhibition of 8 enriched canonical pathways (enrichment p-value<0.01; z-score≥|2|), including ILK, Rho Family GTPase, RhoGDI, and calcium signaling pathways, which have been implicated in neurodegeneration. We also found that expression of TDP-43, of which cytoplasmic aggregates are a hallmark of ALS pathology, was significantly upregulated by 5.7-fold following BMAA/MCLR mixture exposure. Together, our results emphasize the importance of including mixtures of cyanotoxins when investigating the link between environmental cyanotoxins and neurodegeneration as we reveal that BMAA and MCLR interact in vivo to enhance neurotoxicity. ### Competing Interest Statement The authors have declared no competing interest.

911: Use of Therapeutic Drug Monitoring to Characterize Cefepime-Induced Neurotoxicity
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Posted 14 Aug 2020

Use of Therapeutic Drug Monitoring to Characterize Cefepime-Induced Neurotoxicity
139 downloads bioRxiv pharmacology and toxicology

Veena Venugopalan, Cara Nys, Natalie Hurst, Yiqing Chen, Maria Bruzzone, Kartikeya Cherabuddi, Nicole Iovine, Jiajun Liu, Mohammad H. Al-Shaer, Marc H Scheetz, Nathaniel J. Rhodes, Charles A. Peloquin, Kenneth Klinker

Background: The incidence of cefepime-induced neurotoxicity (CIN) in hospitalized patients is highly variable. Although greater cefepime exposures incite neurotoxicity, data evaluating trough thresholds associated with CIN remains limited. The objectives of this study were to evaluate the incidence of CIN, assess the relationship between cefepime trough concentrations and CIN, investigate clinical factors associated with CIN, and describe electroencephalogram (EEG) abnormalities in CIN. Methods: This was a retrospective study of adult patients who had received ≥ 5 days of cefepime with ≥ 1 trough concentration > 25 mg/L. Potential CIN cases were identified utilizing neurological symptoms, neurologist assessments, EEG findings and improvement of neurotoxicity after cefepime discontinuation. Results: One-hundred and forty-two patients were included. The incidence of CIN was 13% (18/142). The mean cefepime trough concentration in CIN patients was significantly greater than the non-neurotoxicity group (74.2 mg/L ± 41.1 vs. 46.6 mg/L {plus minus} 23, p=0.015). Lower renal function (creatinine clearance < 30 ml/min), greater time to therapeutic drug monitoring (TDM) (≥72 hours), and each 1 mg/mL rise in cefepime trough were independently associated with increased risk of CIN. Moderate generalized slowing of the background rhythm was the most common EEG pattern associated with CIN. Conclusion: Cefepime should be used cautiously in hospitalized patients due to the risk of neurotoxicity. Patients with greater renal function and those who had early cefepime TDM (≤ 72 hours) had lower risk of CIN.

912: Reanalysis of in vivo drug synergy validation study rules out synergy in most cases
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Posted 13 Nov 2020

Reanalysis of in vivo drug synergy validation study rules out synergy in most cases
138 downloads bioRxiv pharmacology and toxicology

Olaf van Tellingen, Renee de Menezes

In a recent paper in Nature Communications, Narayan et al described the development of an in silico method to predict synergy of drug combinations, validated in vivo using 5 different models for 5 different drug pairs. The published analysis of the in vivo experimental data used the Chou and Talalay Combination Index, which ignores important aspects of the study design, including, but not limited to the variability between individual mice and the longitudinal nature of the data. Furthermore, the original publication reported the Combination Index as static numbers without properly accounting for experimental variability. When 95% confidence intervals are recalculated using bootstrapping methods, 4 out of 5 drug pairs do not show a statistically significant synergistic effect. Three models (originally figures 5A, B and E) are subject to severe inaccuracies in the data handling and reporting. In one model, (originally figure 5D), the data better supports an additive effect between drugs rather than synergy. As the Chou and Talalay Combination Index is poorly suited to this data, we applied mixed-effects models fitted to the longitudinal tumor growth data as an alternative means of estimating synergy. The results support the findings from the bootstrapping analysis, namely that the majority of the drug pairs do not achieve a synergistic effect. We conclude that the in vivo validation of the in silico method to predict synergy of drug combinations as proposed by Narayan et al has a negative outcome when analyzed with appropriate statistical methods. ### Competing Interest Statement OvT: None RM was recently recruited as group leader of the Biostatistics Centre of the Netherlands Cancer Institute. Before this she was a biostatistician at the VUmc, which is the institute of Narayan and colleagues. RM is a coauthor of the paper under discussion, but she was not involved in the analyses of the in vivo data.

