DOCSLIB.ORG

DOCTORAL THESIS Effects of Glucocorticoid Overload on Central

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
DOCTORAL THESIS Effects of Glucocorticoid Overload on Central DOCTORAL THESIS Effects of glucocorticoid overload on central regulatory systems involved in responses to stress – preclinical investigations into putative molecular targets in neuroimaging of stress-related mood disorders Ahmad, Rabia Award date: 2013 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 07. Oct. 2021 “Effects of glucocorticoid overload on central regulatory systems involved in responses to stress – preclinical investigations into putative molecular targets in neuroimaging of stress-related mood disorders” By Rabia Ahmad, BSc (Hons). A thesis submitted in partial fulfilment of the requirements for the degree of PhD Department of Life Sciences University of Roehampton 2013 Abstract Irregularities of the Hypothalamic Pituitary Adrenal (HPA) axis are implicated in stress-related mood disorders. The ensuing long-term elevations in circulating glucocorticoids are associated with neurobiological changes seen in depression. This thesis aims to identify some of the brain mechanisms by which exposure to chronic stress may lead to depression using a preclinical experimental approach. The role of the serotonin system in the aetiology of mood disorders is well established, although this is not considered to be the only factor which causes these mood disorders. Interactions between the serotoninergic, peptidergic and endocannabinoid systems in response to glucocorticoids have been proposed. As all three neurotransmitter systems are involved in the regulation of the HPA axis, they are implicated in the dysfunction which is seen in depression. Furthermore, oxytocin, vasopressin and endocannabinoids are known to influence serotonergic neurotransmission and therefore it is pertinent to understand how glucocorticoids directly and indirectly impact serotonergic neurotransmission. In this thesis, the effect of chronic exposure to corticosterone on the serotonergic system is determined and also the relative contribution of the peptidergic and endocannabinoid systems to stress-induced mood disorders is considered. In addition, glucocorticoid-dependant receptor changes in these systems are related to neurotransmitter activity in brain regions involved in responses to stress. This has not previously been studied nor have the simultaneous effects of glucocorticoids on the serotonergic, peptidergic and endocannabinoid systems. 1 Here, preclinical approaches are applied to investigate the above mentioned receptor systems and their involvement in depression resulting from exposure to chronic stress. Administration of exogenous corticosterone (400 µg/mL) to rats for 21 days, via addition to drinking water, resulted in changes in expression of central 5-HT1A, oxytocin, vasopressin 1a and CB1 receptors. This dose was selected as it has previously shown to induce depression-like behaviour in rats and also hippocampal atrophy similar to that seen in depressed patients (Magarinos et al 1998; Donner et al., 2012). In order to understand how these changes relate to the central concentrations of endogenous ligands, the concentration of serotonin, 5-HIAA, oxytocin and vasopressin was also measured in brain tissue. Here, circulating corticosterone concentration was increased, as it is in chronic stress and in some depressed patients. Binding of the post synaptic 5- HT1A receptor was upregulated in response to chronic stress in the form of elevated corticosterone concentration without a concomitant change in serotonin turnover suggesting that elevated corticosterone exposure modulates the 5-HT1A receptor independently of serotonin turnover. Whereas presynaptic 5-HT1A receptor binding was unaffected. In addition, chronic corticosterone exposure, as can be seen in depression, resulted in a decrease in binding to the oxytocin receptor in the hypothalamus associated with an increase in oxytocin concentration suggesting possible internalisation