DOCSLIB.ORG

Generalized Anxiety Disorder View Online At

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Generalized Anxiety Disorder View Online At Generalized Anxiety Disorder View online at http://pier.acponline.org/physicians/diseases/d086/d086.html Module Updated: 2013-04-15 CME Expiration: 2016-04-15 Authors Christopher Gale, MB, ChB, MPH (Hon), FRANZCP Jane Millichamp, PhD Table of Contents 1. Prevention .........................................................................................................................2 2. Screening ..........................................................................................................................3 3. Diagnosis ..........................................................................................................................5 4. Consultation ......................................................................................................................8 5. Hospitalization ...................................................................................................................9 6. Therapy ............................................................................................................................10 7. Patient Education ...............................................................................................................18 8. Follow-up ..........................................................................................................................19 References ............................................................................................................................20 Glossary................................................................................................................................24 Tables ...................................................................................................................................26 Quality Ratings: The preponderance of data supporting guidance statements are derived from: level 1 studies, which meet all of the evidence criteria for that study type; level 2 studies, which meet at least one of the evidence criteria for that study type; or level 3 studies, which meet none of the evidence criteria for that study type or are derived from expert opinion, commentary, or consensus. Study types and criteria are defined at http://smartmedicine.acponline.org/criteria.html Disclaimer: The information included herein should never be used as a substitute for clinical judgement and does not represent an official position of the American College of Physicians. Because all PIER modules are updated regularly, printed web pages or PDFs may rapidly become obsolete. Therefore, PIER users should compare the module updated date on the offical web site with any printout to ensure that the information is the most current available. CME Statement: The American College of Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing education for physicians. The American College of Physicians designates this enduring material for a maximum of 1 AMA PRA Category 1 CreditTM. Physicians should claim only credit commensurate with the extent of their participation in the activity. Purpose: This activity has been developed for internists to facilitate the highest quality professional work in clinical applications, teaching, consultation, or research. Upon completion of the CME activity, participants should be able to demonstrate an increase in the skills and knowledge required to maintain competence, strengthen their habits of critical inquiry and balanced judgement, and to contribute to better patient care. Disclosures: Christopher Gale, MB, ChB, MPH (Hon), FRANZCP, current author of this module, was on speakers bureau for Astra-Zeneca, Janssen, and Lilly; and and consulted for Lilly. Jane Millichamp, PhD, current author of this module, has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or health-care related organizations. Deborah Korenstein, MD, FACP, Co-Editor, PIER, has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or health-care related organizations. Richard B. Lynn, MD, FACP, Co-Editor, PIER, has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or health-care related organizations. PIER is copyrighted ©2013 by the American College of Physicians. 190 N. Independence Mall West, Philadelphia, PA 19106, USA. Generalized Anxiety Disorder Top 1. Prevention Recognize that brief interventions may prevent further anxiety symptoms in children, but no similar data exist for adults. 1.1 Reserve preventive strategies for children at higher risk. Recommendations • Recognize that there are no strategies to prevent GAD in adults. • Consider CBT and parent education to prevent the development of GAD in children who exhibit withdrawn or inhibited behavior or early signs of anxiety, such as separation anxiety or simple phobia. • Consider family-based CBT for children who have a parent with a diagnosed anxiety disorder. Evidence • A 2009 systematic review of prospective studies identified 23 papers, 7 of which reported on anxiety, depression with anxiety, or internalizing disorders (disorders relating to distress and fear). Of the studies on anxiety, two noted an association with abuse or neglect, and one found no relationship (1). • A randomized trial compared a 10-week, school-based CBT program with a parental intervention component to monitoring in children who showed early signs of anxiety disorders as determined by self-report and teacher report. Both groups showed improvements immediately after intervention; however, at the 6-month follow-up, only the intervention group maintained