913: The Pharmacodynamic-Toxicodynamic Relationship of AUC and CMAX in Vancomycin Induced Kidney Injury in an Animal Model
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Posted 28 Aug 2020

The Pharmacodynamic-Toxicodynamic Relationship of AUC and CMAX in Vancomycin Induced Kidney Injury in an Animal Model
138 downloads bioRxiv pharmacology and toxicology

Sean N. Avedissian, Gwen Pais, Jiajun Liu, J. Nick O'Donnell, Thomas Lodise, Michael Neely, Walter Prozialeck, Peter Lamar, Leighton Becher, Marc H Scheetz

Background: Vancomycin induces exposure related acute kidney injury. However, the pharmacokinetic toxicodynamic (PK TD) relationship remains unclear. Methods: Sprague Dawley rats received IV vancomycin doses of 300mg/kg/day and 400mg/kg/day, divided once, twice, thrice or 4xdaily (i.e., QD, BID, TID or QID) over 24 hours. Up to 8 samples were drawn during the 24 hour dosing period. Twenty four hour urine was collected and assayed for kidney injury molecule 1 (KIM 1). Vancomycin was quantified via LC MS/MS. Following terminal sampling, nephrectomy and histopathologic analyses were conducted. PK analyses were conducted using Pmetrics. PK exposures (i.e. AUC0 24h, CMAX0 24h,) were calculated for each rat, and PK TD relationships were discerned. Results: A total of 53 rats generated PK TD data. A 2compartment model fit the data well (Bayesian observed vs. predicted concentrations, R2: 0.96). KIM 1 values were greater in QD and BID groups (P values: QD vs TID:<0.002, QD vs QID:<0.004, BID vs TID:<0.002, and BID vs QID:<0.004). Exposure response relationships were observed between KIM 1 vs CMAX0,24 and AUC0,24 (R2; 0.7 and 0.68). Corrected Akaike information criterion showed CMAX0,24 as most predictive PK TD driver for vancomycin induced kidney injury (VIKI) ( 5.28 vs 1.95). ### Competing Interest Statement Transparency Declaration: Dr. Scheetz has ongoing research contracts with Nevakar and filed patent US10688195B2. All other authors have no other related conflicts of interest to declare. Funding: Research reported in this publication was supported by National Institute of Allergy and Infectious Diseases under award numbers R15-AI105742 and R21-AI149026. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health

914: Evaluating the Immunological cross-reactivity of Indian polyvalent antivenoms towards the venom of Hypnale hypnale (hump-nosed pit viper) from the Western Ghats
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Posted 03 Aug 2020

Evaluating the Immunological cross-reactivity of Indian polyvalent antivenoms towards the venom of Hypnale hypnale (hump-nosed pit viper) from the Western Ghats
138 downloads bioRxiv pharmacology and toxicology

Muralidharan Vanuopadath, Dileepkumar Raveendran, Bipin Gopalakrishnan Nair, Sudarslal Sadasivan Nair

Hypnale hypnale (hump-nosed pit viper) is a venomous pit viper species found in the Western Ghats of India and Sri Lanka. Due to the severe life-threatening envenomation effects induced by its venom components, Hypnale hypnale has been classified under ″category 1″ of medically important snake species by the World Health Organization. Since there are no specific antivenoms available to combat its envenomation in India, the only option available is to administer Indian polyvalent antivenoms. However, the cross-neutralization potential of the commercially available polyvalent antivenoms on Indian Hypnale hypnale venom has not been explored so far. In the current study, in vitro immunological cross-reactivity of Hypnale hypnale venom towards various Indian polyvalent antivenoms were assessed using end point titration ELISA and Western blotting. A three to four-fold increase in EC50 values were obtained for Hypnale hypnale venom towards all the antivenoms tested. Observation of minimal binding specificities towards low and high molecular mass venom proteins are suggestive of the fact that commercially available polyvalent antivenoms failed to detect and bind to the antigenic epitopes of considerable number of proteins present in Hypnale hypnale venom. This highlights the importance of including Hypnale hypnale venom in the immunization mixture while raising antivenoms. ### Competing Interest Statement The authors have declared no competing interest.

