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https://www.readbyqxmd.com/read/29356025/identification-and-therapeutic-intervention-of-co-activated-alk-fgfr2-and-epha5-kinases-in-hepatocellular-carcinoma
#1
Xin Wang, Minmin Zhang, Fangfang Ping, Hongchun Liu, Jingya Sun, Yueqin Wang, Aijun Shen, Jian Ding, Meiyu Geng
Though kinase inhibitors are heavily investigated in clinic to combat advanced hepatocellular carcinoma (HCC), clinical outcomes are overall disappointing, which may result from the absence of kinase-addicted subsets in HCC. Recently, a combination strategy that simultaneously inhibits multiple kinases are increasingly appreciated in HCC treatment, yet it is challenged by the dynamic nature of kinase network. This study aims to identify kinase clusters that may cooperate to drive the malignant growth of HCC...
January 21, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29355641/the-nicotinic-receptor-drug-sazetidine-a-reduces-alcohol-consumption-in-mice-without-affecting-concurrent-nicotine-consumption
#2
Jillienne C Touchette, Jamie J Maertens, Margaret M Mason, Kyu Y O'Rourke, Anna M Lee
Alcohol and nicotine addiction are frequently co-morbid. The nicotinic acetylcholine receptors (nAChRs) are critical for both alcohol and nicotine addiction mechanisms, since nAChR drugs that reduce nicotine consumption have been shown to also reduce alcohol consumption. Sazetidine-A, a pre-clinical nAChR drug with agonist and desensitizing effects at α4β2 and α7 nAChRs, has been reported to reduce alcohol consumption and nicotine self-administration in rats when administered at high doses. However, this effect has not been replicated in mice...
January 17, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29343230/the-sybil-aa-real-time-fmri-neurofeedback-study-protocol-of-a-single-blind-randomized-controlled-trial-in-alcohol-use-disorder
#3
Martin Fungisai Gerchen, Martina Kirsch, Nathalie Bahs, Patrick Halli, Sarah Gerhardt, Axel Schäfer, Wolfgang H Sommer, Falk Kiefer, Peter Kirsch
BACKGROUND: Alcohol Use Disorder is a highly prevalent mental disorder which puts a severe burden on individuals, families, and society. The treatment of Alcohol Use Disorder is challenging and novel and innovative treatment approaches are needed to expand treatment options. A promising neuroscience-based intervention method that allows targeting cortical as well as subcortical brain processes is real-time functional magnetic resonance imaging neurofeedback. However, the efficacy of this technique as an add-on treatment of Alcohol Use Disorder in a clinical setting is hitherto unclear and will be assessed in the Systems Biology of Alcohol Addiction (SyBil-AA) neurofeedback study...
January 17, 2018: BMC Psychiatry
https://www.readbyqxmd.com/read/29339170/sub-anesthetic-doses-of-ketamine-attenuate-nicotine-self-administration-in-rats
#4
Amir H Rezvani, Yousef Tizabi, Susan Slade, Bruk Getachew, Edward D Levin
Smoking cessation strategies are of prime medical importance. Despite availability of various pharmacological agents in combating addiction to nicotine, more effective medications are needed. Based on recent findings, the glutamatergic system in the brain may provide novel targets. Here, we evaluated the effects of acute administration of sub-anesthetic doses of ketamine, an NMDA receptor antagonist, in both male and female Sprague-Dawley rats trained to self-administer nicotine. Animals were injected subcutaneously with 5, 7...
January 12, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29330143/breast-cancer-targeting-through-inhibition-of-the-endoplasmic-reticulum-based-apoptosis-regulator-nrh-bcl2l10
#5
Adrien Nougarede, Nikolay Popgeorgiev, Loay Kassem, Soleilmane Omarjee, Stephane Borel, Ivan Mikaelian, Jonathan Lopez, Rudy Gadet, Olivier Marcillat, Isabelle Treilleux, Bruno O Villoutreix, Ruth Rimokh, Germain Gillet
Drug resistance and metastatic relapse remain a top challenge in breast cancer treatment. In this study, we present preclinical evidence for a strategy to eradicate advanced breast cancers by targeting the BCL2 homolog Nrh/BCL2L10, which we discovered to be overexpressed in >45% of a large cohort of breast invasive carcinomas. Nrh expression in these tumors correlated with reduced metastasis-free survival and we determined it to be an independent marker of poor prognosis. Nrh protein localized to the endoplasmic reticulum (ER)...
