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FDA Approved Drugs with Broad Anti-Coronaviral Activity Inhibit SARS-Cov-2 in Vitro
bioRxiv preprint doi: https://doi.org/10.1101/2020.03.25.008482; this version posted March 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. FDA approved drugs with broad anti-coronaviral activity inhibit SARS-CoV-2 in vitro Stuart Weston1, Rob Haupt1, James Logue1, Krystal Matthews1 and Matthew B. Frieman*1 1 - Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 W. Baltimore St., Room 380, Baltimore, MD, 21201, USA *Corresponding author. Email: [email protected] Key words: SARS-CoV-2, nCoV-2019, COVID-19, drug repurposing, FDA approved drugs, antiviral therapeutics, pandemic, chloroquine, hydroxychloroquine AbstraCt SARS-CoV-2 emerged in China at the end of 2019 and has rapidly become a pandemic with over 400,000 recorded COVID-19 cases and greater than 19,000 recorded deaths by March 24th, 2020 (www.WHO.org) (1). There are no FDA approved antivirals or vaccines for any coronavirus, including SARS-CoV-2 (2). Current treatments for COVID-19 are limited to supportive therapies and off-label use of FDA approved drugs (3). Rapid development and human testing of potential antivirals is greatly needed. A potentially quicker way to test compounds with antiviral activity is through drug re-purposing (2, 4). Numerous drugs are already approved for use in humans and subsequently there is a good understanding of their safety profiles and potential side effects, making them easier to test in COVID-19 patients. -
Antidepressants the Old and the New
Antidepressants The Old and The New October, 1998 iii In 1958 researchers discovered that imipramine had antidepressant 1 activity. Since then, a number of antidepressants have been HIGHLIGHTS developed with a variety of pharmacological mechanisms and side effect profiles. All antidepressants show similar efficacy in the treatment of depression when used in adequate dosages. Choosing the most PHARMACOLOGY & CLASSIFICATION appropriate agent depends on specific patient variables, The mechanism of action for antidepressants is not entirely clear; concurrent diseases, concurrent drugs, and cost. however they are known to interfere with neurotransmitters. Non-TCA antidepressants such as the SSRIs have become Tricyclic antidepressants (TCAs) block the reuptake of both first line agents in the treatment of depression due to their norepinephrine (NE) and serotonin (5HT). The relative ratio of relative safety and tolerability. Each has its own advantages and their effect on NE versus 5HT varies. The potentiation of NE and disadvantages for consideration in individualizing therapy. 5HT results in changes in the neuroreceptors and is thought to be TCAs may be preferred in patients who do not respond to or the primary mechanism responsible for the antidepressant effect. tolerate other antidepressants, have chronic pain or migraine, or In addition to the effects on NE and 5HT, TCAs also block for whom drug cost is a significant factor. muscarinic, alpha1 adrenergic, and histaminic receptors. The extent of these effects vary with each agent resulting in differing Secondary amine TCAs (desipramine and nortriptyline) have side effect profiles. fewer side effects than tertiary amine TCAs. Maintenance therapy at full therapeutic dosages should be Selective serotonin-reuptake inhibitors (SSRIs) block the 2 considered for patients at high risk for recurrence. -
The American Journal Of
The American Journal of Psychiatry Residents’ Journal July 2015 Volume 10 Issue 7 Inside IN THIS ISSUE 2 New Formats and New Opportunities: The Time to Get Involved is “Now”! Rajiv Radhakrishnan, M.B.B.S., M.D. 3 Prevention of Posttraumatic Stress Disorder: Predicting Response to Trauma Jennifer H. Harris, M.D. 7 Weight Gain in Patients With Schizophrenia: A Recipe For Timely Intervention Ammar El Sara, M.B.Ch.B. 10 Hyperprolactinemia and Antipsychotics: Update for the Training Psychiatrist Stephanie Pope, M.D. 13 A Clinical Case Conference on Spiritual Growth and Healing Elizabeth S. Stevens, D.O. This issue of the Residents’ Journal features a variety of topics. Jennifer H. Har- ris, M.D., discusses prevention of posttraumatic stress disorder, with an overview 15 Priapism: A Rare but Serious of various responses to trauma. Ammar El Sara, M.B.Ch.B., presents a review of Side Effect of Trazodone clinically applicable evidence-based