of the oxytocin receptor in this region. Conversely, there was an upregulation of the oxytocin receptor in the septal nuclei and raphé, with no associated change in oxytocin content in the same regions. Moreover, vasopressin 1a receptor binding was increased in septal nuclei and PODG subregion of the dorsal hippocampus, but decreased in the 2 hypothalamus. There was no change in vasopressin content in any brain region sampled, suggesting that these may be independent of peptide concentration. For the CB1 receptor, elevated corticosterone concentration, indicative of chronic stress, resulted in a decrease in receptor binding was found in the striata and raphé after chronic corticosterone treatment. Taken together, in particular the effect on receptor binding in the raphé, the present data suggest that elevated corticosterone exposure may modulate serotonergic neurotransmission via the oxytocin and CB1 receptor. In addition, the hypothalamic peptidergic responses imply a potential role in glucocorticoid- induced dysregulation of the HPA axis. These changes may help further elucidate their respective roles in depression and stress related mood disorders. In conclusion, the work presented in this thesis shows that the response to glucocorticoids is multifaceted and that there are changes observed in multiple neurotransmitter systems which regulate the HPA axis. Thus, the combined effect of the neurotransmitter systems studied here is of relevance to stress related mood disorders. 3 Acknowledgments This thesis would not have been possible without the help of many people to whom I am indebted. Firstly, I would like to thank my supervisors Dr Jolanta Opacka-Juffry and Dr Ella Hirani, both have provided immense support and guidance. This work would not have been completed without their encouragement and advice throughout, and in all aspects of the work. I would also like to thank Dr Kevin Murphy of Imperial College, School of Medicine for his help, and scientific guidance. His in depth knowledge of the neuropeptidergic system has been most helpful and I am also grateful for the opportunity to work in his lab. I am also thankful for the help of Dr Leksi Cokoromo and Mrs Josephine Symons at Roehampton University for their assistance in the use of the lab equipment. I am grateful to GE Healthcare for allowing me to partake in this study. In particular, to Drs. Ian Wilson and Matthew Morrison, for providing me the opportunity to develop my scientific career further, and funding the study. Many thanks also to all my colleagues and friends, who have provided friendship and support on a daily basis. Amongst many, I would like to give special mention to Anjna Rising and Drs. James Whiteside and Kamlesh Chauhan for their encouragement. Thank you for the words of kindness that have kept me motivated. I am forever grateful and indebted to my family without whom; this would never have been possible. Especially, my parents, sisters and extended family for their prayers and support. I would like to thank my children, Tahir and Hashim, for their patience during the past few years and for enduring the demands of this undertaking. Finally, very special thanks to my husband, Umer, for his understanding, love, support and patience. I am truly grateful for his continued support of my career choices and sharing the highs and lows. 4 Declaration I declare that all the work in this thesis is original and my own work except where otherwise specified. Rabia Ahmad 5 Table of Contents Abbreviations 13 Chapter 1 General Introduction 16 1.1 Aims and Hypothesis 17 1.1.1 Aims 17 1.1.2 Hypothesis 20 1.2 Outline of thesis 21 Chapter 2 Depression and anxiety as stress related disorders 23 2.1 Different types of depression 24 2.1.1 Diagnosis of depression 25 2.1.2 Factors causing depression 27 2.1.3 Neurobiology of depression 29 2.1.3.1 Neuroimaging in depression 30 2.1.3.2 Neurochemistry of glucocorticoid related depression 32 2.2 Stress 33 2.2.1 Homeostasis, allostasis and allostatic load 34 2.2.2 Hypothalamic Pituitary Adrenal Axis (HPA