improvement, with reduced rates of existing anxiety disorders and prevention of the onset of new anxiety disorders. Results showed that although the intervention and control groups converged at 12 months, the intervention group showed superior gains at the 2-year follow-up (2; 3). • A randomized trial compared a six-session parent education program with cognitive-behavioral components to no intervention in preschool children who displayed inhibited or withdrawn behaviors, a known risk factor for later anxiety disorders. Children whose parents received the educational intervention showed a significantly greater reduction in anxiety diagnoses at the 12- month follow-up but no significant change in measures of inhibition or withdrawal (4). • A randomized trial evaluated the long-term effectiveness of a universal prevention program using CBT components (the Friends program) in school children. Schools were randomly assigned to either intervention or control and 737 children from grades 6 and 9 were enrolled. At 3-year follow- up, 6th graders who received the CBT prevention program had significantly fewer anxiety and depression symptoms than those in the control condition (5). • A randomized trial evaluated the effects of an 8-week preventive intervention (family-based CBT) on children aged 7 to 12 years whose parents had been diagnosed with an anxiety disorder. At 1- year follow-up, 30% of children in the waitlist control condition had developed an anxiety disorder, compared with 0% of children in the family-based CBT condition (6). Rationale • Cognitive-behavioral interventions in children may be helpful in preventing later development of GAD. Comments • There are no data on the prevention of GAD in patients aged over 14 years. The pediatric trials use any anxiety disorder as the outcome. • Internet-based family CBT programs may be useful for young people and their families who cannot access specialist services. PIER is copyrighted ©2013 by the American College of Physicians. 190 N. Independence Mall West, Philadelphia, PA 19106, USA. Page 2 of 36 Generalized Anxiety Disorder Top 2. Screening Consider using appropriate instruments to screen all adults in primary care settings and in children with risk factors. 2.1 Consider screening adults in primary care settings. Recommendations • Consider screening at-risk adults including those with unexplained symptoms, chronic illnesses, comorbid psychiatric disorders, or family history of anxiety disorders. • Screen adults for GAD in primary care settings by: Asking one question, e.g., “Are you bothered by nerves?” Asking the two questions which comprise the GAD-2: o Do you feel nervous, anxious, or on edge? o Are you unable to stop or control worrying? Using other instruments such as the GAD-7 or the patient questionnaire PRIME-MD • See table GAD-2 Screening Instrument. • See the GAD-7 Screening Instrument. Evidence • The National Comorbidity Survey Replication estimated that 6.1% of the U.S. population will have GAD during their lifetime, and that 2.9% will have GAD in any 12-month period. (7). • A 2007 study measured the accuracy of brief screening tools compared with a structured psychiatric interview in 965 primary care patients. Overall, 19.5% of patients had an anxiety disorder and 7.6% had GAD. For GAD, a GAD-7 score of ≥7 had sensitivity of 95% and specificity of 70%; a GAD-2 score of ≥2 had sensitivity of 95% and specificity of 64%, and a score of ≥3 had sensitivity of 86% and specificity of 83% (8). • A review of 15 epidemiologic studies of GAD in Europe estimated that the 12-month prevalence is between 0.1% to 2.1%, and the 1-month prevalence is in the range of 0.2% to 1.0%. (9). • One question (“Are you bothered by nerves?”) was used to screen for GAD in 801 primary care patients who then were interviewed using the CIDI. When compared with the CIDI, this question was 100% sensitive and 59% specific
Load more

Recommended publications
  • Gabitril® (Tiagabine)
    Gabitril (Tiagabine) What is Gabitril (Tiagabine)? Gabitril is an anti-epileptic drug that has been used to treat patients with epilepsy since 1997. It is helpful in the treatment of partial seizures. Starting the Medicine: We usually gradually increase the dose, until your body gets adjusted to the medication. Since each patient is unique in that he/she breaks down the medication differently or may need a higher or lower dosage to control their seizures, there is no standard dose that is appropriate for all patients. What dosages does the pill come in and what does it look like? 4 mg round, yellow tablet 12 mg oval, green tablet 16 mg oval, blue tablet 20 mg oval, pink tablet What Side Effects Can Be Caused By Gabitril? Side effects can be dose related (common) or idiosyncratic (rare): Common Dose - Related Side Effects: Dizziness, drowsiness, difficulty concentrating, or nausea may occur. If you have these side effects, your doctor may: • spread out the dose more frequently during the day • slow the rate of dose increase Comprehensive Epilepsy Center (734) 936-9020 - 1 - • instruct you to take the pills with food since this will slow the rate at which the medicine gets into the blood, but will not affect the total amount that is absorbed. Rare Side Effects: Rare side effects may include: difficulty sleeping, nervousness, or balance problems. Skin Rash: An allergic reaction, or rash, may occur with Gabitril. If this occurs, notify your doctor immediately. Pregnancy: Currently, no information is available about the effects of Gabitril during pregnancy. Any woman taking Gabitril should discuss this issue with her doctor BEFORE becoming pregnant.
