DOCSLIB.ORG

Statistical Analysis Plan: GEM-301 10 July 2017

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Statistical Analysis Plan: GEM-301 10 July 2017 Title: A 12-Week, Phase 2 Randomized, Placebo-Controlled, Double-Blind Study to Assess the Efficacy, Safety, and Tolerability of Gemcabene in Subjects with Hypercholesterolemia Not Adequately Controlled on High-Intensity or Moderate-Intensity Stable Statin Therapy (ROYAL-1) NCT ID: NCT02634151 Approval Date: 10-Jul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onfidentiality Statement 7KLVGRFXPHQWFRQWDLQVFRQILGHQWLDODQGSURSULHWDU\LQIRUPDWLRQDQGLVQRWWR EHGLVWULEXWHGWRDQ\WKLUGSDUW\ &RQILGHQWLDO 3DJHRI Gemcabene Gemphire Therapeutics Inc. Statistical Analysis Plan: GEM-301 10 July 2017 1 TABLE OF CONTENTS 1 TABLE OF CONTENTS ...................................................................................................2 LIST OF TABLES .....................................................................................................................3 LIST OF APPENDICES ............................................................................................................3 2 SIGNATURE PAGE .........................................................................................................4 3 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................6 4 INTRODUCTION .............................................................................................................9 5 TRIAL OBJECTIVES .....................................................................................................10 5.1 Primary Objectives.................................................................................................10 5.2 Secondary Objectives.............................................................................................10 5.3 Exploratory Objectives ..........................................................................................10 6 STUDY DESIGN CONSIDERATIONS .........................................................................11 6.1 Study Design ..........................................................................................................11 6.2 Efficacy Measures ..................................................................................................12 6.3 Safety Measures .....................................................................................................13 7 STUDY POPULATIONS ................................................................................................14 7.1 Analysis Populations ..............................................................................................14 7.1.1 Full Analysis Set ..........................................................................................14 7.1.2 Per-Protocol Set ...........................................................................................14 7.1.3 Safety Analysis Set ......................................................................................14 8 CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE PROTOCOL ..15 9 OVERALL STATISTICAL CONSIDERATIONS .........................................................16 9.1 Sample Size Computation ......................................................................................16 9.2 General Conventions ..............................................................................................16 9.3 Baseline Definitions ...............................................................................................17 9.4 Handling of Missing Data ......................................................................................18 9.5 Interim Analysis .....................................................................................................18 9.6 Visit Windows .......................................................................................................18 10 STATISTICAL ANALYSIS METHODS .......................................................................20 10.1 Subject Disposition ................................................................................................20 10.2 Demographics and Baseline Characteristics ..........................................................20 10.3 Treatment Compliance and Exposure ....................................................................21 10.3.1 Treatment Compliance .................................................................................21 10.3.2 Treatment Exposure .....................................................................................22 11 EFFICACY PARAMETERS ...........................................................................................23 11.1 Primary Analysis ....................................................................................................23 Confidential Page 2 of 43 Gemcabene Gemphire Therapeutics Inc. Statistical Analysis Plan: GEM-301 10 July 2017 11.2 