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https://www.readbyqxmd.com/read/28346058/promising-pharmacogenetic-targets-for-treating-alcohol-use-disorder-evidence-from-preclinical-models
#1
Jennifer A Rinker, Patrick J Mulholland
Inherited genetic variants contribute to risk factors for developing an alcohol use disorder, and polymorphisms may inform precision medicine strategies for treating alcohol addiction. Targeting genetic mutations linked to alcohol phenotypes has provided promising initial evidence for reducing relapse rates in alcoholics. Although successful in some studies, there are conflicting findings and the reports of adverse effects may ultimately limit their clinical utility, suggesting that novel pharmacogenetic targets are necessary to advance precision medicine approaches...
March 27, 2017: Pharmacogenomics
https://www.readbyqxmd.com/read/28340145/human-abuse-potential-of-the-new-opioid-analgesic-molecule-nktr-181-compared-with-oxycodone
#2
Lynn Webster, Jack Henningfield, August R Buchhalter, Suresh Siddhanti, Lin Lu, Aleksandrs Odinecs, Carlo J Di Fonzo, Michael A Eldon
Objective.:  Evaluate the human abuse potential, pharmacokinetics, pharmacodynamics, and safety of NKTR-181, a novel mu-opioid agonist molecule, relative to oxycodone. Design.:  This randomized, single-center, double-blind, active- and placebo-controlled five-period crossover study enrolled healthy, adult, non-physically dependent recreational opioid users. Setting.:  Inpatient clinical research site. Subjects. : Forty-two randomized subjects (73...
March 10, 2017: Pain Medicine: the Official Journal of the American Academy of Pain Medicine
https://www.readbyqxmd.com/read/28332047/mechanisms-of-resistance-to-target-therapies-in-non-small-cell-lung-cancer
#3
Francesco Facchinetti, Claudia Proto, Roberta Minari, Marina Garassino, Marcello Tiseo
Targeted therapies are revolutionizing the treatment of advanced non-small cell lung cancer (NSCLC). The discovery of key oncogenic events mainly in lung adenocarcinoma, like EGFR mutations or ALK rearrangements, has changed the treatment landscape while improving the prognosis of lung cancer patients. Inevitably, virtually all patients initially treated with targeted therapies develop resistance because of the emergence of an insensitive cellular population, selected by pharmacologic pressure. Diverse mechanisms of resistance, in particular to EGFR, ALK and ROS1 tyrosine-kinase inhibitors (TKIs), have now been discovered and may be classified in three different groups: (1) alterations in the target (such as EGFR T790M and ALK or ROS1 mutations); (2) activation of alternative pathways (i...
March 23, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28326026/pre-clinical-studies-with-d-penicillamine-as-a-novel-pharmacological-strategy-to-treat-alcoholism-updated-evidences
#4
REVIEW
Alejandro Orrico, Lucía Martí-Prats, María J Cano-Cebrián, Luis Granero, Ana Polache, Teodoro Zornoza
Ethanol, as other drugs of abuse, is able to activate the ventral tegmental area dopamine (VTA-DA) neurons leading to positively motivational alcohol-seeking behavior and use, and, ultimately to ethanol addiction. In the last decades, the involvement of brain-derived acetaldehyde (ACD) in the ethanol actions in the mesolimbic pathway has been widely demonstrated. Consistent published results have provided a mechanistic support to the use of ACD inactivating agents to block the motivational and reinforcing properties of ethanol...
2017: Frontiers in Behavioral Neuroscience
https://www.readbyqxmd.com/read/28323108/chronic-methamphetamine-exposure-significantly-decreases-microglia-activation-in-the-arcuate-nucleus
#5
Steven A Lloyd, Beau Corkill, Matthew C Bruster, Rick L Roberts, Ryan A Shanks
Methamphetamine is a powerful psychostimulant drug and its use and abuse necessitates a better understanding of its neurobiobehavioral effects. The acute effects of binge dosing of methamphetamine on the neurons in the CNS are well studied. However, the long-term effects of chronic, low-dose methamphetamine are less well characterized, especially in other cell types and areas outside of the major dopamine pathways. Mice were administered 5mg/kg/day methamphetamine for ten days and brain tissue was analyzed using histochemistry and image analysis...