    [Show full text]
  • GABA Receptors
    D Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews Review No.7 / 1-2011 GABA receptors Wolfgang Froestl , CNS & Chemistry Expert, AC Immune SA, PSE Building B - EPFL, CH-1015 Lausanne, Phone: +41 21 693 91 43, FAX: +41 21 693 91 20, E-mail: [email protected] GABA Activation of the GABA A receptor leads to an influx of chloride GABA ( -aminobutyric acid; Figure 1) is the most important and ions and to a hyperpolarization of the membrane. 16 subunits with γ most abundant inhibitory neurotransmitter in the mammalian molecular weights between 50 and 65 kD have been identified brain 1,2 , where it was first discovered in 1950 3-5 . It is a small achiral so far, 6 subunits, 3 subunits, 3 subunits, and the , , α β γ δ ε θ molecule with molecular weight of 103 g/mol and high water solu - and subunits 8,9 . π bility. At 25°C one gram of water can dissolve 1.3 grams of GABA. 2 Such a hydrophilic molecule (log P = -2.13, PSA = 63.3 Å ) cannot In the meantime all GABA A receptor binding sites have been eluci - cross the blood brain barrier. It is produced in the brain by decarb- dated in great detail. The GABA site is located at the interface oxylation of L-glutamic acid by the enzyme glutamic acid decarb- between and subunits. Benzodiazepines interact with subunit α β oxylase (GAD, EC 4.1.1.15). It is a neutral amino acid with pK = combinations ( ) ( ) , which is the most abundant combi - 1 α1 2 β2 2 γ2 4.23 and pK = 10.43.
    [Show full text]
  • Tiagabine Synergistically Interacts with Gabapentin in the Electroconvulsive Threshold Test in Mice
    Neuropsychopharmacology (2003) 28, 1817–1830 & 2003 Nature Publishing Group All rights reserved 0893-133X/03 $25.00 www.neuropsychopharmacology.org Tiagabine Synergistically Interacts with Gabapentin in the Electroconvulsive Threshold Test in Mice 1,5 2 3 ,1,4 Jarogniew J Łuszczki , Mariusz S´ wia˛der , Jolanta Parada-Turska and Stanisław J Czuczwar* 1 2 Department of Pathophysiology, Medical University, Lublin, Poland; Department of Pharmacology and Toxicology, Medical University, Lublin, 3 4 Poland; Department of Rheumatology, Medical University, Lublin, Poland; Isotope Laboratory, Institute of Agricultural Medicine, Lublin, Poland Polytherapy, based on the rational combining of antiepileptic drugs (AEDs), is required for patients with drug-resistant epilepsy. In such cases, the combinations of AEDs usually offer a significant enhancement of their protective effects against seizures. There has appeared a hypothesis that combining two AEDs, influencing the same neurotransmitter system, results in the potentialization of their anticonvulsant effects. For corroborating this hypothesis, a pharmacological character of interaction between tiagabine (TGB) and gabapentin F (GBP) two novel AEDs affecting the GABA-ergic system, in the maximal electroshock seizure threshold (MEST)-test in mice was evaluated. TGB at the dose of 4 mg/kg and GBP at 75 mg/kg significantly raised the electroconvulsive threshold. Further, using the isobolographic calculations, TGB was coadministered with GBP at three fixed-ratios (1 : 3, 1 : 1, and 3 : 1) of their respective protective drug doses. All examined combinations of TGB with GBP exerted supra-additive (synergistic) interactions against MEST-induced seizures in mice. The interaction index, describing the strength and magnitude of interaction, ranged between 0.25 and 0.50 indicating supra- additivity.
