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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 124,258 papers from 533,988 authors.

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in category pharmacology and toxicology

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

981: Quantifying synergy in the bioassay-guided fractionation of natural product extracts
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Posted 23 Jun 2020

Quantifying synergy in the bioassay-guided fractionation of natural product extracts
91 downloads bioRxiv pharmacology and toxicology

Micah Dettweiler, Lewis Marquez, Max Bao, Cassandra L. Quave

Mixtures of drugs often have greater therapeutic value than any of their constituent drugs alone, and such combination therapies are widely used to treat diseases such as cancer, malaria, and viral infections. However, developing useful drug mixtures is challenging due to complex interactions between drugs. Natural substances can be fruitful sources of useful drug mixtures because secondary metabolites produced by living organisms do not often act in isolation in vivo. In order to facilitate the study of interactions within natural substances, a new analytical method to quantify interactions using data generated in the process of bioassay-guided fractionation is presented here: the extract fractional inhibitory concentration index (EFICI). The EFICI method uses the framework of Loewe additivity to calculate fractional inhibitory concentration values by which interactions can be determined for any combination of fractions that make up a parent extract. The EFICI method was applied to data on the bioassay-guided fractionation of Lechea mucronata and Schinus terebinthifolia for growth inhibition of the pathogenic bacterium Acinetobacter baumannii. The L. mucronata extract contained synergistic interactions (EFICI = 0.4181) and the S. terebinthifolia extract was non-interactive overall (EFICI = 0.9129). Quantifying interactions in the bioassay-guided fractionation of natural substances does not require additional experiments and can be useful to guide the experimental process and to support the development of standardized extracts as botanical drugs.

982: Impact of Chrysin on Vitamin D and Bone Health - Preclinical Studies
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Posted 20 Nov 2020

Impact of Chrysin on Vitamin D and Bone Health - Preclinical Studies
91 downloads bioRxiv pharmacology and toxicology

Siva Swapna Kasarla, Sujatha Dodoala, Sunitha Sampathi, Narendra Kumar Talluri

Vitamin D deficiency is an endemic problem existing worldwide. Although several strategies were established to enhance vitamin D3 levels, studies specifically focussing inhibition of vitamin D metabolism which may prolong the availability of active vitamin D in pathological conditions are less explored. Studies also suggest that higher doses of vitamin D3 fail to achieve optimum vitamin D levels. In this context, we focussed on the enzyme CYP3A4 which promotes inactivation of active vitamin D. The current study was aimed to decipher the impact of chrysin, a proven CYP3A4 inhibitor as an intervention and its effects in combination with low dose vitamin D3 (40 IU) and bone health in vitamin D deficiency condition. The in-vivo activity of chrysin was evaluated on female Wistar albino rats fed with a vitamin D deficient diet to attain vitamin D deficiency for 28 days. Chrysin was given alone and in combination with calcium carbonate (CaCO3) and/or vitamin D3. All the therapeutic interventions were assessed for serum 25-OH-D3 by LC-MS, biochemical, urinary, and bone parameters. Animals treated with chrysin alone and in combination with low dose vitamin D3 and/or CaCO3 showed an eminent rise in serum 25-OH-D3 levels along with increased serum biochemical parameters. On contrary, a significant decrease in the urinary parameters followed by beneficial effects on bone parameters was noticed in contrast with the vitamin D deficient diet group. Our findings revealed that although chrysin alone showed a notable effect on 25-OH-D3 and osseous tissue, comparatively it showed intensified therapeutic effect in combination with vitamin D3 and CaCO3 which can be employed as a cost-effective option to improve bone health.

983: Improved bioavailability of montelukast through a novel oral mucoadhesive film in humans and mice
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Posted 08 Nov 2020

Improved bioavailability of montelukast through a novel oral mucoadhesive film in humans and mice
89 downloads bioRxiv pharmacology and toxicology

Johanna Michael, Diana Marisa de Sousa, Justin Conway, Erick Gonzalez-Labrada, Rodolphe Obeid, Julia Tevini, Thomas Felder, Birgt Hutter-Paier, Horst Zerbe, Nadine Paiement, Ludwig Aigner