interventions targeting obesity in schizophre- Kamalika Roy, M.D. nia patients. Stephanie Pope, M.D., examines antipsychotic-induced hyperprolac- 17 Classifying Psychopathology: tinemia, including variables affecting prolactin and clinical implications. Elizabeth Mental Kinds and Natural Kinds S. Stevens, D.O., discusses several psychological, social, and spiritual developmen- Reviewed by Aaron J. Hauptman, tal frameworks in a clinical case conference. Kamalika Roy, M.D., presents a case M.D. of priapism as a side effect of trazodone in a middle-aged patient. Lastly, Aaron J. Hauptman, M.D., offers his review of the book Classifying Psychopathology: Mental 18 Residents’ Resources Kinds and Natural Kinds. Editor-in-Chief Associate Editors Editors Emeriti Rajiv Radhakrishnan, M.B.B.S., M.D. -
Detecting Depression and Anxiety in Older Adults
Detecting Depression and Anxiety in Older Adults Dr Nick Woodthorpe Depression in Older Adults Introduction to Depression • 1 in 5 older people living in the community • 2 in 5 living in care homes Causes of Depression • Painful events • Past depression or family history • Personality • Physical illness • Medicines • Drugs and Alcohol • Loneliness Particular Issues in Depression • Physical symptoms, for example, thyroid problems, heart disease or arthritis. • Long-term illness • Confusion and memory problems • A new sense of loneliness/lack of purpose Depression - Symptoms • 2 weeks • No hypomania or mania • No psychoactive drugs • No organic mental disorder Depression - Symptoms • Feeling low or sad (they may not report this) • Loss of interest in life • Low energy and tired for no reason Depression - Symptoms • Change in appetite and weight • Restlessness or psychomotor retardation • Anxious • Avoidance • Irritable • Sleep disturbance • Loss of confidence and self-esteem Depression - Symptoms • Hopelessness and worthlessness • Poor concentration • Panicky • Loss of libido • Sense of guilt • Suicidal thoughts • Delusions or hallucinations Depression - Diagnostic Categories • Mild • Moderate • Severe with or without psychosis • Recurrent Anxiety in Later Life Everyone gets anxious sometimes Everyone gets anxious sometimes Fight or Flight Response Fight or Flight Response Causes of anxiety in later life • Painful events • Stress • Past experiences- upbringing/Childhood • Personality • Physical illness • Medicines • Diet - caffeine, excess -
Adverse Effects of First-Line Pharmacologic Treatments of Major Depression in Older Adults
Draft Comparative Effectiveness Review Number xx Adverse Effects of First-line Pharmacologic Treatments of Major Depression in Older Adults Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 5600 Fishers Lane Rockville, MD 20857 www.ahrq.gov This information is distributed solely for the purposes of predissemination peer review. It has not been formally disseminated by the Agency for Healthcare Research and Quality. The findings are subject to change based on the literature identified in the interim and peer-review/public comments and should not be referenced as definitive. It does not represent and should not be construed to represent an Agency for Healthcare Research and Quality or Department of Health and Human Services (AHRQ) determination or policy. Contract No. 290-2015-00012I Prepared by: Will be included in the final report Investigators: Will be included in the final report AHRQ Publication No. xx-EHCxxx <Month, Year> ii Purpose of the Review To assess adverse events of first-line antidepressants in the treatment of major depressive disorder in adults 65 years or older. Key Messages • Acute treatment (<12 weeks) with o Serotonin norepinephrine reuptake inhibitors (SNRIs) (duloxetine, venlafaxine), but not selective serotonin reuptake inhibitors (SSRIs) (escitalopram, fluoxetine) led to a greater number of adverse events compared with placebo. o SSRIs (citalopram, escitalopram and fluoxetine) and SNRIs (duloxetine and venlafaxine) led to a greater number of patients withdrawing from studies due to adverse events compared with placebo o Details of the contributing adverse events in RCTs were rarely reported to more clearly characterize what adverse events to expect. -
Association of Selective Serotonin Reuptake Inhibitors with the Risk for Spontaneous Intracranial Hemorrhage