March 18, 2017: Journal of Chemical Neuroanatomy
https://www.readbyqxmd.com/read/28322982/toward-biomarkers-of-the-addicted-human-brain-using-neuroimaging-to-predict-relapse-and-sustained-abstinence-in-substance-use-disorder
#6
REVIEW
Scott J Moeller, Martin P Paulus
The ability to predict relapse is a major goal of drug addiction research. Clinical and diagnostic measures are useful in this regard, but these measures do not fully and consistently identify who will relapse and who will remain abstinent. Neuroimaging approaches have the potential to complement these standard clinical measures to optimize relapse prediction. The goal of this review was to survey the existing drug addiction literature that either used a baseline functional or structural neuroimaging phenotype to longitudinally predict a clinical outcome, or that examined test-retest of a neuroimaging phenotype during a course of abstinence or treatment...
March 18, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
https://www.readbyqxmd.com/read/28315272/sigma-receptors-and-substance-use-disorders
#7
Valentina Sabino, Callum Hicks, Pietro Cottone
Thanks to advances in neuroscience, addiction is now recognized as a chronic brain disease with genetic, developmental, and cultural components. Drugs of abuse, including alcohol, are able to produce significant neuroplastic changes responsible for the profound disturbances shown by drug addicted individuals. The current lack of efficacious pharmacological treatments for substance use disorders has encouraged the search for novel and more effective pharmacotherapies. Growing evidence strongly suggests that Sigma Receptors are involved in the addictive and neurotoxic properties of abused drugs, including cocaine , methamphetamine , and alcohol...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28302509/binding-mode-analyses-of-nap-derivatives-as-mu-opioid-receptor-selective-ligands-through-docking-studies-and-molecular-dynamics-simulation
#8
Huiqun Wang, Saheem A Zaidi, Yan Zhang
Mu opioid receptor selective antagonists are highly desirable because of their utility as pharmacological probes for receptor characterization and functional studies. Furthermore, the mu opioid receptors act as an important target in drug abuse and addiction treatment. Previously, we reported NAP as a novel lead compound with high selectivity and affinity towards the mu opioid receptor. Based on NAP, we have synthesized its derivatives and further characterized their binding affinities and selectivity towards the receptor...
March 6, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28291693/synthesis-and-evaluation-of-a-ligand-targeting-the-%C3%AE-and-%C3%AE-opioid-receptors-for-drug-delivery-to-lung-cancer
#9
Guo Li, Philip S Low
A well-established approach to developing new imaging agents and treatments for cancer begins with the recognition of receptors that are overexpressed in cancer cells. Ideally, these same receptors would also be absent, or minimally expressed, in healthy tissue. The mu (μ) and delta (δ) opioid receptors (MOR and DOR respectively) match these criteria, with expression in cancer cells that is higher than primary lung epithelial cells. Naltrexone is a drug approved by the U.S. Food and Drug Administration (FDA) for treatment of alcohol dependence or prevention of relapse from opioid addiction...
June 28, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28272550/activin-a-is-increased-in-the-nucleus-accumbens-following-a-cocaine-binge
#10
Zi-Jun Wang, Jennifer A Martin, Amy M Gancarz, Danielle N Adank, Fraser J Sim, David M Dietz
Drug addiction is a long-lasting disease characterized by compulsive drug intake mediated in part by neuronal and biological adaptations in key brain areas, such as the nucleus accumbens (NAc). While we previously demonstrated involvement of the activin 2a receptor in drug taking, the role of its ligand, activin A, in cocaine relapse is unknown. Activin A levels in the NAc were assessed via ELISA and immunohistochemistry (in neurons, astrocytes, and microglia) following a cocaine binge paradigm. Cocaine exposure significantly increased the levels of activin A in the NAc of animals that had self-administered cocaine prior to the 14-day withdrawal compared with levels in saline controls...
March 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28271453/effects-of-a-food-specific-inhibition-training-in-individuals-with-binge-eating-disorder-findings-from-a-randomized-controlled-proof-of-concept-study
#11
Katrin Elisabeth Giel, Eva Speer, Kathrin Schag, Elisabeth Johanna Leehr, Stephan Zipfel
PURPOSE: Impulsivity might contribute to the development and maintenance of obesity and eating disorders. Patients suffering from binge eating disorder (BED) show an impulsive eating pattern characterized by regular binge eating episodes. Novel behavioral interventions increasing inhibitory control could improve eating behavior in BED. We piloted a novel food-specific inhibition training in individuals with BED. METHODS: N = 22 BED patients according to SCID-I were randomly assigned to three sessions of a training or control condition...