The leukotriene receptor antagonist Montelukast (MTK) is an approved medication for the treatment of asthma and allergic rhinitis. The existing marketed tablet forms of MTK exhibit inconsistent uptake and bioavailability, which partially explains the presence of a significant proportion of MTK low and non-responders in the population. Besides that, tablets are suboptimal formulations for patients suffering of dysphagia, for example seen in COVID19 patients or in patients with neurodegenerative diseases such as Alzheimers Disease. The increasing interest in repurposing of MTK for the treatment of such patients and the need for an improved bioavailability triggered us to reformulate MTK. The aim was to develop a mucoadhesive MTK film with a good safety and improved pharmacological, i.e. improved bioavailability, profile in humans as well as in a mouse model of Alzheimers Disease. We tested dissolution of the mucoadhesive film containing MTK in saliva buffer and assessed pharmacoexposure and kinetics after acute and chronic oral application in mice. Furthermore, we performed a Phase I safety / bioavailability / pharmacokinetic analysis in healthy volunteers. The latter included a comparison with the marketed tablet form as well as a quantitative analysis of the MTK levels in the cerebrospinal fluid. The novel MTK film demonstrated significantly improved bioavailability compared to the marketed tablet in the clinical phase 1a study in healthy humans. Furthermore, there were measurable amounts of MTK present in the cerebrospinal fluid (CSF) at the 3.0 and 7.0 hour time points post drug administration in humans. In mice, MTK was detected in serum and CSF after acute and chronic exposure in a dose dependent manner. The developed mucoadhesive film of MTK represents a promising alternative for the tablet delivery. The oral film might lower the non-responder rate in patients with asthma and might be an interesting product for repurposing of MTK in other diseases. As we demonstrate BBB penetrance in a preclinical model as well as in a clinical study, the oral film of MTK might find its use as a therapeutic for acute and chronic neurodegenerative diseases such as dementias and stroke. ### Competing Interest Statement Justin Conway, Erick Gonzales-Labrada, Rodolphe Obeid, Horst Zerbe, Nadine Paiement are from IntelgenX, who has filed patent applications on the MTK film and its use. Ludwig Aigner is consultant at IntelgenX.

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

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

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

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

985: ExHuMId: A curated resource and analysis of Exposome of Human Milk across India
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Posted 08 Nov 2020

ExHuMId: A curated resource and analysis of Exposome of Human Milk across India
88 downloads bioRxiv pharmacology and toxicology

Bagavathy Shanmugam Karthikeyan, Janani Ravichandran, S.R. Aparna, Areejit Samal

Human milk is a vital source of nourishment for infants, containing nutrients, immunoprotective components, and bioactive substances. However, several environmental contaminants find their way into human milk. Although lactation physiology has been well documented, the effect of human milk contaminants on maternal and infant health remains unclear. Human milk is the major route of contaminant exposure to infants; these contaminants and their effects can themselves be considered an exposome. While there are chemical regulations in India and scientific literature on environmental contaminants is available, yet there is a lack of systematic compilation, monitoring, and risk management of human milk contaminants. We have harnessed the potential of this large body of literature to develop the Exposome of Human Milk across India (ExHuMId) containing detailed information on 101 environmental contaminants detected in human milk samples, studied across 13 Indian states, compiled from 36 research articles. ExHuMId also compiles the detected concentrations of the contaminants, structural and physicochemical properties, and factors associated with the donor of the sample. Here, we also present findings from a three-pronged analysis of ExHuMId and two other resources on human milk contaminants, with a focus on the Indian scenario. Through a comparative analysis with global chemical regulations and guidelines, we identify human milk contaminants of high concern, such as potential carcinogens, endocrine disruptors and neurotoxins. We then study the physicochemical properties of the contaminants to gain insights on their propensity to transfer into human milk. Further, we employ a systems biology approach to shed light on potential effects of human milk contaminants on maternal and infant health, by identifying contaminant-gene interactions associated with lactation, cytokine signalling and production, and protein-mediated transport. ExHuMId is accessible online at: https://cb.imsc.res.in/exhumid/. ### Competing Interest Statement The authors have declared no competing interest.