axis) 35 2.2.3 Regulation of HPA axis - Negative feedback mechanism 40 2.2.4 Diseases associated with HPA axis dysfunction 41 Chapter 3 Neurotransmitter systems involved in stress related depression 44 3.1 Introduction 45 3.2 The serotonergic system 47 3.2.1 The 5-HT1A receptor 50 3.2.2 Serotonergic system and depression 52 3.3 The neuropeptidergic system 55 3.3.1 The oxytocinergic neuromodulatory system 58 3.3.1.1 The oxytocin receptor 60 3.3.1.2 Oxytocin and depression 61 3.3.2 The vasopressinergic neuromodulatory system 64 3.3.2.1 The vasopressin receptors 65 3.3.2.2 Vasopressin and depression 66 3.4 The endocannabinoid system 68 3.4.1 The endocannabinoid receptors 70 3.4.2 Endocannabinoids and depression 72 6 Chapter 4 General Methodology 75 4.1 Introduction 77 4.2 Study design used in thesis 77 4.2.1 Ethical considerations 78 4.1.3 Exposure to corticosterone in
Load more

Recommended publications
  • Cochrane Database of Systematic Reviews
    Fluphenazine decanoate (depot) and enanthate for schizophrenia Author Maayan, Nicola, Quraishi, Seema N, David, Anthony, Jayaswal, Aprajita, Eisenbruch, Maurice, Rathbone, John, Asher, Rosie, Adams, Clive E Published 2015 Journal Title Cochrane Database of Systematic Reviews Version Version of Record (VoR) DOI https://doi.org/10.1002/14651858.CD000307.pub2 Copyright Statement © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. This review is published as a Cochrane Review in the Cochrane Database of Systematic Reviews 2015, Issue 2. Art. No.: CD000307. Cochrane Reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and the Cochrane Database of Systematic Reviews should be consulted for the most recent version of the Review. Downloaded from http://hdl.handle.net/10072/391173 Griffith Research Online https://research-repository.griffith.edu.au Cochrane Library Cochrane Database of Systematic Reviews Fluphenazine decanoate (depot) and enanthate for schizophrenia (Review) Maayan N, Quraishi SN, David A, Jayaswal A, Eisenbruch M, Rathbone J, Asher R, Adams CE Maayan N, Quraishi SN, David A, Jayaswal A, Eisenbruch M, Rathbone J, Asher R, Adams CE. Fluphenazine decanoate (depot) and enanthate for schizophrenia. Cochrane Database of Systematic Reviews 2015, Issue 2. Art. No.: CD000307. DOI: 10.1002/14651858.CD000307.pub2. www.cochranelibrary.com Fluphenazine decanoate (depot) and enanthate for schizophrenia (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley
    [Show full text]
  • Booklet 4 Stimulants Preface
    4 STIMULANTS 4 STIMULANTS 2019 2019 © United Nations, June 2019. All rights reserved worldwide. ISBN: 978-92-1-148314-7 eISBN: 978-92-1-004174-4 United Nations publication, Sales No. E.19.XI.8 This publication may be reproduced in whole or in part and in any form for educational or non-profit purposes without special permission from the copyright holder, provided acknowledgement of the source is made. The United Nations Office on Drugs and Crime (UNODC) would appreciate receiving a copy of any publication that uses this publication as a source. Suggested citation: World Drug Report 2019 (United Nations publication, Sales No. E.19.XI.8). No use of this publication may be made for resale or any other commercial purpose whatsoever without prior permission in writing from UNODC. Applications for such permission, with a statement of purpose and intent of the reproduction, should be addressed to the Research and Trend Analysis Branch of UNODC. DISCLAIMER The content of this publication does not necessarily reflect the views or policies of UNODC or contributory organizations, nor does it imply any endorsement. Comments on the report are welcome and can be sent to: Division for Policy Analysis and Public Affairs United Nations Office on Drugs and Crime PO Box 500 1400 Vienna Austria Tel: (+43) 1 26060 0 Fax: (+43) 1 26060 5827 E-mail: [email protected] Website: www.unodc.org/wdr2019 PREFACE The findings of this year’s World Drug Report fill in same time clamping down on organized crime and and further complicate the global picture of drug trafficking.