915: Experimental Evolution of Pseudomonas putida under Silver Ion versus Nanoparticle Stress
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Posted 18 Sep 2020

Experimental Evolution of Pseudomonas putida under Silver Ion versus Nanoparticle Stress
137 downloads bioRxiv pharmacology and toxicology

Feng Dong, Ana C. Quevedo, Xiang Wang, Eugenia Valsami-Jones, Jan-Ulrich Kreft

Whether the antibacterial properties of silver nanoparticles (AgNPs) are simply due to the release of silver ions (Ag+) or, additionally, nanoparticle-specific effects, has been debated for over a decade. We used experimental evolution of the model environmental bacterium Pseudomonas putida to ask whether bacteria respond differently to Ag+ or AgNP treatment. We pre-evolved five cultures of strain KT2440 for 70 d without Ag to reduce confounding adaptations before dividing the fittest pre-evolved culture into five cultures each, evolving in the presence of low concentrations of Ag+, well-defined AgNPs or Ag-free controls for a further 75 d. The mutations in the Ag+ or AgNP evolved populations displayed different patterns that were statistically significant. The non-synonymous mutations in AgNP-treated populations were mostly associated with cell surface proteins, including cytoskeletal membrane protein (FtsZ), membrane sensor and regulator (EnvZ and GacS) and periplasmic protein (PP_2758). In contrast, Ag+ treatment selected for mutations linked to cytoplasmic proteins, including metal ion transporter (TauB) and those with metal binding domains (ThiL and PP_2397). These results suggest the existence of AgNP-specific effects, either caused by sustained delivery of Ag+ from AgNP-dissolution, more proximate delivery from cell-surface bound AgNPs, or by direct AgNP action on the cell’s outer membrane. Originality-Significance Statement The increasing use of silver nanoparticles (AgNPs) and their release into the environment may affect environmental microorganisms and their communities and evolution. It has long been debated whether the toxicity of AgNPs towards microorganisms is solely due to their dissolution into toxic Ag+ or whether distinct nanoparticle related toxicity exists. We set up an evolution experiment to explore the adaptation of the environmental model bacterium Pseudomonas putida to Ag+ versus AgNP stress in order to elucidate the potentially different toxicity mechanisms of ionic and nanoparticulate Ag. We found novel mutations and distinct mutation patterns under Ag+ and AgNP treatment by whole genome sequencing. Our work highlights the association of the mutations selected by Ag+ stress with metal ion metabolism inside the cells and the mutations specific to AgNP stress with the cell’s surface. The finding that P. putida cells evolved in different directions under selection by Ag+ and AgNPs demonstrates a need for assessing the toxicity of nanomaterials separately in any environmental risk assessments. ### Competing Interest Statement The authors have declared no competing interest.

916: Tracking the Movement of Electronic Cigarette Flavor Chemicals and Nicotine from Refill Fluids to Aerosol, Lungs and Exhale
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Posted 15 Nov 2020

Tracking the Movement of Electronic Cigarette Flavor Chemicals and Nicotine from Refill Fluids to Aerosol, Lungs and Exhale
137 downloads bioRxiv pharmacology and toxicology