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

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

Somayeh Mirlohi, Chris Bladen, Marina Santiago, Mark Connor

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

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

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

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

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

988: Large-Scale Transcriptional Profiling of Molecular Perturbations Reveals Cell Type Specific Responses and Implications for Environmental Screening
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Posted 27 Aug 2020

Large-Scale Transcriptional Profiling of Molecular Perturbations Reveals Cell Type Specific Responses and Implications for Environmental Screening
87 downloads bioRxiv pharmacology and toxicology

Kun Zhang, Yanbin Zhao

Cell-based assays represent nearly half of all high-throughput screens currently conducted for risk assessment of environmental chemicals. However, the sensitivity and heterogeneity among cell lines has long been concerned but explored only in a limited manner. Here, we address this question by conducting a large scale transcriptomic analysis of the responses of discrete cell lines to specific small molecules. Our results illustrate heterogeneity of the extent and timing of responses among cell lines. Interestingly, high sensitivity and/or heterogeneity was found to be cell type-specific or universal depending on the different mechanism of actions of the compounds. Our data provide a novel insight into the understanding of cell-small molecule interactions and have substantial implications for the design, execution and interpretation of high-throughput screening assays. ### Competing Interest Statement The authors have declared no competing interest.

989: Effects of prophylactic and therapeutic antimicrobial uses in small-scale chicken flocks
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Posted 02 Jul 2020

Effects of prophylactic and therapeutic antimicrobial uses in small-scale chicken flocks
87 downloads bioRxiv pharmacology and toxicology

Nguyen Van Cuong, Bach Tuan Kiet, Doan Hoang Phu, Nguyen Thi Bich Van, Vo Be Hien, Guy Thwaites, Juan Carrique-Mas, Marc Choisy

Background: Antimicrobials are extensively used both prophylactically and therapeutically in poultry production. Despite this, there are little data on the effect of antimicrobial use (AMU) on disease incidence and mortality rate. Objective: We investigated the relationships between AMU and disease and between AMU and mortality using data from a large (n=322 flocks) cohort of small-scale chicken flocks in the Mekong Delta, Vietnam, that were followed longitudinally from day-old to slaughter (5,566 observation weeks). Methods: We developed a parameterized algorithm to categorize the observation weeks into ‘non-AMU’, ‘prophylactic AMU’ and ‘therapeutic AMU’. To evaluate the prophylactic AMU effect, we compared the frequencies of clinical signs in ‘non-AMU’ and ‘prophylactic AMU’ periods. To analyse therapeutic AMU, we compared mortality rates between the weeks of disease episodes before and after AMU. Analyses were stratified by clinical signs (4) and antimicrobial classes (13). Results: Prophylactic AMU never reduced the probability of disease, some antimicrobial classes such as lincosamides, amphenicols and penicillins increased the risk. The risk of diarrhoea consistently increased with prophylactic AMU. Therapeutic AMU often had an effect on mortality but the pattern was inconsistent across the combinations of antimicrobial classes and clinical signs with 14/29 decreasing and 11/29 increasing the mortality rate. Lincosamides, methenamines and cephalosporins were the only three antimicrobial classes that always decreased the mortality rate when used therapeutically. Results were robust respective to the parameters values of the weeks categorization algorithm. Conclusion: This information should help support policy efforts and interventions aiming at reducing AMU in animal production. ### Competing Interest Statement The authors have declared no competing interest.

990: Immunosuppressive effect of the Fusarium secondary metabolite butenolide in human colon epithelial cells.
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Posted 18 Apr 2020

Immunosuppressive effect of the Fusarium secondary metabolite butenolide in human colon epithelial cells.
87 downloads bioRxiv pharmacology and toxicology