January 12, 2018: Cancer Research
https://www.readbyqxmd.com/read/29296175/organotypic-three-dimensional-cancer-cell-cultures-mirror-drug-responses-in-vivo-lessons-learned-from-the-inhibition-of-egfr-signaling
#6
Nico Jacobi, Rita Seeboeck, Elisabeth Hofmann, Helmut Schweiger, Veronika Smolinska, Thomas Mohr, Alexandra Boyer, Wolfgang Sommergruber, Peter Lechner, Corina Pichler-Huebschmann, Kamil Önder, Harald Hundsberger, Christoph Wiesner, Andreas Eger
Complex three-dimensional (3D) in vitro models that recapitulate human tumor biology are essential to understand the pathophysiology of the disease and to aid in the discovery of novel anti-cancer therapies. 3D organotypic cultures exhibit intercellular communication, nutrient and oxygen gradients, and cell polarity that is lacking in two-dimensional (2D) monolayer cultures. In the present study, we demonstrate that 2D and 3D cancer models exhibit different drug sensitivities towards both targeted inhibitors of EGFR signaling and broad acting cytotoxic agents...
December 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/29287237/a-novel-approach-of-substitution-therapy-with-inhalation-of-essential-oil-for-the-reduction-of-inhalant-craving-a-double-blinded-randomized-controlled-trial
#7
Rasmon Kalayasiri, Wanjaree Maneesang, Michael Maes
Inhalants, which are neurotoxic central nervous system (CNS) suppressants, are frequently abused by young adults. Unlike other CNS depressants, including alcohol and opiates, no treatment is currently approved for inhalant dependence. In this report, a novel approach of substitution treatment for inhalant addiction was explored in a double-blinded, randomized, controlled crossover design to examine the effects of inhalation of essential oil and perfume on the reduction of cue-induced craving for inhalant in thirty-four Thai males with inhalant dependence...
December 11, 2017: Psychiatry Research
https://www.readbyqxmd.com/read/29273415/design-synthesis-and-opioid-activity-of-arodyn-analogs-cyclized-by-ring-closing-metathesis-involving-tyr-allyl
#8
Wei-Jie Fang, Thomas F Murray, Jane V Aldrich
Kappa (κ) opioid receptor selective antagonists are useful pharmacological tools in studying κ opioid receptors and have potential to be used as therapeutic agents for the treatment of a variety of diseases including mood disorders and drug addiction. Arodyn (Ac[Phe1-3,Arg4,d-Ala8]Dyn A-(1-11)NH2) is a linear acetylated dynorphin A (Dyn A) analog that is a potent and selective κ opioid receptor antagonist (Bennett et al. J Med Chem 2002;45:5617-5619) and prevents stress-induced reinstatement of cocaine-seeking behavior following central administration (Carey et al...
November 21, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29251283/genome-wide-expression-profiles-drive-discovery-of-novel-compounds-that-reduce-binge-drinking-in-mice
#9
Laura B Ferguson, Angela R Ozburn, Igor Ponomarev, Pamela Metten, Matthew Reilly, John C Crabbe, R Adron Harris, R Dayne Mayfield
Transcriptome-based drug discovery has identified new treatments for some complex diseases, but has not been applied to alcohol use disorder (AUD) or other psychiatric diseases, where there is a critical need for improved pharmacotherapies. High Drinking in the Dark (HDID-1) mice are a genetic model of AUD risk that have been selectively bred (from the HS/Npt line) to achieve intoxicating blood alcohol levels (BALs) after binge-like drinking. We compared brain gene expression of HDID-1 and HS/Npt mice to determine a molecular signature for genetic risk for high intensity, binge-like drinking...
December 18, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29247759/repeated-methamphetamine-and-modafinil-induce-differential-cognitive-effects-and-specific-histone-acetylation-and-dna-methylation-profiles-in-the-mouse-medial-prefrontal-cortex
#10
Betina González, Subramaniam Jayanthi, Natalia Gomez, Oscar V Torres, Máximo H Sosa, Alejandra Bernardi, Francisco J Urbano, Edgar García-Rill, Jean-Lud Cadet, Verónica Bisagno
Methamphetamine (METH) and modafinil are psychostimulants with different long-term cognitive profiles: METH is addictive and leads to cognitive decline, whereas modafinil has little abuse liability and is a cognitive enhancer. Increasing evidence implicates epigenetic mechanisms of gene regulation behind the lasting changes that drugs of abuse and other psychotropic compounds induce in the brain, like the control of gene expression by histones 3 and 4 tails acetylation (H3ac and H4ac) and DNA cytosine methylation (5-mC)...