    [Show full text]
  • Multimodality Molecular Imaging of Inflammation and Fibrosis in Pressure Overload-Induced Heart Failure and After Mechanical Ventricular Unloading
    University of Veterinary Medicine Hannover Multimodality Molecular Imaging of Inflammation and Fibrosis in Pressure Overload-Induced Heart Failure and After Mechanical Ventricular Unloading INAUGURAL - DISSERTATION in fulfillment of the requirements of the degree of Doctor of Veterinary Medicine -Doctor medicinae veterinariae- (Dr. med. vet.) submitted by Aylina Glasenapp Kaltenkirchen Hannover 2020 Scientific supervision: Prof. Dr. med. vet. Marion Bankstahl Central Animal Facility and Institute for Laboratory Animal Science, Hannover Medical School Prof. Dr. med. Frank Michael Bengel Department of Nuclear Medicine, Hannover Medical School PD Dr. med. Katja Derlin Department of Radiology, Hannover Medical School James Thomas Thackeray, PhD Department of Nuclear Medicine, Hannover Medical School 1st supervisors: Prof. Dr. med. vet. Marion Bankstahl Prof. Dr. med. Frank Michael Bengel PD Dr. med. Katja Derlin 2nd supervisor: Prof. Dr. med. vet. Michael Fehr Clinic for Small Mammals, Reptiles and Birds, University of Veterinary Medicine Hannover Day of the oral examination: 11.05.2020 Table of Contents 1.1 Previously Published Parts of This Thesis ............................................................... V 1.2 List of Abbreviations ............................................................................................. VII 1.3 List of Figures .......................................................................................................... IX 1.4 List of Tables ...........................................................................................................
    [Show full text]
  • Use of Sildenafil in Patients with Cardiovascular Disease
    Arq Bras Cardiol GuimarãesReview et al volume 73, (nº6), 1999 Sildenafil in patients with cardiovascular disease Use of Sildenafil in Patients with Cardiovascular Disease Armênio Costa Guimarães, Marcus Vinícius Bolívar Malachias, Otávio Rizzi Coelho, Emílio Cesar Zilli, Rafael Leite Luna Introduction of phosphodiesterase inhibitors. The erectile action of sildenafil combines increase in arterial flow with reduction Erectile dysfunction, formerly called impotence, is the in the venous flow of cavernous body of penis. Sildenafil inability of the male to achieve or maintain penile erection and leads to relaxation of smooth muscle of penile arteries and thus engage in coitus1. It is common among patients with trabeculae surrounding the sinusoidal spaces, resulting in cardiovascular diseases or their risk factors. This dysfunc- a greater engorgement of cavernous body. The trabeculae tion occurs mainly among individuals with coronary artery of engorged sinusoidal spaces compress the penile disease, after episodes of acute ischemic syndrome, hyper- venules against the tunica albuginea, reducing venous tensive patients underpharmacologic treatment, and among flow, contributing to maintenance of engorgement of patients with heart failure. In approximately 85% of these ca- cavernous body8. Relaxation of this smooth muscle ses, the fear of a cardiac event during coitus constitutes an results from a decrease in intracellular calcium mediated important factor for erectile dysfunction 2-4. by accumulation of the second messenger, the cyclic Discovery of sildenafil citrate has represented a great de- guanosine monophosphate (cGMP), whose production velopment in the treatment of erectile dysfunction; it may results from activation of guanyl cyclase by nitric oxide benefit, among many others, those patients with cardiovascu- produced by the stimulus of endothelial cells generated lar diseases or with their risk factors 5.
    [Show full text]
  • Guideline for Preoperative Medication Management
    Guideline: Preoperative Medication Management Guideline for Preoperative Medication Management Purpose of Guideline: To provide guidance to physicians, advanced practice providers (APPs), pharmacists, and nurses regarding medication management in the preoperative setting. Background: Appropriate perioperative medication management is essential to ensure positive surgical outcomes and prevent medication misadventures.1 Results from a prospective analysis of 1,025 patients admitted to a general surgical unit concluded that patients on at least one medication for a chronic disease are 2.7 times more likely to experience surgical complications compared with those not taking any medications. As the aging population requires more medication use and the availability of various nonprescription medications continues to increase, so does the risk of polypharmacy and the need for perioperative medication guidance.2 There are no well-designed trials to support evidence-based recommendations for perioperative medication management; however, general principles and best practice approaches are available. General considerations for perioperative medication management include a thorough medication history, understanding of the medication pharmacokinetics and potential for withdrawal symptoms, understanding the risks associated with the surgical procedure and the risks of medication discontinuation based on the intended indication. Clinical judgement must be exercised, especially if medication pharmacokinetics are not predictable or there are significant risks associated with inappropriate medication withdrawal (eg, tolerance) or continuation (eg, postsurgical infection).2 Clinical Assessment: Prior to instructing the patient on preoperative medication management, completion of a thorough medication history is recommended – including all information on prescription medications, over-the-counter medications, “as needed” medications, vitamins, supplements, and herbal medications. Allergies should also be verified and documented.