Lydia Woelflingseder, Gerhard Adam, Doris Marko

Butenolide (BUT, 4-acetamido-4-hydroxy-2-butenoic acid gamma-lactone) is a secondary metabolite produced by several Fusarium species and is co-produced with the major trichothecene mycotoxin deoxynivalenol (DON) on cereal grains throughout the world. BUT has low acute toxicity and only very limited occurrence and exposure data are available. The intestinal epithelium represents the first physiological barrier against food contaminants. We aimed to elucidate the intestinal inflammatory response of the human, non cancer epithelial HCEC-1CT cells to BUT and to characterize potential combinatory interactions with co-occurring trichothecenes, such as DON and NX-3. Using a reporter gene approach, BUT (≥5 μM, 20 h) was found to decrease lipopolysaccharide (LPS; 10 ng/mL) induced nuclear factor kappa B (NF-κB) activation in a dose-dependent manner, and in combinatory treatments represses trichothecene-induced enhancement of this important inflammatory pathway. Analyzing transcription and secretion levels of NF-κB-dependent, pro-inflammatory cytokines, revealed a significant down-regulation of IL-1β, IL-6 and TNF-α in IL-1β-stimulated (25 ng/mL) HCEC-1CT cells after BUT exposure (10 μM). Trichothecene-induced expression of pro-inflammatory cytokines by the presence of 1 μM DON or NX-3 was substantially suppressed in the presence of 10 μM BUT. The emerging mycotoxin BUT has the ability to suppress NF-κB-induced intestinal inflammatory response mechanisms and to modulate substantially the immune responsiveness of HCEC-1CT cells after trichothecene treatment. Our results suggest that BUT, present in naturally occurring mixtures of Fusarium fungal metabolites, should be increasingly monitored, and the mechanism of inhibition of NF-κB that might affect the pathogenesis or progression of intestinal inflammatory disorders, should be further investigated. ### Competing Interest Statement The authors have declared no competing interest.

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

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

Giulia Cheloni, Vera I. Slaveykova

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

992: Chemotherapeutic cardiotoxicity is associated with elevated β1-adrenergic receptor density
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Posted 18 Sep 2020

Chemotherapeutic cardiotoxicity is associated with elevated β1-adrenergic receptor density
87 downloads bioRxiv pharmacology and toxicology

Manveen K Gupta, Elizabeth E. Martelli, Kate T. Stenson, Sathyamangla V. Naga Prasad

Objective To understand the underlying pathways that promote cardiotoxicity following chemotherapy. Background Anthracyclines are associated with cardiotoxicity which could be potentiated with use of complementary agents (like anti-ERBB2 inhibitors) which together afford robust anti-neoplastic effects. Anthracyclines lead to oxidative stress and thought to induce cardiotoxicity. However, interventions reducing oxidative stress in patients have been unsuccessful suggesting mechanisms beyond oxidative stress. Despite β-adrenergic receptors (βARs) being key regulators of cardiac function, nothing is known about their role in chemotherapy-mediated cardiotoxicity. Methods β1 and/or β2-AR density was assessed in end-stage human heart failure patient samples either due to anthracycline cardiotoxicity or non-anthracycline dilated cardiomyopathy (DCM). Since ERBB2 inhibition is integral to overall chemotherapeutic arsenal, we assessed β1- and/or β2-AR density, cardiac function by echocardiography and immunohistochemistry in mice following ERBB2-specific inhibitor AG825. Results Selective increase in cardiac β1AR density is observed in end-stage human heart failure patient samples due to anthracycline cardiotoxicity as well as in ERBB2 inhibitor-treated mice. Conclusions Elevated β1AR density may be the key common underlying mechanism which is altered in response to chemotherapy promoting cardiac dilation of otherwise healthy hearts. Highlights In contrast to downregulation of β1-adrenergic receptors (β1AR) in end-stage human heart failure, anthracycline cardiotoxicity-mediated failure is associated with selective increase in β1AR density. ERBB2 inhibitor (AG825) treatment in mice results in cardiac dilation and selective rise in β1AR density showing that increased β1AR density in the heart could be a common mechanism underlying cardiotoxicity. ### Competing Interest Statement The authors have declared no competing interest. * EGFR : Epidermal growth factor receptor ERBB2 : Erythroblastic oncogene B DCM : Dilated Cardiomyopathy βAR : beta-adrenergic receptor

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

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

Arnold Gutierrez, Kevin M Creehan, Michael A Taffe

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

994: Acetylation of L-leucine switches its carrier from the L-amino acid transporter (LAT) to organic anion transporters (OAT)
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Posted 13 Nov 2020

Acetylation of L-leucine switches its carrier from the L-amino acid transporter (LAT) to organic anion transporters (OAT)
86 downloads bioRxiv pharmacology and toxicology

G.C. Churchill, Michael Strupp, Tatiana Bremova-Ertl, Mallory Factor, M. Patterson, F.M. Platt, A. Galione