December 13, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
https://www.readbyqxmd.com/read/29227643/structure-activity-relationship-studies-on-a-series-of-3%C3%AE-bis-4-fluorophenyl-methoxy-tropanes-and-3%C3%AE-bis-4-fluorophenyl-methylamino-tropanes-as-novel-atypical-dopamine-transporter-dat-inhibitors-for-the-treatment-of-cocaine-use-disorders
#11
Mu-Fa Zou, Jianjing Cao, Ara M Abramyan, Theresa Kopajtic, Claudio Zanettini, Daryl A Guthrie, Rana Rais, Barbara S Slusher, Lei Shi, Claus J Loland, Amy Hauck Newman
The development of medications to treat cocaine use disorders has thus far defied success, leaving this patient population without pharmacotherapeutic options. As the dopamine transporter (DAT) plays a prominent role in the reinforcing effects of cocaine that can lead to addiction, atypical DAT inhibitors have been developed that prevent cocaine from binding to DAT, but they themselves are not cocaine-like. Herein, a series of novel DAT inhibitors were synthesized, and based on its pharmacological profile, the lead compound 10a was evaluated in phase I metabolic stability studies in mouse liver microsomes and compared to cocaine in locomotor activity and drug discrimination paradigms in mice...
December 11, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29225566/cdk5-is-essential-for-amphetamine-to-increase-dendritic-spine-density-in-hippocampal-pyramidal-neurons
#12
Soledad Ferreras, Guillermo Fernández, Víctor Danelon, María V Pisano, Luján Masseroni, Christopher A Chapleau, Favio A Krapacher, Estela C Mlewski, Daniel H Mascó, Carlos Arias, Lucas Pozzo-Miller, María G Paglini
Psychostimulant drugs of abuse increase dendritic spine density in reward centers of the brain. However, little is known about their effects in the hippocampus, where activity-dependent changes in the density of dendritic spine are associated with learning and memory. Recent reports suggest that Cdk5 plays an important role in drug addiction, but its role in psychostimulant's effects on dendritic spines in hippocampus remain unknown. We used in vivo and in vitro approaches to demonstrate that amphetamine increases dendritic spine density in pyramidal neurons of the hippocampus...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29223953/potential-role-for-acupuncture-in-the-treatment-of-food-addiction-and-obesity
#13
Jason Aaron Chen, Justin Albert Chen, Sanghoon Lee, Gerard Mullin
Addressing the global obesity epidemic requires innovative approaches that are also acceptable to affected individuals. There is growing evidence suggesting that food addiction, one contributor to obesity, bears many similarities to drug and alcohol addiction, presenting a potential role for addiction-focused acupuncture as a novel treatment modality. In this perspective article, we begin by briefly reviewing the evidence linking food and drug/alcohol addiction. We then describe the development of an acupuncture-based protocol for treating opioid addiction in Hong Kong in the 1970s and discuss the evidence base for acupuncture's efficacy in treating a range of substance use disorders...
December 9, 2017: Acupuncture in Medicine: Journal of the British Medical Acupuncture Society
https://www.readbyqxmd.com/read/29222992/inflammatory-chemokine-eotaxin-1-is-correlated-with-age-in-heroin-dependent-patients-under-methadone-maintenance-therapy
#14
Hsiang-Wei Kuo, Tung-Hsia Liu, Hsiao-Hui Tsou, Ya-Ting Hsu, Sheng-Chang Wang, Chiu-Ping Fang, Chia-Chen Liu, Andrew C H Chen, Yu-Li Liu
BACKGROUND: Degeneration of central neurons and fibers has been observed in postmortem brains of heroin dependent patients. However, there are no biomarkers to predict the severity of neurodegeneration related to heroin dependence. A correlation has been reported between inflammatory C-C motif chemokine ligand 11 (CCL11, or eotaxin-1) and neurodegeneration in Alzheimer's disease. METHODS: Three-hundred-forty-four heroin dependent, Taiwanese patients under methadone maintenance treatment (MMT) were included with clinical assessment and genomics information...
November 28, 2017: Drug and Alcohol Dependence
https://www.readbyqxmd.com/read/29217682/overexpression-of-the-histone-dimethyltransferase-g9a-in-nucleus-accumbens-shell-increases-cocaine-self-administration-stress-induced-reinstatement-and-anxiety
#15
Ethan M Anderson, Erin B Larson, Daniel Guzman, Anne Marie Wissman, Rachael L Neve, Eric J Nestler, David W Self
Repeated exposure to cocaine induces lasting epigenetic changes in neurons that promote the development and persistence of addiction. One epigenetic alteration involves reductions in levels of the histone dimethyltransferase, G9a, in nucleus accumbens (NAc) after chronic cocaine administration. This reduction in G9a may enhance cocaine reward since overexpressing G9a in the NAc decreases cocaine-conditioned place preference. Thus, we hypothesized that HSV-mediated G9a overexpression in the NAc shell (NAcSh) would attenuate cocaine self-administration and cocaine-seeking behavior...