    [Show full text]
  • 52Nd Annual Meeting
    ACNP 52nd Annual Meeting Final Program December 8-12, 2013 The Westin Diplomat Resort & Spa Hollywood, Florida President: David A. Lewis, M.D. Program Committee Chair: Randy D. Blakely, Ph.D. Program Committee Co-Chair: Pat R. Levitt, Ph.D. This meeting is jointly sponsored by the Vanderbilt University School of Medicine Department of Psychiatry and the American College of Neuropsychopharmacology. Dear ACNP Members and Guests, It is a distinct pleasure to welcome you to the 2014 meeting of the American College of Neuropsychopharmacology! This 52nd annual meeting will again provide opportunities for the exercise of the College’s core values: the spirit of Collegiality, promoting in each other the best in science, training and service; participation in Community, pursuing together the goals of understanding the neurobiology of brain diseases and eliminating their burden on individuals and our society; and engaging in Celebration, taking the time to recognize and enjoy the contributions and accomplishments of our members and guests. Under the excellent leadership of Randy Blakely and Pat Levitt, the Program Committee has done a superb job in assembling an outstanding slate of scientific presentations. Based on membership feedback, the meeting schedule has been designed with the goals of achieving an optimal mix of topics and types of sessions, increasing the diversity of participating scientists and creating more time for informal interactions. The presentations will highlight both the breadth of the investigative interests of ACNP membership
    [Show full text]
  • Supplementary Tables, Figures and Other Documents
    Clinical Relevance of a 16-Gene Pharmacogenetic Panel Test for Medication Management in a Cohort of 135 Patients David Niedrig1,2, Ali Rahmany1,3, Kai Heib4, Karl-Dietrich Hatz4, Katja Ludin5, Andrea M. Burden3, Markus Béchir6, Andreas Serra7, Stefan Russmann1,3,7,* 1 drugsafety.ch; Zurich, Switzerland 2 Hospital Pharmacy, Clinic Hirslanden Zurich; Zurich Switzerland 3 Swiss Federal Institute of Technology Zurich (ETHZ); Zurich, Switzerland 4 INTLAB AG; Uetikon am See, Switzerland 5 Labor Risch, Molecular Genetics; Berne, Switzerland 6 Center for Internal Medicine, Clinic Hirslanden Aarau; Aarau, Switzerland 7 Institute of Internal Medicine and Nephrology, Clinic Hirslanden Zurich; Zurich, Switzerland * Correspondence: [email protected]; Tel.: +41 (0)44 221 1003 Supplementary Tables, Figures and Other Documents Figure S1: Example of credit-card sized pharmacogenomic profile issued to patients 1 Table S2: SNPs analyzed by the 16-gene panel test Gene Allele rs number ABCB1 Haplotypes 1236-2677- rs1045642 ABCB1 3435 rs1128503 ABCB1 rs2032582 COMT Haplotypes 6269-4633- rs4633 COMT 4818-4680 rs4680 COMT rs4818 COMT rs6269 CYP1A2 *1C rs2069514 CYP1A2 *1F rs762551 CYP1A2 *1K rs12720461 CYP1A2 *7 rs56107638 CYP1A2 *11 rs72547513 CYP2B6 *6 rs3745274 CYP2B6 *18 rs28399499 CYP2C19 *2 rs4244285 CYP2C19 *3 rs4986893 CYP2C19 *4 rs28399504 CYP2C19 *5 rs56337013 CYP2C19 *6 rs72552267 CYP2C19 *7 rs72558186 CYP2C19 *8 rs41291556 CYP2C19 *17 rs12248560 CYP2C9 *2 rs1799853 CYP2C9 *3 rs1057910 CYP2C9 *4 rs56165452 CYP2C9 *5 rs28371686 CYP2C9 *6 rs9332131 CYP2C9
    [Show full text]
  • Shared Care Guideline for Tiagabine (Gabitril®) for Use As Add on Therapy for Partial Seizures in Adults and Children Over 12