Careen Khachatoorian, Kevin J McWhirter, Wentai Luo, James F Pankow, Prue Talbot

Electronic cigarettes (ECs) have been linked to lung diseases, including COVID-19, with little understanding of exposure, retention, and exhalation of EC aerosol chemicals. Here, flavor chemicals and nicotine were quantified in two refill fluids, their transfer efficiency to EC aerosols was determined, exhalation by human participants was measured, and chemical retention was modeled. Nicotine transferred well to aerosols irrespective of topography; however, transfer efficiencies of flavor chemicals depended on the chemical, puff volume, puff duration, pump head, and EC power. Participants could be classified as mouth inhalers or lung inhalers based on their retention and exhale of flavor chemicals and nicotine. Only mouth inhalers exhaled sufficient concentrations of flavor chemicals and nicotine to contribute to chemical deposition on environmental surfaces. These data help distinguish two types of EC users, add to our knowledge of chemical exposure during vaping, and provide information useful in treating EC-related diseases and regulating EC use. ### Competing Interest Statement The authors have declared no competing interest.

917: The PK/PD Integration and Resistance of Ti lmi cosin Against Mycoplasma hyopneumoniae
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Posted 04 Mar 2020

The PK/PD Integration and Resistance of Ti lmi cosin Against Mycoplasma hyopneumoniae
137 downloads bioRxiv pharmacology and toxicology

Zilong Huang, Zixuan Hu, Xirui Xia, Haorui Zheng, Xiaoyan Gu, Xiangguang Shen, Hong Yang, Huanzhong Ding

Mycoplasma hyopneumoniae is the major pathogen causing enzootic pneumonia in pigs. M. hyopneumoniae infection can lead to considerable economic losses in the pig-breeding industry. Here, this study established a first-order absorption, one-compartment model to study the relationship between the pharmacokinetics/pharmacodynamics (PK/PD) index of tilmicosin against M. hyopneumoniae in vitro . We simulated the drug concentration of timicosin in the fluid lining the lung epithelia of pigs. The minimum inhibitory concentration (MIC) of tilmicosin against M. hyopneumoniae with an inoculum of 10 6 CFU/mL was 1.6 μg/mL using the microdilution method. Static time–kill curves showed that , if the drug concentration >1 MIC, the antibacterial effect showed different degrees of inhibition. At 32 MIC, the amount of bacteria decreased by 3.16 log 10 CFU/mL, thereby achieving a mycoplasmacidal effect. The M. hyopneumoniae count was reduced from 3.61 to 5.11 log 10 CFU/mL upon incubation for 96 h in a dynamic model with a dose of 40–200 mg, thereby achieving mycoplasmacidal activity. The peak concentration by MIC (C max /MIC) and the area under the concentration-time curve over 96 h divided by the MIC (AUC 0–96 h /MIC) were the best-fit PK/PD parameters for predicting the antibacterial activity of tilmicosin against M. hyopneumoniae (R 2 = 0.99), suggesting that tilmicosin had concentration-dependent activity. The estimated value for C max /MIC and AUC 0–96 h /MIC for 2log 10 (CFU/mL) reduction and 3log 10 (CFU/mL) reduction from baseline was 1.44 and 1.91, and 70.55 h and 96.72 h, respectively. Four M. hyopneumoniae strains (M1–M4) with reduced sensitivity to tilmicosin were isolated from the four dose groups. The susceptibility of these strains to tylosin, erythromycin and lincomycin was also reduced significantly. For sequencing analyses of 23S rRNA, an acquired A2058G transition in region V was found only in resistant M. hyopneumoniae strains (M3, M4). In conclusion, in an in vitro model, the effect of tilmicosin against M. hyopneumoniae was concentration-dependent and had a therapeutic effect. These results will help to design the optimal dosing regimen for tilmicosin in M. hyopneumoniae infection, and minimize the emergence of resistant bacteria.