March 7, 2017: Eating and Weight Disorders: EWD
https://www.readbyqxmd.com/read/28268215/randomised-comparison-of-a-novel-buprenorphine-oral-lyophilisate-versus-existing-buprenorphine-sublingual-tablets-in-opioid-dependent-patients-a-first-in-patient-phase-ii-randomised-open-label-safety-study
#12
John Strang, Kylie Reed, Karolina Bogdanowicz, James Bell, Rob van der Waal, Jenny Keen, Pete Beavan, Shelagh Baillie, Alastair Knight
AIMS: To test the safety of new buprenorphine oral lyophilisate wafer ("bup-lyo") versus standard sub-lingual buprenorphine ("bup-SL"). DESIGN: Randomised (2:1) open-label study; opioid-dependent subjects; subsequent partial cross-over. SETTINGS: Specialised clinical trials facility and addictions treatment facility. PARTICIPANTS: Opioid-dependent subjects (n = 36) commencing buprenorphine maintenance (personalised dose-titration) including patients co-using alcohol, cocaine and benzodiazepines (below thresholds)...
March 8, 2017: European Addiction Research
https://www.readbyqxmd.com/read/28266501/the-novel-modafinil-analog-jjc8-016-as-a-potential-cocaine-abuse-pharmacotherapeutic
#13
Hai-Ying Zhang, Guo-Hua Bi, Hong-Ju Yang, Yi He, Gilbert Xue, Jian-Jing Cao, Gianluigi Tanda, Eliot L Gardner, Amy Hauck Newman, Zheng-Xiong Xi
(±)Modafinil ((±)MOD) and its R-enantiomer (R-modafinil; R-MOD) have been investigated for their potential as treatments for psychostimulant addiction. We recently reported a series of (±)MOD analogues, of which JJC8-016 (N-(2-((bis(4-fluorophenyl)methyl)thio)ethyl)-3-phenylpropan-1-amine) was selected for further development. JJC8-016 and R-MOD were evaluated for binding across ~70 receptors, transporters and enzymes. Although at a concentration of 10 μM, there were many hits for JJC8-016, binding affinities in the range of its DAT affinity were only observed at the serotonin transporter (SERT), dopamine D2-like and sigma1 receptors...
March 7, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28265716/don-t-stress-about-crf-assessing-the-translational-failures-of-crf1antagonists
#14
REVIEW
Samantha R Spierling, Eric P Zorrilla
BACKGROUND: Dr. Athina Markou sought treatments for a common neural substrate shared by depression and drug dependence. Antagonists of corticotropin-releasing factor (CRF) receptors, a target of interest to her, have not reached the clinic despite strong preclinical rationale and sustained translational efforts. METHODS: We explore potential causes for the failure of CRF1 antagonists and review recent findings concerning CRF-CRF1 systems in psychopathology. RESULTS: Potential causes for negative outcomes include (1) poor safety and efficacy of initial drug candidates due to bad pharmacokinetic and physicochemical properties, (2) specificity problems with preclinical screens, (3) the acute nature of screens vs...
March 7, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28229895/impulse-control-disorders-and-levodopa-induced-dyskinesias-in-parkinson-s-disease-an-update
#15
REVIEW
Valerie Voon, T Celeste Napier, Michael J Frank, Veronique Sgambato-Faure, Anthony A Grace, Maria Rodriguez-Oroz, Jose Obeso, Erwan Bezard, Pierre-Olivier Fernagut
Dopaminergic medications used in the treatment of patients with Parkinson's disease are associated with motor and non-motor behavioural side-effects, such as dyskinesias and impulse control disorders also known as behavioural addictions. Levodopa-induced dyskinesias occur in up to 80% of patients with Parkinson's after a few years of chronic treatment. Impulse control disorders, including gambling disorder, binge eating disorder, compulsive sexual behaviour, and compulsive shopping occur in about 17% of patients with Parkinson's disease on dopamine agonists...
March 2017: Lancet Neurology
https://www.readbyqxmd.com/read/28221362/disrupted-iron-regulation-in-the-brain-and-periphery-in-cocaine-addiction
#16
K D Ersche, J Acosta-Cabronero, P S Jones, H Ziauddeen, R P L van Swelm, C M M Laarakkers, R Raha-Chowdhury, G B Williams
Stimulant drugs acutely increase dopamine neurotransmission in the brain, and chronic use leads to neuroadaptive changes in the mesolimbic dopamine system and morphological changes in basal ganglia structures. Little is known about the mechanisms underlying these changes but preclinical evidence suggests that iron, a coenzyme in dopamine synthesis and storage, may be a candidate mediator. Iron is present in high concentrations in the basal ganglia and stimulant drugs may interfere with iron homeostasis. We hypothesised that morphological brain changes in cocaine addiction relate to abnormal iron regulation in the brain and periphery...