December 7, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29217282/atypical-dopamine-transporter-inhibitors-attenuate-compulsive-like-methamphetamine-self-administration-in-rats
#16
Brendan J Tunstall, Chelsea P Ho, Jianjing Cao, Janaína C M Vendruscolo, Brooke E Schmeichel, Rachel D Slack, Gianluigi Tanda, Alexandra J Gadiano, Rana Rais, Barbara S Slusher, George F Koob, Amy H Newman, Leandro F Vendruscolo
Methamphetamine (METH) is a highly addictive drug, but no pharmacological treatment is yet available for METH use disorders. Similar to METH, the wake-promoting drug (R)-modafinil (R-MOD) binds to the dopamine transporter (DAT). Unlike METH, R-MOD is not a substrate for transport by DAT and has low abuse potential. We tested the hypothesis that the atypical DAT inhibitor R-MOD and compounds that are derived from Modafinil would decrease METH intake by reducing the actions of METH at the DAT. We tested the effects of systemic injections of R-MOD and four novel Modafinil-derived ligands with increased DAT affinity (JJC8-016, JJC8-088, JJC8-089, and JJC8-091) on intravenous (i...
December 4, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/29208673/biomarkers-of-primary-resistance-to-trastuzumab-in-her2-positive-metastatic-gastric-cancer-patients-the-amnesia-case-control-study
#17
Filippo Pietrantonio, Giovanni Fucà, Federica Morano, Annunziata Gloghini, Simona Corso, Giuseppe Aprile, Federica Perrone, Ferdinando De Vita, Elena Tamborini, Gianluca Tomasello, Ambra V Gualeni, Elena Ongaro, Adele Busico, Elisa Giommoni, Chiara C Volpi, Maria Maddalena Laterza, Salvatore Corallo, Michele Prisciandaro, Maria Antista, Alessandro Pellegrinelli, Lorenzo Castagnoli, Serenella Maria Pupa, Giancarlo Pruneri, Filippo G De Braud, Silvia Giordano, Chiara Cremolini, Maria Di Bartolomeo
PURPOSE: Refining the selection of HER2 positive metastatic gastric cancer patients candidates for trastuzumab is a challenge of precision oncology. Preclinical studies have suggested several genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than HER2 or downstream signaling pathways. EXPERIMENTAL DESIGN: We carried out this multicenter, prospective, case-control study to demonstrate the negative predictive impact of a panel of candidate genomic alterations (AMNESIA panel), including EGFR/MET/KRAS/PI3K/PTEN mutations and EGFR/MET/KRAS amplifications...
December 5, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29187012/targeted-therapies-in-non-small-cell-lung-cancer-a-focus-on-alk-ros1-tyrosine-kinase-inhibitors
#18
Assunta Sgambato, Francesca Casaluce, Paolo Maione, Cesare Gridelli
Anaplastic lymphoma kinase (ALK) and ROS1 rearrangements define important molecular subgroups of advanced non-small cell lung cancer (NSCLC). The identification of these genetic driver alterations created new potential for highly active therapeutic interventions. After discovery of ALK rearrangements in NSCLC, it was recognized that these confer sensitivity to ALK inhibition. Areas covered: Crizotinib, the first-in-class ALK/ROS1/MET inhibitor, was initially approved as second-line treatment of ALK-positive advanced NSCLC but after this, it was firmly established as the standard first-line therapy for advanced ALK-positive NSCLC...
January 2018: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/29177353/switch-on-fluorescent-fret-probes-to-study-human-histidine-triad-nucleotide-binding-protein-1-hhint1-a-novel-target-for-opioid-tolerance-and-neuropathic-pain
#19
Rachit Shah, Andrew Zhou, Carston R Wagner
Histidine Triad Nucleotide Binding Protein 1 (Hint1) has emerged to be an important post-synaptic protein associated with a variety of central nervous system disorders such as pain, addiction, and schizophrenia. Recently, inhibition of histidine nucleotide binding protein 1 (Hint1) with a small nucleoside inhibitor has shown promise as a new therapeutic strategy for the treatment of neuropathic pain. Herein, we describe the first rationally designed small molecule switch-on probes with dual fluorescence and FRET properties to study Hint1...
November 27, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/29175958/amphetamine-reverses-escalated-cocaine-intake-via-restoration-of-dopamine-transporter-conformation
#20
Cody A Siciliano, Kaustuv Saha, Erin S Calipari, Steve C Fordahl, Rong Chen, Habibeh Khoshbouei, Sara R Jones
Cocaine abuse disrupts dopamine system function, including reduced cocaine inhibition of the dopamine transporter (DAT), which results in tolerance. Although tolerance is a hallmark of cocaine addiction and a DSM-V criteria for substance abuse disorders, the molecular adaptations producing tolerance are unknown, and testing the impact of DAT changes on drug taking behaviors has proven difficult. In regard to treatment, amphetamine has shown efficacy in reducing cocaine intake; however, the mechanisms underlying these effects have not been explored...
November 24, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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