918: Safety and Efficacy of Avaren-Fc Lectibody Targeting HCV High-Mannose Glycans in a Human Liver Chimeric Mouse Model
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Posted 24 Apr 2020

Safety and Efficacy of Avaren-Fc Lectibody Targeting HCV High-Mannose Glycans in a Human Liver Chimeric Mouse Model
137 downloads bioRxiv pharmacology and toxicology

Matthew Dent, Krystal Hamorsky, Thibaut Vausselin, Jean Dubuisson, Yoshinari Miyata, Yoshio Morikawa, Nobuyuki Matoba

Infection with hepatitis C virus (HCV) remains to be a major cause of morbidity and mortality worldwide despite the recent advent of highly effective direct-acting antivirals. The envelope glycoproteins of HCV are heavily glycosylated with a high proportion of high-mannose glycans (HMGs), which serve as a shield against neutralizing antibodies and assist in the interaction with cell-entry receptors. However, currently there is no approved therapeutic targeting this potentially druggable biomarker. Here, we investigated the therapeutic potential of the lectibody Avaren-Fc (AvFc), a HMG-binding lectin-Fc fusion protein. In vitro assays showed AvFc's capacity to neutralize cell culture-derived HCV in a genotype independent manner with IC50 values in the low nanomolar range. A histidine buffer-based AvFc formulation was developed for in vivo studies using the PXB human liver chimeric mouse model. Systemic administration of AvFc was well tolerated; after 11 consecutive doses every other day at 25 mg/kg, there were no significant changes in body or liver weights, nor any impact noted in blood human albumin levels or serum alanine aminotransferase activity. Gross necropsy and liver pathology further confirmed the lack of discernible toxicity. This treatment regimen successfully prevented genotype 1a HCV infection in all animals, while an AvFc mutant lacking HMG binding activity failed to block the infection. These results suggest that targeting envelope HMGs is a promising therapeutic approach against HCV infection. In particular, AvFc may provide a safe and efficacious means to prevent recurrent infection upon liver transplantation in HCV-related end-stage liver disease patients.

919: Computational design of two new soluble epoxide hydrolase (sEH) inhibitors
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Posted 20 Sep 2020

Computational design of two new soluble epoxide hydrolase (sEH) inhibitors
137 downloads bioRxiv pharmacology and toxicology

Jennifer Liem, Sambid Adhikari, Peishan Huang, Justin B Siegel

Inhibitors of soluble epoxide hydrolase (sEH) enzymes have shown great potential for the treatment of neuropathic pain. However, current sEH inhibitors have poor physicochemical properties and has not been proven to be safe for human treatments yet. New inhibitor designs could have the potential to improve current drugs’ efficacy, and so in this work, chemical intuition and bioisosteric replacement were used to computationally design two novel sEH inhibitors. These new candidates showed good pharmacokinetic properties and presented better docking scores compared to a known sEH inhibitor, t-TUCB, used in the treatment of pain in horses. Homology analysis revealed that Mus musculus may not be suitable organism for preclinical trials studies of these novel inhibitors. ### Competing Interest Statement The authors have declared no competing interest.

920: Negative controls of chemical probes can be misleading
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Posted 02 Oct 2020

Negative controls of chemical probes can be misleading
137 downloads bioRxiv pharmacology and toxicology

Jinyoung Lee, Matthieu Schapira

Chemical probes are selective modulators that are used in cell assays to link a phenotype to a gene and have become indispensable tools to explore gene function and discover therapeutic targets. While binding to off-targets can be acceptable or beneficial for drugs, it is a confounding factor for chemical probes, as the observed phenotype may be driven by inhibition of an unknown off-target instead of the targeted protein. A negative control – a close chemical analog of the chemical probe that is inactive against the intended target – is typically used to verify that the phenotype is indeed driven by targeted protein. Here, we compare the selectivity profiles of four unrelated chemical probes and their respective negative controls and find that the control is sometimes inactive against up to 80% of known off-targets, suggesting that a lost phenotype upon treatment with the negative control may be driven by loss of inhibition of the off-target. To extend this analysis, we inspect the crystal structures of 90 pairs of unrelated proteins, where both proteins within each pair is in complex with the same drug-like ligand, and estimate that in 50% of cases, methylation (a simple chemical modification often used to generate negative controls) of the ligand at a position that will preclude binding to one protein (intended target) will also preclude binding to the other (off-target). These results uncover a risk associated with the use of negative controls to confirm gene-phenotype associations. We propose that a best practice should rather be to verify that two chemically unrelated chemical probes targeting the same protein lead to the same phenotype. ![Figure][1]</img> ### Competing Interest Statement The authors have declared no competing interest. [1]: pending:yes

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