    [Show full text]
  • Viagra, INN-Sildenafil
    SCIENTIFIC DISCUSSION This module reflects the initial scientific discussion for the approval of VIAGRA. This scientific discussion has been updated until 1 December 2002. For information on changes after this date please refer to module 8B. 1. Introduction Male erectile dysfunction (ED) has been defined as the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance as part of the overall process of male sexual function (NIH Consensus Conference, 1993). ED can have a profound impact on the quality of life with subjects often reporting increased anxiety, loss of self-esteem, lack of self-confidence, tension and difficulty in the relationship with their partner. The prevalence of ED has been found to be associated with age. Complete ED has an estimated prevalence of about 5% in men aged 40 years to 15% at age 70 years. It should be recognised that desire, orgasmic capacity and ejaculatory capacity may be intact even in the presence of erectile dysfunction or may be deficient to some extent and contribute to the sense of inadequate sexual function. The term impotence, together with its pejorative implications, is less precise and should not be used. The degree of erectile dysfunction can vary and may range from a partial decrease in penile rigidity to complete erectile failure and the frequency of these failures may also range from “a few times a year” to “usually unable to obtain an erection”. ED is often multifactorial in etiology (organic, psychogenic, or mixed). Sometimes ED is related to stress problems with the sexual partner or transient psychological factors.
    [Show full text]
  • Parkinson's Disease Diagnosis and Management in Primary And
    DRAFT FOR FIRST CONSULTATION Full version of NICE Guideline No. X Parkinson’s Disease Diagnosis and Management in Primary and Secondary Care. Developed by National Collaborating Centre for Chronic Conditions Royal College of Physicians Parkinson’s disease: full guideline DRAFT (August 2005) Page 1 of 277 DRAFT FOR FIRST CONSULTATION Table of contents Guideline Development Group Membership ................................................5 Acknowledgments: .......................................................................................6 Preface.........................................................................................................7 1. Introduction ..................................................................................................8 Background ..................................................................................................8 Modern Definition .........................................................................................8 Health and resource implications .................................................................8 2. Methodology ..............................................................................................10 Aim .............................................................................................................10 Scope .........................................................................................................10 Methodology...............................................................................................12 3. Key Messages
    [Show full text]
  • Comparison of the Efficacy and Safety of Sildenafil Citrate (Viagra®) And
    International Journal of Impotence Research (2002) 14, Suppl 2, S48–S53 ß 2002 Nature Publishing Group All rights reserved 0955-9930/02 $25.00 www.nature.com/ijir Comparison of the efficacy and safety of sildenafil citrate (Viagra1) and oral phentolamine for the treatment of erectile dysfunction F Ugarte1* and A Hurtado-Coll2 for the Sildenafil Study Group 1Hospital Angeles del Pedegral, Consultorio 827, Mexico, DF; and 2Centro Medico Nacional 20 de Noviembre, ISSSTE, Mexico DF This open-label, multi-center study from Mexico compared the efficacy and safety of oral sildenafil and phentolamine in men with erectile dysfunction. Patients received sildenafil (25 – 100 mg; n ¼ 123) or phentolamine (40 mg; n ¼ 119) for 8 weeks, and efficacy was assessed using the International Index of Erectile Function (IIEF) as well as two global efficacy questions. Mean scores for the erectile function domain of the IIEF were significantly higher for sildenafil (27.23 Æ 0.62; P ¼ 0.0001) than for phentolamine (19.35 Æ 0.66). Approximately twice as many men receiving sildenafil had successful attempts at sexual intercourse (88% vs 42%), improved erections (95% vs 51.1%), and improved ability to have sexual intercourse (94.4% vs 46.4%) compared with phentolamine. The most common adverse events included rhinitis, headache, tachycardia, and nausea, with a higher frequency reported in patients receiving phentolamine than sildenafil (41% vs 33%), with the exception of headache, which was reported more frequently in sildenafil users. Overall, sildenafil was more effective and appeared to be better tolerated than phentolamine for the treatment of erectile dysfunction.