February 21, 2017: Translational Psychiatry
https://www.readbyqxmd.com/read/28202458/sensitivity-to-pi3k-and-akt-inhibitors-is-mediated-by-divergent-molecular-mechanisms-in-subtypes-of-dlbcl
#17
Tabea Erdmann, Pavel Klener, James T Lynch, Michael Grau, Petra Vočková, Jan Molinsky, Diana Tuskova, Kevin Hudson, Urszula M Polanska, Michael Grondine, Michele Mayo, Beiying Dai, Matthias Pfeifer, Kristian Erdmann, Daniela Schwammbach, Myroslav Zapukhlyak, Annette M Staiger, German Ott, Wolfgang E Berdel, Barry R Davies, Francisco Cruzalegui, Marek Trneny, Peter Lenz, Simon T Barry, Georg Lenz
Activated B-cell-like (ABC) and germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL) represent the two major molecular DLBCL subtypes. They are characterized by differences in clinical course and by divergent addiction to oncogenic pathways. To determine activity of novel compounds in these two subtypes, we conducted an unbiased pharmacologic in vitro screen. The phosphatidylinositol-3-kinase (PI3K) alpha/delta (PI3Kα/δ) inhibitor AZD8835 showed marked potency in ABC DLBCL models, whereas the protein kinase B (AKT) inhibitor AZD5363 induced apoptosis in PTEN-deficient DLBCLs irrespective of their molecular subtype...
February 15, 2017: Blood
https://www.readbyqxmd.com/read/28199070/randomized-controlled-trial-comparing-exercise-to-health-education-for-stimulant-use-disorder-results-from-the-ctn-0037-stimulant-reduction-intervention-using-dosed-exercise-stride-study
#18
Madhukar H Trivedi, Tracy L Greer, Chad D Rethorst, Thomas Carmody, Bruce D Grannemann, Robrina Walker, Diane Warden, Kathy Shores-Wilson, Mark Stoutenberg, Neal Oden, Meredith Silverstein, Candace Hodgkins, Lee Love, Cindy Seamans, Angela Stotts, Trey Causey, Regina P Szucs-Reed, Paul Rinaldi, Hugh Myrick, Michele Straus, David Liu, Robert Lindblad, Timothy Church, Steven N Blair, Edward V Nunes
OBJECTIVE: To evaluate exercise as a treatment for stimulant use disorders. METHODS: The STimulant Reduction Intervention using Dosed Exercise (STRIDE) study was a randomized clinical trial conducted in 9 residential addiction treatment programs across the United States from July 2010 to February 2013. Of 497 adults referred to the study, 302 met all eligibility criteria, including DSM-IV criteria for stimulant abuse and/or dependence, and were randomized to either a dosed exercise intervention (Exercise) or a health education intervention (Health Education) control, both augmenting treatment as usual and conducted thrice weekly for 12 weeks...
February 14, 2017: Journal of Clinical Psychiatry
https://www.readbyqxmd.com/read/28194001/enhancing-vta-cav1-3-l-type-ca-2-channel-activity-promotes-cocaine-and-mood-related-behaviors-via-overlapping-ampa-receptor-mechanisms-in-the-nucleus-accumbens
#19
A Martínez-Rivera, J Hao, T F Tropea, T P Giordano, M Kosovsky, R C Rice, A Lee, R L Huganir, J Striessnig, N A Addy, S Han, A M Rajadhyaksha
Genetic factors significantly influence susceptibility for substance abuse and mood disorders. Rodent studies have begun to elucidate a role of Cav1.3 L-type Ca(2+) channels in neuropsychiatric-related behaviors, such as addictive and depressive-like behaviors. Human studies have also linked the CACNA1D gene, which codes for the Cav1.3 protein, with bipolar disorder. However, the neurocircuitry and the molecular mechanisms underlying the role of Cav1.3 in neuropsychiatric phenotypes are not well established...
February 14, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28174112/epigenetic-basis-of-the-dark-side-of-alcohol-addiction
#20
REVIEW
Subhash C Pandey, Evan J Kyzar, Huaibo Zhang
Alcoholism is a complex brain disease characterized by three distinct stages of the addiction cycle that manifest as neuroadaptive changes in the brain. One such stage of the addiction cycle is alcohol withdrawal and the negative affective states that promote drinking and maintain addiction. Repeated alcohol use, genetic predisposition to alcoholism and anxiety, and alcohol exposure during crucial developmental periods all contribute to the development of alcohol-induced withdrawal and negative affective symptoms...
February 4, 2017: Neuropharmacology
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