Supplementary Online Content Renoux C, Vahey S, Dell’Aniello S, Boivin J-F. Association of selective serotonin reuptake inhibitors with the risk for spontaneous intracranial hemorrhage. JAMA Neurol. Published online December 5, 2016. doi:10.1001/jamaneurol.2016.4529 eMethods 1. List of Antidepressants for Cohort Entry eMethods 2. List of Antidepressants According to the Degree of Serotonin Reuptake Inhibition eMethods 3. Potential Confounding Variables Included in Multivariate Models eMethods 4. Sensitivity Analyses eFigure. Flowchart of Incident Antidepressant (AD) Cohort Definition and Case- Control Selection eTable 1. Crude and Adjusted Rate Ratios of Intracerebral Hemorrhage Associated With Current Use of SSRIs Relative to TCAs eTable 2. Crude and Adjusted Rate Ratios of Subarachnoid Hemorrhage Associated With Current Use of SSRIs Relative to TCAs eTable 3. Crude and Adjusted Rate Ratios of Intracranial Extracerebral Hemorrhage Associated With Current Use of SSRIs Relative to TCAs. eTable 4. Crude and Adjusted Rate Ratios of Intracerebral Hemorrhage Associated With Current Use of Antidepressants With Strong Degree of Inhibition of Serotonin Reuptake Relative to Weak eTable 5. Crude and Adjusted Rate Ratios of Subarachnoid Hemorrhage Associated With Current Use of Antidepressants With Strong Degree of Inhibition of Serotonin Reuptake Relative to Weak eTable 6. Crude and Adjusted Rate Ratios of Intracranial Extracerebral Hemorrhage Associated With Current Use of Antidepressants With Strong Degree of Inhibition of Serotonin Reuptake Relative to Weak This supplementary material has been provided by the authors to give readers additional information about their work. © 2016 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 eMethods 1. -
Doxepin (Dox-E-Pin) Description: Tricyclic Antidepressant; Antihistamine Other Names for This Medication: Sinequan®, Silenor® Common Dosage Forms: Veterinary: None
Prescription Label Patient Name: Species: Drug Name & Strength: Directions (amount to give how often & for how long): Prescribing Veterinarian's Name & Contact Information: Refills: [Content to be provided by prescribing veterinarian] Doxepin (dox-e-pin) Description: Tricyclic Antidepressant; Antihistamine Other Names for this Medication: Sinequan®, Silenor® Common Dosage Forms: Veterinary: None. Human: 3 mg, 6 mg, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, & 150 mg capsules; 10 mg/mL oral liquid concentrates. This information sheet does not contain all available information for this medication. It is to help answer commonly asked questions and help you give the medication safely and effectively to your animal. If you have other questions or need more information about this medication, contact your veterinarian or pharmacist. Key Information When used as an antihistamine, doxepin should be used on a regular, ongoing basis in animals that respond to it. This drug works better if used before exposure to an allergen (eg, pollens). When used for behavior modification, it may take several days to weeks to determine if doxepin is effective. May be given with or without food. If your animal vomits or acts sick after receiving the drug on an empty stomach, try giving the next dose with food or a small treat. If vomiting continues, contact your veterinarian. Most common side effects are sleepiness, dry mouth, and constipation. Be sure your animal always has access to plenty of fresh, clean water. Rare side effects that can be serious (contact veterinarian immediately) include abnormal bleeding, lack of an appetite, seizures, collapse, or profound sleepiness. -
Diagnosis and Management of Post-Traumatic Stress Disorder BRADLEY D
Diagnosis and Management of Post-traumatic Stress Disorder BRADLEY D. GRINAGE, M.D., University of Kansas School of Medicine–Wichita, Wichita, Kansas Although post-traumatic stress disorder (PTSD) is a debilitating anxiety disorder that may cause significant distress and increased use of health resources, the condition O A patient informa- often goes undiagnosed. The lifetime prevalence of PTSD in the United States is 8 to tion handout on post- traumatic stress disor- 9 percent, and approximately 25 to 30 percent of victims of significant trauma der, written by the develop PTSD. The emotional and physical symptoms of PTSD occur in three clusters: author of this article, re-experiencing the trauma, marked avoidance of usual activities, and increased is provided on page symptoms of arousal. Before a diagnosis of PTSD can be made, the patient’s symp- 2409. toms must significantly disrupt