    [Show full text]
  • Wednesday, June 12, 2019 4:00Pm
    Wednesday, June 12, 2019 4:00pm Oklahoma Health Care Authority 4345 N. Lincoln Blvd. Oklahoma City, OK 73105 The University of Oklahoma Health Sciences Center COLLEGE OF PHARMACY PHARMACY MANAGEMENT CONSULTANTS MEMORANDUM TO: Drug Utilization Review (DUR) Board Members FROM: Melissa Abbott, Pharm.D. SUBJECT: Packet Contents for DUR Board Meeting – June 12, 2019 DATE: June 5, 2019 Note: The DUR Board will meet at 4:00pm. The meeting will be held at 4345 N. Lincoln Blvd. Enclosed are the following items related to the June meeting. Material is arranged in order of the agenda. Call to Order Public Comment Forum Action Item – Approval of DUR Board Meeting Minutes – Appendix A Update on Medication Coverage Authorization Unit/Use of Angiotensin Converting Enzyme Inhibitor (ACEI)/ Angiotensin Receptor Blocker (ARB) Therapy in Patients with Diabetes and Hypertension (HTN) Mailing Update – Appendix B Action Item – Vote to Prior Authorize Aldurazyme® (Laronidase) and Naglazyme® (Galsulfase) – Appendix C Action Item – Vote to Prior Authorize Plenvu® [Polyethylene Glycol (PEG)-3350/Sodium Ascorbate/Sodium Sulfate/Ascorbic Acid/Sodium Chloride/Potassium Chloride] – Appendix D Action Item – Vote to Prior Authorize Consensi® (Amlodipine/Celecoxib) and Kapspargo™ Sprinkle [Metoprolol Succinate Extended-Release (ER)] – Appendix E Action Item – Vote to Update the Prior Authorization Criteria For H.P. Acthar® Gel (Repository Corticotropin Injection) – Appendix F Action Item – Vote to Prior Authorize Fulphila® (Pegfilgrastim-jmdb), Nivestym™ (Filgrastim-aafi),
    [Show full text]
  • PRODUCT INFORMATION VIAGRAÒ TABLETS Sildenafil (As Citrate)
    PRODUCT INFORMATION VIAGRAÒ TABLETS sildenafil (as citrate) NAME OF THE MEDICINE Sildenafil citrate is an orally active selective inhibitor of cGMP - specific PDE5 (phosphodiesterase type 5) which is the predominant PDE isoenzyme in human corpora cavernosa. Sildenafil citrate is 5-[2-Ethoxy-5-[(4-methylpiperazin-1-yl)sulfonyl]phenyl]-1-methyl-3- propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one dihydrogen 2-hydroxypropane-1,2,3- tricarboxylate. CAS number: 171599-83-0. The empirical formula for sildenafil citrate is C28H38N6O11S with a molecular weight of 666.7 Sildenafil citrate has the following structural formula: DESCRIPTION Sildenafil citrate is a white to almost white, crystalline powder. Its aqueous solubility is equivalent to 2.6 mg sildenafil per mL at 25°C. In addition to sildenafil citrate, each VIAGRA tablet contains the following inactive ingredients: microcrystalline cellulose, calcium hydrogen phosphate anhydrous, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, lactose, glycerol triacetate, indigo carmine aluminium lake. VIAGRA tablets may contain PF0102 (PI3329). Version: pfpviagt10513 Supersedes: pfpviagt31009 Page 1 of 14 PHARMACOLOGY Pharmacodynamics VIAGRA is an oral therapy for erectile dysfunction which restores impaired erectile function by increasing blood flow to the penis, resulting in a natural response to sexual stimulation. The physiological mechanism responsible for erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme, guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) which is responsible for degradation of cGMP in the corpus cavernosum.