Secondary Analysis ................................................................................................23 11.3 Exploratory Analysis .............................................................................................25 11.4 Manuscript Analysis ..............................................................................................26 12 SAFETY AND TOLERABILITY ...................................................................................27 12.1 Adverse Events ......................................................................................................27 12.2 Clinical Laboratory Assessments ...........................................................................28 12.3 ECGs ......................................................................................................................30 12.4 Vital Signs and Weight ..........................................................................................31 12.5 Physical Examinations ...........................................................................................31 13 OTHER RELEVANT DATA ANALYSES/SUMMARIES ...........................................32 13.1 Medical History .....................................................................................................32 13.2 Prior and Concomitant Medications ......................................................................32 13.3 Concomitant Procedures ........................................................................................32 14 REFERENCES ................................................................................................................33 15 APPENDICES .................................................................................................................34 LIST OF TABLES Table 1. Overview of Study Periods .....................................................................................11 Table 2. Visit Windows for Assessments Done at Day 1, Weeks 2, 4, 8, and 12a ...............19 Table 3. Lab PCS Criteria .....................................................................................................29 Table 4. ECG PCS Criteria ...................................................................................................30 LIST OF APPENDICES Appendix 1. Schedule of Assessments and Procedures ..........................................................34 Appendix 2. Prior and Concomitant Medications and Smoking Status Date Imputation .......37 Appendix 3. ATC Categories and Descriptions of Hypertensive Treatments ........................38 Appendix 4. Sex-specific Framingham Risk Score algorithms ..............................................42 Appendix 5. Manuscript Analyses ..........................................................................................43 Confidential Page 3 of 43 *HPFDEHQH *HPSKLUH7KHUDSHXWLFV,QF 6WDWLVWLFDO$QDO\VLV3ODQ*(0 -XO\ 2 SIGNATURE PAGE 6WXG\7LWOH $:HHN3KDVH5DQGRPL]HG3ODFHER&RQWUROOHG 'RXEOH%OLQG6WXG\WR$VVHVVWKH(IILFDF\6DIHW\DQG 7ROHUDELOLW\RI*HPFDEHQHLQ6XEMHFWVZLWK+\SHUFKROHVWHUROHPLD 1RW$GHTXDWHO\&RQWUROOHGRQ+LJK,QWHQVLW\RU 0RGHUDWH,QWHQVLW\6WDEOH6WDWLQ7KHUDS\ 52<$/ 6WXG\1XPEHU *(0 PI 3UHSDUHG PI E\ PI 5HYLHZHG PI E\ PI PI $SSURYHG E\ *HPSKLUH7KHUDSHXWLFV,QF PI $SSURYHG E\ *HPSKLUH7KHUDSHXWLFV,QF &RQILGHQWLDO 3DJHRI Gemcabene Gemphire Therapeutics Inc. Statistical Analysis Plan: GEM-301 10 July 2017 Document History – Major changes compared to previous versions of the analysis plan Version Date Changes Final 1.0 17-Apr-17 N/A Amendment 1.0 10-Jul-17 Added that potentially clinically significant laboratory values, single occurrences, will also be summarized by statin-intensity stratum. Added information on imputing drug interruptions with partial start/stop dates to be 1 day in length along with technical comments regarding assignment. Added that we are summarizing days on treatment and days drug was interrupted for. Added 2 urinalysis parameters to PCS criteria. Updated PPS section. Edited text to reflect hsCRP and TG being analyzed using ranked ANCOVA. Confidential Page 5 of 43 Gemcabene Gemphire Therapeutics Inc. Statistical Analysis Plan: GEM-301 10 July 2017
Load more

Recommended publications
  • Additions and Deletions to the Drug Product List