N-acetyl-DL-leucine is an analogue of the alpha amino acid leucine with a chiral stereocenter. The active L-enantiomer of the racemate is currently under development for rare neurological disorders. Here we present evidence that a selective recognition of N-acetyl-L-leucine versus L-leucine by different uptake transporters significantly contributes to the therapeutic effects of N-acetyl-L-leucine. A previous study of the pharmacokinetics of racemic N-acetyl-DL-leucine and N-acetyl-L-leucine revealed D-L enantiomer competition and saturation kinetics, best explained by carrier-mediated uptake. The strategy we used was to first analyze the physicochemical properties associated with good oral bioavailable drugs and how these are alerted by N-acetylation by comparing N-acetyl-L-leucine with L-leucine. Using in silico computational chemistry we found that N-acetylation has a profound impact on certain physicochemical properties that can rationalize why N-acetyl-L-leucine is drug-like compared to L-leucine. Our calculations show that at physiological pH, L-leucine is a zwitterion, whereas N-acetyl-L-leucine is present as mainly an anion. Specifically, N-acetylation removes a charge from the nitrogen at physiological pH and N-acetyl-L-leucine is an anion that is then a substrate for the organic anion transporters. We examined N-acetyl-L-leucine uptake in human embryonic kidney cells overexpression candidate organic anion transporters (OAT) and pharmacological inhibitors. We found that N-acetyl-L-leucine is a translocated substrate for OAT1 and OAT3 with low affinity (Km ~10 mM). In contrast, L-leucine is known to be transported by the L-type Amino Acid Transporter (LAT) with high affinity (Km ~0.2 mM) and low capacity. The clinical consequence is that L-leucine uptake becomes saturated at 50-fold lower concentration than N-acetyl-L-leucine. These results demonstrate a mechanism of action that explains why N-acetyl-L-leucine is effective as a drug and L-leucine itself is not. ### Competing Interest Statement GCC is a cofounder, shareholder and consultant to IntraBio. MS is a shareholder to IntraBio, and consultant for Abbott, Actelion, AurisMedical, Heel, IntraBio and Sensorion; he has received speaker's honoraria from Abbott, Actelion, Auris Medical, Biogen, Eisai, Grunenthal, GSK, Henning Pharma, Interacoustics, Johnson & Johnson, MSD, Otometrics, Pierre-Fabre, TEVA, UCB. TBE received honoraria for lecturing from Actelion and Sanofi Genzyme. MF is a co-founder, shareholder, and Chairman of IntraBio. MCP is a shareholder of IntraBio, and has received consulting fees, honoraria and research grants from Actelion Pharmaceuticals Ltd. and Biomarin. FMP is a cofounder, shareholder, and consultant to IntraBio and consultant to Actelion and Orphazyme. AG is a cofounder, shareholder and consultant to IntraBio. IntraBio owns patents EP3359146 and EP3416631 (related to treatment of lysosomal storage disorders and neurodegenerative diseases with acetyl-Leucine and its analogues). IntraBio has pending patent applications EP19174007.5, EP3482754, PCT/US2018/056420, PCT/US2018/018420, PCT/IB2018/054676, PCT/IB2019/051214, PCT/IB2017/054928, PCT/GB2017/051090, PCT/IB2017/054929, USPTO 62/812,987, USPTO 62/842,296, USPTO 62/888,894, USPTO 62/895,144, USPTO 62/868,383, USPTO 62/931,003, USPTO 62/960,637, and PCT/IB2019/060525 relating to treatment of lysosomal storage disorders, neurodegenerative diseases and neurodegeneration with acetyl-leucine and its analogues.

995: Allosteric modulation of GABAA receptors in rat basolateral amygdala blocks stress-enhanced reacquisition of nicotine self-administration
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Posted 11 Jul 2020

Allosteric modulation of GABAA receptors in rat basolateral amygdala blocks stress-enhanced reacquisition of nicotine self-administration
86 downloads bioRxiv pharmacology and toxicology

Burt M Sharp, Qin Jiang, Xenia Simone, Petra Scholze

Stress is a major determinant of relapse to smoked tobacco. In a rat model, repeated stress during abstinence from nicotine self-administration (SA) results in enhanced reacquisition of nicotine SA, which is dependent on the basolateral amygdala (BLA). We postulate that repeated stress during abstinence causes hyperexcitability of BLA principal output neurons (PN) due to disinhibition of PN from reduced inhibitory regulation by local GABAergic interneurons. To determine if enhanced GABAergic regulation of BLA PNs can lessen the effects of stress on nicotine intake, positive allosteric modulators (PAMs) of GABAA receptors were infused into the BLA immediately prior to reacquisition of nicotine SA. Three selective PAMs (e.g., NS 16085, DCUK-OEt, DS2) with varied GABAA subunit specificities abolished the stress-induced amplification of nicotine taking during reacquisition. These studies indicate that highly selective PAMS targeting α3 or δ subunit-containing GABAA in BLA may be effective in ameliorating the stress-induced relapse to smoked tobacco during abstinence from cigarettes. ### Competing Interest Statement The authors have declared no competing interest.