normal activities and last for more than one month. Approximately 80 percent of patients with PTSD have at least one comorbid psychi- atric disorder. The most common comorbid disorders include depression, alcohol and drug abuse, and other anxiety disorders. Treatment relies on a multidimensional approach, including supportive patient education, cognitive behavior therapy, and psychopharmacology. Selective serotonin reuptake inhibitors are the mainstay of pharmacologic treatment. (Am Fam Physician 2003;68:2401-8,2409. Copyright© 2003 American Academy of Family Physicians) ost-traumatic stress disorder Background (PTSD) is an anxiety disorder The psychologic effects of trauma have that occurs following exposure to been described throughout military history. a traumatic event. The disorder Da Costa syndrome (“soldier’s heart”), which has not been extensively studied is characterized by cardiac symptoms associ- Pin primary care; however, the events of Sep- ated with irritability and increased arousal, tember 11, 2001, raised both public and pro- was described in veterans of the American fessional awareness of PTSD. -
Pharmacotherapy of Post-Traumatic Stress Disorder: Going Beyond the Guidelines Jonathan Davidson
BJPsych Open (2016) 2, e16–e18. doi: 10.1192/bjpo.bp.116.003707 Editorial Pharmacotherapy of post-traumatic stress disorder: going beyond the guidelines Jonathan Davidson Summary royalties in connection with publications by Springer, Guilford This article discusses the study of Harpaz-Rotem and associates, and McFarland Publishers and use of the Connor-Davidson who examined patterns of medication use in first-diagnosed Resilience Scale, Davidson Trauma Scale, Social Phobia veterans with post-traumatic stress disorder (PTSD). It considers Inventory (SPIN) and Mini-SPIN; service on the INTRuST Data the difference between practice guidelines and actual Safety and Monitoring Board, University of California, San prescribing; selectively identifies issues with antidepressants, Diego. antipsychotics, benzodiazepines and prazosin; and reviews the possible impact of new medications in the pipeline. Copyright and usage © The Royal College of Psychiatrists 2016. This is an open Declaration of interests access article distributed under the terms of the Creative In the past 36 months, J.D. has received compensation for Commons Non-Commercial, No Derivatives (CC BY-NC-ND) consulting with Edgemont, Turing and Tonix Pharmaceuticals; license. For some decades, there has been steady progress in the treatment Each drug group will be considered in turn, the matter of of post-traumatic stress reactions. The growth of evidence-based polypharmacy will be discussed, and concluding remarks will medicine over the past 20 years has placed a premium on ran‐ sketch out five ways in which pharmacotherapy advances might domised controlled trials (RCTs), which are typically based on impact the treatment of PTSD. samples that do not represent real-world clinical practice. -
The Role of Tricyclic Drugs in Selective Triggering of Mitochondrially-Mediated Apoptosis in Neoplastic Glia: a Therapeutic Option in Malignant Glioma?
Radiol Oncol 2006; 40(2): 73-85. review The role of tricyclic drugs in selective triggering of mitochondrially-mediated apoptosis in neoplastic glia: a therapeutic option in malignant glioma? Geoffrey J. Pilkington1, James Akinwunmi2 and Sabrina Amar1 1Cellular & Molecular Neuro-Oncology Group, School of Pharmacy & Biomedical Sciences, Institute of Biomedical & Biomolecular Sciences, University of Portsmouth, Portsmouth and 2Hurstwood Park Neurological Centre, Haywards Heath West Sussex, UK We have previously demonstrated that the tricyclic antidepressant, Clomipramine, exerts a concentration- dependant, tumour cell specific, pro-apoptotic effect on human glioma cells in vitro and that this effect is not mirrored in non-neoplastic human astrocytes. Moreover, the drug acts by triggering mitochondrially-media- ted apoptosis by way of complex 3 of the respiratory chain. Here, through reduced reactive oxygen species and neoplastic cell specific, altered membrane potential, cytochrome c is released, thereby activating a cas- pase pathway to apoptosis. In addition, while we and others have shown that further antidepressants, in- cluding those of the selective serotonin reuptake inhibitor (SSRI) group, also mediate cancer cell apoptosis in both glioma and lymphoma, clomipramine appears to