    Prescription and Over-the-Counter Drug Product List 40TH EDITION Cumulative Supplement Number 09 : September 2020 ADDITIONS/DELETIONS FOR PRESCRIPTION DRUG PRODUCT LIST ACETAMINOPHEN; BUTALBITAL; CAFFEINE TABLET;ORAL BUTALBITAL, ACETAMINOPHEN AND CAFFEINE >A> AA STRIDES PHARMA 325MG;50MG;40MG A 203647 001 Sep 21, 2020 Sep NEWA ACETAMINOPHEN; CODEINE PHOSPHATE SOLUTION;ORAL ACETAMINOPHEN AND CODEINE PHOSPHATE >D> AA WOCKHARDT BIO AG 120MG/5ML;12MG/5ML A 087006 001 Jul 22, 1981 Sep DISC >A> @ 120MG/5ML;12MG/5ML A 087006 001 Jul 22, 1981 Sep DISC TABLET;ORAL ACETAMINOPHEN AND CODEINE PHOSPHATE >A> AA NOSTRUM LABS INC 300MG;15MG A 088627 001 Mar 06, 1985 Sep CAHN >A> AA 300MG;30MG A 088628 001 Mar 06, 1985 Sep CAHN >A> AA ! 300MG;60MG A 088629 001 Mar 06, 1985 Sep CAHN >D> AA TEVA 300MG;15MG A 088627 001 Mar 06, 1985 Sep CAHN >D> AA 300MG;30MG A 088628 001 Mar 06, 1985 Sep CAHN >D> AA ! 300MG;60MG A 088629 001 Mar 06, 1985 Sep CAHN ACETAMINOPHEN; HYDROCODONE BITARTRATE TABLET;ORAL HYDROCODONE BITARTRATE AND ACETAMINOPHEN >A> @ CEROVENE INC 325MG;5MG A 211690 001 Feb 07, 2020 Sep CAHN >A> @ 325MG;7.5MG A 211690 002 Feb 07, 2020 Sep CAHN >A> @ 325MG;10MG A 211690 003 Feb 07, 2020 Sep CAHN >D> AA VINTAGE PHARMS 300MG;5MG A 090415 001 Jan 24, 2011 Sep DISC >A> @ 300MG;5MG A 090415 001 Jan 24, 2011 Sep DISC >D> AA 300MG;7.5MG A 090415 002 Jan 24, 2011 Sep DISC >A> @ 300MG;7.5MG A 090415 002 Jan 24, 2011 Sep DISC >D> AA 300MG;10MG A 090415 003 Jan 24, 2011 Sep DISC >A> @ 300MG;10MG A 090415 003 Jan 24, 2011 Sep DISC >D> @ XIROMED 325MG;5MG A 211690
    [Show full text]
  • Imidazoline Antihypertensive Drugs: Selective I1-Imidazoline Receptors Activation K
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by FarFar - Repository of the Faculty of Pharmacy, University of Belgrade REVIEW Imidazoline Antihypertensive Drugs: Selective I1-Imidazoline Receptors Activation K. Nikolic & D. Agbaba Faculty of Pharmacy, Institute of Pharmaceutical Chemistry, University of Belgrade, Vojvode Stepe, Belgrade, Serbia Keywords SUMMARY α2-Adrenergic receptors; Centrally acting antihypertensives; Clonidine; Hypertension; Involvement of imidazoline receptors (IR) in the regulation of vasomotor tone as well as in Imidazoline receptors; Rilmenidine. the mechanism of action of some centrally acting antihypertensives has received tremen- dous attention. To date, pharmacological studies have allowed the characterization of three Correspondence main imidazoline receptor classes, the I1-imidazoline receptor which is involved in central K. Nikolic, Faculty of Pharmacy, Institute of inhibition of sympathetic tone to lower blood pressure, the I2-imidazoline receptor which Pharmaceutical Chemistry, University of is an allosteric binding site of monoamine oxidase B (MAO-B), and the I3-imidazoline re- Belgrade, Vojvode Stepe 450, 11000 Belgrade, ceptor which regulates insulin secretion from pancreatic β-cells. All three imidazoline re- Serbia. ceptors represent important targets for cardiovascular research. The hypotensive effect of + Tel: 381-63-84-30-677; clonidine-like centrally acting antihypertensives was attributed both to α2-adrenergic re- + Fax: 381-11-3974-349; ceptors and nonadrenergic I1-imidazoline receptors, whereas their sedative action involves E-mail: [email protected] activation of only α2-adrenergic receptors located in the locus coeruleus. Since more selec- tive I1-imidazoline receptors ligands reduced incidence of typical side effects of other cen- trally acting antihypertensives, there is significant interest in developing new agents with higher selectivity and affinity for I1-imidazoline receptors.
    [Show full text]
  • Comparison of the Anti-Inflammatory Effects of Cilomilast, Budesonide
    Ratcliffe and Dougall BMC Pharmacology and Toxicology 2012, 13:15 http://www.biomedcentral.com/2050-6511/13/15 RESEARCH ARTICLE Open Access Comparison of the anti-inflammatory effects of Cilomilast, Budesonide and a p38 Mitogen activated protein kinase inhibitor in COPD lung tissue macrophages Marianne Jennifer Ratcliffe1* and Iain Gordon Dougall2 Abstract Chronic Obstructive Pulmonary Disease (COPD) is a disease characterized by a largely irreversible airflow obstruction and a persistent, excessive inflammatory response. Alveolar macrophages (AMs) are increased in the lungs of COPD patients, and act as orchestrators of the inflammatory response, releasing a range of mediators to coordinate recruitment and activation of leukocytes. Attempts to treat the inflammatory component of COPD with anti-inflammatory drugs such as steroids has met with limited success. In this study, we compared the ability of the phosphodiesterase IV (PDEIV) inhibitor Cilomilast, the steroid Budesonide, and the p38 mitogen activated protein kinase inhibitor BIRB-796 to inhibit tumour necrosis factor alpha (TNFα) and interleukin 6 (IL-6) releases from AMs isolated from COPD lung transplant tissue. All studies were carried out with appropriate ethical approval and written, informed consent was obtained from each subject. Cilomilast had little effect on cytokine release from AMs. There was considerable variability in the responsiveness of AMs to Budesonide, with a subset of AMs responding poorly to Budesonide. BIRB-796 inhibited TNFα release from all AM donors, including those that responded poorly to steroids. Treatment with BIRB-796 and Budesonide together gave an additive decrease in TNFa release. These results suggest that a p38 inhibitor may provide advantages over existing anti-inflammatory treatments for COPD, either as an add-on to existing therapy, or to treat patients who respond poorly to steroids.