996: Genetic ablation of serotonin receptor 2B improves aortic valve hemodynamics in a high-cholesterol diet mouse model
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Posted 18 Aug 2020

Genetic ablation of serotonin receptor 2B improves aortic valve hemodynamics in a high-cholesterol diet mouse model
85 downloads bioRxiv pharmacology and toxicology

J. Ethan Joll, Cyndi Clark, Christine Scott, Michael Raddatz, Matthew R. Bersi, WD Merryman

Calcific aortic valve disease (CAVD) is a deadly disease that is rising in prevalence due to population aging. While the disease is complex and poorly understood, one well-documented driver of valvulopathy is serotonin agonism. Both serotonin overexpression, as seen with carcinoid tumors and drug-related agonism, such as with Fenfluramine use, are linked with various diseases of the valves. Thus, the objective of this study was to determine if genetic ablation or pharmacological antagonism of the 5-HT 2B serotonin receptor (gene: Htr2b ) could improve the hemodynamic and histological progression of calcific aortic valve disease. Htr2b mutant mice were crossed with Notch1 +/- mice, an established small animal model of CAVD, to determine if genetic ablation affects CAVD progression. To assess the effect of pharmacological inhibition on CAVD progression, Notch1 +/- mice were treated with the 5-HT 2B receptor antagonist SB204741. Mice were analyzed using echocardiography, histology, immunofluorescence, and real-time quantitative polymerase chain reaction. Htr2b mutant mice showed lower aortic valve peak velocity and mean pressure gradient – classical hemodynamic indicators of aortic valve stenosis – without concurrent left ventricle change. 5-HT 2B receptor antagonism, however, did not affect hemodynamic progression. Leaflet thickness, collagen density, and CAVD-associated transcriptional markers were not significantly different in any group. This study reveals that genetic ablation of Htr2b attenuates hemodynamic development of CAVD in the Notch1 +/- mice, but pharmacological antagonism may require high doses or long-term treatment to slow progression.

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

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

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

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

998: 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
84 downloads bioRxiv pharmacology and toxicology

Benjamin Z. Gbolo, K. N. Ngbolua, Damien S. T. Tshibangu, Patrick B. Memvanga, Dorothée D. Tshilanda, Aristote Matondo, Jason T. Kilembe, Bienvenu M. Lebwaze, Amandine Nachtergael, Pius T. Mpiana, Pierre Duez

This study was carried out in order to investigate the safety of Drepanoalpha hard capsules, a phytomedicine used for the management of sickle cell disease in the Democratic Republic of Congo, by acute and sub-acute administration in Guinea pigs. The hard capsules were dissolved in normal saline solution (NaCl 9{per thousand}). The animals were randomly selected, marked and divided into 2 groups of 5 animals each (3 males and 2 females) for acute toxicity and 4 groups of 3 animals each for sub-acute toxicity. They received by gavage a single dose of 5000 mg/ kg of body weight (B.W.) of Drepanoalpha hard capsules for acute toxicity and 125 mg/ kg, 250 mg/ kg and 500 mg/ kg of B.W. twice daily for 28 days for 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. The results showed that the median lethal dose (LD50) is greater than 5000 mg/ kg of B.W., and the relative weights of vital organs (kidney, liver, lungs, and heart) collected from Guinea pigs at the end of treatment on D14 (acute toxicity) and D28 (sub-acute toxicity) did not undergone significant changes (p>0.05). The results of haematological (Red Blood Cells, White Blood Cells, 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. In conclusion, the results confirm the safety of Drepanoalpha, as shown in previous studies in rats and Guinea pigs using lyophilizate and decoction. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/411124v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1e3e05borg.highwire.dtl.DTLVardef@19e7755org.highwire.dtl.DTLVardef@ac7990org.highwire.dtl.DTLVardef@160efbf_HPS_FORMAT_FIGEXP M_FIG C_FIG