    [Show full text]
  • The Potential Role of Sildenafil in Cancer Management Through EPR Augmentation
    Journal of Personalized Medicine Review The Potential Role of Sildenafil in Cancer Management through EPR Augmentation Mohamed Haider 1,2,* , Amr Elsherbeny 3 , Valeria Pittalà 4 , Antonino N. Fallica 4 , Maha Ali Alghamdi 5,6 and Khaled Greish 6,* 1 Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates 2 Research Institute of Medical & Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates 3 Division of Molecular Therapeutics and Formulation, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK; [email protected] 4 Department of Drug and Health Science, University of Catania, 95125 Catania, Italy; [email protected] (V.P.); [email protected] (A.N.F.) 5 Department of Biotechnology, College of Science, Taif University, Taif 21974, Saudi Arabia; [email protected] 6 Department of Molecular Medicine, Princess Al-Jawhara Centre for Molecular Medicine, School of Medicine and Medical Sciences Arabian Gulf University, Manama 329, Bahrain * Correspondence: [email protected] (M.H.); [email protected] (K.G.); Tel.: +97-156-761-5401 (M.H.); +973-1723-7393 (K.G.) Abstract: Enhanced permeation retention (EPR) was a significant milestone discovery by Maeda et al. paving the path for the emerging field of nanomedicine to become a powerful tool in the fight against cancer. Sildenafil is a potent inhibitor of phosphodiesterase 5 (PDE-5) used for the treatment of erectile dysfunction (ED) through the relaxation of smooth muscles and the modulation of vascular endothelial permeability. Overexpression of PDE-5 has been reported in lung, colon, metastatic Citation: Haider, M.; Elsherbeny, A.; breast cancers, and bladder squamous carcinoma.
    [Show full text]
  • Flibanserin Drug Monograph
    Flibanserin Drug Monograph Flibanserin (ADDYI) National Drug Monograph August 2016 VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives The purpose of VA PBM Services drug monographs is to provide a focused drug review for making formulary decisions. Updates will be made when new clinical data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current. FDA Approval Information1 Description/Mechanism of The mechanism of flibanserin in the treatment of hypoactive sexual desire Action disorder (HSDD) is unknown. Flibanserin is a high affinity 5- hydroxytryptamine (HT)1A agonist/5-HT2A antagonist and a moderate antagonist of 5-HT2B, 5-HT2C, and dopamine D4. Flibanserin was originally developed as an antidepressant, but preliminary studies failed to show efficacy. Flibanserin was found to have a favorable effect on female sex drive in post hoc analysis, leading to additional study and eventual approval for this indication. Indication(s) Under Review in Flibanserin is indicated for the treatment of premenopausal women with this document (may include acquired, generalized HSDD as characterized by low sexual desire that causes off label) marked distress or interpersonal difficulty and is NOT due to: . A co-existing medical or psychiatric condition . Problems within the relationship . The effects of a medication or other drug substance Dosage Form(s) Under 100 mg oral tablets Review REMS REMS No REMS Postmarketing Requirements See Other Considerations for additional REMS information Pregnancy Rating There are no studies of flibanserin in pregnant women. Animal studies cannot rule out the potential for fetal harm.
    [Show full text]