    Dorset Medicines Advisory Group SHARED CARE GUIDELINE FOR TIAGABINE (GABITRIL®) FOR USE AS ADD ON THERAPY FOR PARTIAL SEIZURES IN ADULTS AND CHILDREN OVER 12 INDICATION Licensed indications & therapeutic class Tiagabine is an anti-epileptic drug indicated as add-on therapy for partial seizures with or without secondary generalisation where control is not achieved by optimal doses of at least one other anti- epileptic drug. Tiagabine is licensed only for use in adults and children over the age of 12. It is not licensed for monotherapy. NICE CG137: Epilepsies: diagnosis and management (page 26) states: Offer carbamazepine, clobazam, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, sodium valproate or topiramate as adjunctive treatment to children, young people and adults with focal seizures if first-line treatments [carbamazepine or lamotrigine, levetiracetam, oxcarbazepine or sodium valoprate] are ineffective or not tolerated. If adjunctive treatment is ineffective or not tolerated, discuss with, or refer to, a tertiary epilepsy specialist. Other AEDs that may be considered by the tertiary epilepsy specialist are eslicarbazepine acetate, lacosamide, phenobarbital, phenytoin, pregabalin, tiagabine, vigabatrin and zonisamide. Carefully consider the risk–benefit ratio when using vigabatrin because of the risk of an irreversible effect on visual fields. NICE also has a “Do not do” recommendation in relation to tiagabine: “Do not offer carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine or vigabatrin as adjunctive treatment in children, young people and adults with childhood absence epilepsy, juvenile absence epilepsy or other absence epilepsy syndromes.” AREAS OF RESPONSIBILITY FOR SHARED CARE Patients should be at the centre of any shared care arrangements. Individual patient information and a record of their preferences should accompany shared care prescribing guidelines, where appropriate.
    [Show full text]
  • The Use of Stems in the Selection of International Nonproprietary Names (INN) for Pharmaceutical Substances
    WHO/PSM/QSM/2006.3 The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances 2006 Programme on International Nonproprietary Names (INN) Quality Assurance and Safety: Medicines Medicines Policy and Standards The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 © World Health Organization 2006 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: [email protected]). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
    [Show full text]
  • Predicting Drug Interactions from Dissolution Studies
    PREDICTING DRUG INTERACTIONS FROM DISSOLUTION STUDIES Imre Klebovich Semmelweis University Department of Pharmaceutics Disso India – Goa 2015 International Annual Symposium on Dissolution Science 31 st August– 1st September, 2015, Goa, India THE BASIC LOGIC OF NOVEL DRUG RESEARCH CONCEPT in-celebro in-silico in-vitro in-vivo MAIN TYPES OF DRUG INTERACTIONS - Drug - Food - Alcohol Pleasure-giving - Smoking materials - Caffeine Drug - Transporters Interactions - Pharmacogenomics - Psychoactive drugs - Antacid and inhibitor of gastric juice secretion DRUG-FOOD INTERACTION COMPARISON ON IN VITRO DISSOLUTION AND IN VIVO HUMAN ABSORPTION PARAMETERS ON FIVE DIFFERENT ORAL FLUMECINOL PREPARATIONS CHEMICAL STRUCTURE OF FLUMECINOL (ZIXORYNR) hepatic enzyme inducer (CYP-450 2B1) METHOD OF FORMULATION OF DIFFERENT ORAL FLUMECINOL PREPARATIONS Symbol Formulation Methodfortechnology adsorbate in hard absorption of flumecinol on O—O Adsorbate gelatine capsule the surface of silicium dioxide microcapsules in hard microencapsulation by Δ—Δ Microcapsules gelaine capsule coacervation technique ß-cyclodextrine inclusion complexation by x—x tablet inclusion complex ß-cyclodextrine micropellets in hard forming of micropellets by a □—□ Micropellets I. gelaine capsule I. centrifugal granulator micropellets in hard forming of micropellets by a ●—● Micropellets II. gelaine capsule II. centrifugal granulator MEAN CUMULATIVE PERCENT OF FLUMECINOL IN VITRO DISSOLVED AT PH 1.2 OF FIVE FORMULATIONS PHARMACOKINETIC CURVES OF FLUMECINOL IN HUMAN AFTER 100 MG SINGLE ORAL