be most effective in this context. More recently, oth- er groups have reported that clomipramine causes apoptosis, preceded by a rapid increase in p-c-Jun levels, cytochrome c release from mitochondria and increased caspase-3-like activity. In addition to clomipramine we have investigated the possible pro-apoptotic activity of a range of further tricyclic drugs. Only two such agents (amitriptyline and doxepin) showed a similar, or better, effect when compared with clomipramine. Since both orally administered clomipramine and amitriptyline are metabolised to desmethyl clomipramine (norclomipramine) and nortriptyline respectively it is necessary for testing at a tumour cell level to be car- ried out with both the parent tricyclic and the metabolic product. -
Clomipramine 25 Mg Capsules, Hard
Package leaflet: Information for the patient Other medicines and Clomipramine Tell your doctor if you are taking, have recently Clomipramine 10 mg Capsules, Hard taken or might take any other medicines. Clomipramine 25 mg Capsules, Hard Some medicines may increase the side effects of Clomipramine 50 mg Capsules, Hard Clomipramine and may sometimes cause very clomipramine hydrochloride serious reactions. Do not take any other medicines whilst taking Clomipramine without first talking to Read all of this leaflet carefully before you your doctor, especially: start taking this medicine because it contains - medicines for depression, particularly MAOIs (see important information for you. section “Do not take” above) e.g. tranylcypromine, - Keep this leaflet. You may need to read it again. phenelzine, moclobemide; SSRIs e.g. fluoxetine (or - If you have any further questions, ask your have taken within the last 3 weeks), fluvoxamine, doctor or pharmacist. paroxetine, sertraline; SNaRIs e.g. venlafaxine; - This medicine has been prescribed for you only. tricyclic and tetracyclic antidepressants e.g. Do not pass it on to others. It may harm them, amitriptyline, dothiepin, maprotiline even if their signs of illness are the same as yours. - diuretics, also known as ‘water tablets’, e.g. - If you get any side effects, talk to your doctor bendroflumethiazide, furosemide or pharmacist. This includes any possible side - anaesthetics, used for the temporary loss of effects not listed in this leaflet. See section 4. bodily sensation - antihistamines e.g. terfenadine What is in this leaflet - medicines for other mental health conditions 1. What Clomipramine is and what it is used for. such as schizophrenia or manic depression 2. -
3,2,4 Tricyclic Antidepressants and the Risk of Congenital Malformation
Tricyclic antidepressants and the risk of congenital malformations CONFIDENTIAL Medicines Adverse Reactions Committee Meeting date 3/12/2020 Agenda item 3.2.4 Title Tricyclic antidepressants and the risk of congenital malformations Submitted by Medsafe Pharmacovigilance Paper type For advice Team Active ingredient Product name Sponsor Amitriptyline Arrow-Amitriptyline Film coated tablet, 10 mg, 25 Teva Pharm (NZ) Ltd mg & 50 mg Amirol Film coated tablet, 10 mg & 25 mg AFT Pharmaceuticals Ltd Clomipramine Apo-Clomipramine Film coated tablet, 10 mg & Apotex NZ Ltd 25 mg Anafranil Tablet, 10 mg Section 29 Dosulepin Dosulepin Mylan Film coated tablet, 75 mg Mylan New Zealand Ltd Dosulepin Mylan Capsule, 25 mg Section 29 Doxepin Anten 50 Capsule, 50 mg Mylan New Zealand Ltd Imipramine Tofranil Coated tablet, 10 mg & 25 mg AFT Pharmaceuticals Ltd Nortriptyline Norpress Tablet, 10 mg & 25 mg Mylan New Zealand Ltd PHARMAC funding Product highlighted in bold above are funded on the Community Schedule. Two products (shown in italics) are funded but only available under Section 29 of the Medicines Act (ie, the products have not been approved by Medsafe). Previous MARC In utero exposure to serotonin reuptake inhibitors and risk of congenital meetings abnormalities 141st meeting March 2010 International action None Prescriber Update The use of antidepressants in pregnancy September 2010 Classification Prescription medicine Usage data The following pregnancy usage data for 2019 was obtained from the National Collections using the Pharmaceutical Dispensing in Pregnancy application in Qlik. The table shows the total number of dispensings, repeat dispensings and number of pregnancies exposed during first trimester (defined as 30 days prior to the estimated pregnancy start date to week 13) for pregnancies that ended in 2019.