999: Cytoplasmic aggregation of uranium in human dopaminergic cells after continuous exposure to soluble uranyl at non-cytotoxic concentrations
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Posted 16 Jul 2020

Cytoplasmic aggregation of uranium in human dopaminergic cells after continuous exposure to soluble uranyl at non-cytotoxic concentrations
84 downloads bioRxiv pharmacology and toxicology

Asuncion Carmona, Francesco Porcaro, Andrea Somogyi, Stéphane Roudeau, Florelle Domart, Kadda Medjoubi, Michel Aubert, Hélène Isnard, Anthony Nonell, Anaïs Rincel, Eduardo Paredes, Claude Vidaud, Véronique Malard, Carole Bresson, Richard Ortega

Uranium exposure can lead to neurobehavioral alterations in particular of the monoaminergic system, even at non-cytotoxic concentrations. However, the mechanisms of uranium neurotoxicity after non-cytotoxic exposure are still poorly understood. In particular, imaging uranium in neurons at low intracellular concentration is still very challenging. We investigated uranium intracellular localization by means of synchrotron X-ray fluorescence imaging with high spatial resolution (< 300 nm) and high analytical sensitivity (< 1 μg.g-1 per 300 nm pixel). Neuron-like SH-SY5Y human cells differentiated into a dopaminergic phenotype were continuously exposed, for seven days, to a non-cytotoxic concentration (10 μM) of soluble natural uranyl. Cytoplasmic submicron uranium aggregates were observed accounting on average for 62% of the intracellular uranium content. In some aggregates, uranium and iron were co-localized suggesting common metabolic pathways between uranium and iron storage. Uranium aggregates contained no calcium or phosphorous indicating that detoxification mechanisms in neuron-like cells are different from those described in bone or kidney cells. Uranium intracellular distribution was compared to fluorescently labeled organelles (lysosomes, early and late endosomes) and to fetuin-A, a high affinity uranium-binding protein. A strict correlation could not be evidenced between uranium and the labelled organelles, or with vesicles containing fetuin-A. Our results indicate a new mechanism of uranium cytoplasmic aggregation after non-cytotoxic uranyl exposure that could be involved in neuronal defense through uranium sequestration into less reactive species. The remaining soluble fraction of uranium would be responsible for protein binding and the resulting neurotoxic effects. ### Competing Interest Statement The authors have declared no competing interest.

1000: An exploratory analysis of the current chemical regulations and guidelines from the perspective of endocrine disrupting chemicals using public resources
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Posted 08 Oct 2020

An exploratory analysis of the current chemical regulations and guidelines from the perspective of endocrine disrupting chemicals using public resources
83 downloads bioRxiv pharmacology and toxicology

Bagavathy Shanmugam Karthikeyan, Janani Ravichandran, S. R. Aparna, Areejit Samal

The regulatory assessment of endocrine disrupting chemicals (EDCs) is complex due to the lack of a standardized definition of EDCs and validated testing criteria. In spite of these challenges, there is growing scientific interest in EDCs which has resulted in the rapid expansion of published literature on endocrine disruption upon chemical exposure. Here, we explore how academic research leading to curated knowledgebases can inform current chemical regulations on EDCs. To this end, we present an updated knowledgebase, DEDuCT 2.0, containing 792 potential EDCs with supporting evidence from 2218 research articles. Thereafter, we study the distribution of potential EDCs across several chemical lists that reflect guidelines for use or regulations. Further, to understand the scale of possible exposure to the potential EDCs present in chemical lists, we compare them with high production volume chemicals. Notably, we find many potential EDCs are in use across various product categories such as ‘Food additives and Food contact materials’ and ‘Cosmetics and household products’. Several of these EDCs are also produced or manufactured in high volume across the world. Lastly, we illustrate using an example how diverse information in curated knowledgebases such as DEDuCT 2.0 can be helpful in the risk assessment of EDCs. In sum, we highlight the need to bridge the gap between academic and regulatory aspects of chemical safety, as a step towards the better management of environment and health hazards such as EDCs. ### Competing Interest Statement Some of the compiled data on potential EDCs was previously submitted as a compilation to the copyright office, Government of India. Based on this copyright application, the authors were granted a literary copyright (L-79979/2019) by the Government of India and the copyright owner is the authors' institution, The Institute of Mathematical Sciences, Chennai, India.

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