    [Show full text]
  • An Open-Label Study to Evaluate Switching from an SSRI Or SNRI To
    Annals of Clinical Psychiatry, 19[1]:25–30, 2007 Copyright © American Academy of Clinical Psychiatrists ISSN: 1040-1237 print / 1547-3325 online DOI: 10.1080/10401230601163535 AnUACP Open-Label Study to Evaluate Switching from an SSRI or SNRI to Tiagabine to Alleviate Antidepressant- Induced Sexual Dysfunction in Generalized Anxiety Disorder THOMASEffect of Tiagabine on sexual dysfunction in GAD L. SCHWARTZ, MD Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA GEORGE S. NASRA, MD Unity Behavioral Health, Rochester, NY, USA ADAM K. ASHTON, MD Department of Psychiatry, SUNY Buffalo School of Medicine, Buffalo, NY, USA DAVID KANG, MD, HARI KUMARESAN, MD, MARK CHILTON, MS, and FRANCESCA BERTONE, BA Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA Background. This study investigated tiagabine monotherapy in subjects with generalized anxiety disorder (GAD) who had been switched from selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) as a result of antidepressant-induced sexual dysfunction. Methods. Adults with DSM-IV GAD, an adequate therapeutic response (≥50% decrease in Hamilton Rating Scale for Anxiety [HAM-A] total score) to SSRI or SNRI and sexual dysfunction were switched to open-label tiagabine 4–12 mg/day for 14 weeks. Assessments included the HAM-A, Hospital Anxiety & Depression Scale (HADS) and the Arizona Sexual Experiences Scale (ASEX); assessments were made at baseline and at Weeks 4, 8, and 14. Results. Twenty six subjects were included in the analysis. Tiagabine showed no worsening in baseline symptoms of GAD, with non-significant changes from baseline in mean HAM-A total scores and HADS Anxiety and Depression subscale scores.
    [Show full text]
  • Phd Thesis Project: Pharmacological and Toxicological Investigations of New Psychoactive Substances, Supervised by Prof
    PHARMACOLOGICAL AND TOXICOLOGICAL INVESTIGATIONS OF NEW PSYCHOACTIVE SUBSTANCES Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Dino Lüthi aus Rüderswil, Bern Basel, 2018 Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel edoc.unibas.ch Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung-Nicht kommerziell 4.0 International Lizenz (https://creativecommons.org/licenses/by-nc-sa/4.0/deed.de). Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von Prof. Stephan Krähenbühl, Prof. Matthias E. Liechti und Prof. Anne Eckert. Basel, den 26.06.2018 Prof. Martin Spiess Dekan der Philosophisch- Naturwissenschaftlichen Fakultät PHARMACOLOGICAL AND TOXICOLOGICAL INVESTIGATIONS OF NEW PSYCHOACTIVE SUBSTANCES “An adult must make his own decision as to whether or not he should expose himself to a specific drug, be it available by prescription or proscribed by law, by measuring the potential good and bad with his own personal yardstick.” ― Alexander Shulgin, Pihkal: A Chemical Love Story. PREFACE This thesis is split into a pharmacology part and a toxicology part. The pharmacology part consists of investigations on the monoamine transporter and receptor interactions of traditional and newly emerged drugs, mainly stimulants and psychedelics; the toxicology part consists of investigations on mechanisms of hepatocellular toxicity of synthetic cathinones. All research described in this thesis has been published in peer-reviewed journals, and was performed between October 2014 and June 2018 in the Division of Clinical Pharmacology and Toxicology at the Department of Biomedicine of the University Hospital Basel and University of Basel, and partly at the pRED Roche Innovation Center Basel at F.
    [Show full text]
  • GPCR/G Protein
    Inhibitors, Agonists, Screening Libraries www.MedChemExpress.com GPCR/G Protein G Protein Coupled Receptors (GPCRs) perceive many extracellular signals and transduce them to heterotrimeric G proteins, which further transduce these signals intracellular to appropriate downstream effectors and thereby play an important role in various signaling pathways. G proteins are specialized proteins with the ability to bind the nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP). In unstimulated cells, the state of G alpha is defined by its interaction with GDP, G beta-gamma, and a GPCR. Upon receptor stimulation by a ligand, G alpha dissociates from the receptor and G beta-gamma, and GTP is exchanged for the bound GDP, which leads to G alpha activation. G alpha then goes on to activate other molecules in the cell. These effects include activating the MAPK and PI3K pathways, as well as inhibition of the Na+/H+ exchanger in the plasma membrane, and the lowering of intracellular Ca2+ levels. Most human GPCRs can be grouped into five main families named; Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, and Secretin, forming the GRAFS classification system. A series of studies showed that aberrant GPCR Signaling including those for GPCR-PCa, PSGR2, CaSR, GPR30, and GPR39 are associated with tumorigenesis or metastasis, thus interfering with these receptors and their downstream targets might provide an opportunity for the development of new strategies for cancer diagnosis, prevention and treatment. At present, modulators of GPCRs form a key area for the pharmaceutical industry, representing approximately 27% of all FDA-approved drugs. References: [1] Moreira IS. Biochim Biophys Acta. 2014 Jan;1840(1):16-33.
    [Show full text]
  • Rat Animal Models for Screening Medications to Treat Alcohol Use Disorders
    ACCEPTED MANUSCRIPT Selectively Bred Rats Page 1 of 75 Rat Animal Models for Screening Medications to Treat Alcohol Use Disorders Richard L. Bell*1, Sheketha R. Hauser1, Tiebing Liang2, Youssef Sari3, Antoinette Maldonado-Devincci4, and Zachary A. Rodd1 1Indiana University School of Medicine, Department of Psychiatry, Indianapolis, IN 46202, USA 2Indiana University School of Medicine, Department of Gastroenterology, Indianapolis, IN 46202, USA 3University of Toledo, Department of Pharmacology, Toledo, OH 43614, USA 4North Carolina A&T University, Department of Psychology, Greensboro, NC 27411, USA *Send correspondence to: Richard L. Bell, Ph.D.; Associate Professor; Department of Psychiatry; Indiana University School of Medicine; Neuroscience Research Building, NB300C; 320 West 15th Street; Indianapolis, IN 46202; e-mail: [email protected] MANUSCRIPT Key Words: alcohol use disorder; alcoholism; genetically predisposed; selectively bred; pharmacotherapy; family history positive; AA; HAD; P; msP; sP; UChB; WHP Chemical compounds studied in this article Ethanol (PubChem CID: 702); Acamprosate (PubChem CID: 71158); Baclofen (PubChem CID: 2284); Ceftriaxone (PubChem CID: 5479530); Fluoxetine (PubChem CID: 3386); Naltrexone (PubChem CID: 5360515); Prazosin (PubChem CID: 4893); Rolipram (PubChem CID: 5092); Topiramate (PubChem CID: 5284627); Varenicline (PubChem CID: 5310966) ACCEPTED _________________________________________________________________________________ This is the author's manuscript of the article published in final edited form as: Bell, R. L., Hauser, S. R., Liang, T., Sari, Y., Maldonado-Devincci, A., & Rodd, Z. A. (2017). Rat animal models for screening medications to treat alcohol use disorders. Neuropharmacology. https://doi.org/10.1016/j.neuropharm.2017.02.004 ACCEPTED MANUSCRIPT Selectively Bred Rats Page 2 of 75 The purpose of this review is to present animal research models that can be used to screen and/or repurpose medications for the treatment of alcohol abuse and dependence.
    [Show full text]