    [Show full text]
  • Guanidine-Containing Polyhydroxyl Macrolides: Chemistry, Biology, and Structure-Activity Relationship
    molecules Review Guanidine-Containing Polyhydroxyl Macrolides: Chemistry, Biology, and Structure-Activity Relationship Xiaoyuan Song 1, Ganjun Yuan 1,* , Peibo Li 2 and Sheng Cao 1 1 College of Bioscience and Bioengineering, Jiangxi Agricultural University, Nanchang 330045, China; [email protected] (X.S.); [email protected] (S.C.) 2 School of Life Sciences, Sun Yat-sen University, 135 Xingang Road, Guangzhou 510275, China; [email protected] * Correspondence: [email protected]; Tel.: +86-0791-83813459 Academic Editor: Jesus Simal-Gandara Received: 7 October 2019; Accepted: 29 October 2019; Published: 30 October 2019 Abstract: Antimicrobial resistance has been seriously threatening human health, and discovering new antimicrobial agents from the natural resource is still an important pathway among various strategies to prevent resistance. Guanidine-containing polyhydroxyl macrolides, containing a polyhydroxyl lactone ring and a guanidyl side chain, can be produced by many actinomycetes and have been proved to possess many bioactivities, especially broad-spectrum antibacterial and antifungal activities. To explore the potential of these compounds to be developed into new antimicrobial agents, a review on their structural diversities, spectroscopic characterizations, bioactivities, acute toxicities, antimicrobial mechanisms, and the structure-activity relationship was first performed based on the summaries and analyses of related publications from 1959 to 2019. A total of 63 guanidine-containing polyhydroxyl macrolides were reported, including
    [Show full text]
  • Mediated Pulmonary Hypertension in Neonatal Rats: a Role for Products of Lipid Peroxidation
    0031-3998/00/4803-0289 PEDIATRIC RESEARCH Vol. 48, No. 3, 2000 Copyright © 2000 International Pediatric Research Foundation, Inc. Printed in U.S.A. Endothelin-1 and O2-Mediated Pulmonary Hypertension in Neonatal Rats: A Role for Products of Lipid Peroxidation ROBERT P. JANKOV, XIAOPING LUO, JUDY CABACUNGAN, ROSETTA BELCASTRO, HELENA FRNDOVA, STEPHEN J. LYE, AND A. KEITH TANSWELL Medical Research Council Group in Lung Development and Lung Biology Programme [R.P.J., X.L., J.C., R.B., H.F., A.K.T.], Hospital for Sick Children Research Institute, the MRC Group in Developmental and Fetal Health, Samuel Lunenfeld Research Institute, Mt. Sinai Hospital [S.J.L.], and the Departments of Obstetrics and Gynaecology [S.J.L.], Paediatrics [A.K.T.] and Physiology [A.K.T., S.J.L.], University of Toronto, Toronto, Ontario, M5S 1A8 Canada. ABSTRACT We hypothesized that reactive O2 species, or their interme- lung cell cultures. We conclude that reactive O2 species, or their diary products, generated during exposure to elevated O2 lead to bioactive intermediaries, are causative in O2-mediated pulmo- pathologic endothelin-1 expression in the newborn lung. Endo- nary hypertension and endothelin-1 up-regulation. It is likely that thelin-1 expression and 8-isoprostane content (an in vivo marker the bioactive lipid peroxidation product, 8-isoprostane, plays a of lipid peroxidation) were examined and found to be elevated key role in pathologic endothelin-1 expression and pulmonary (p Ͻ 0.05) in the lungs of newborn rats with abnormal lung hypertension during oxidant stress. (Pediatr Res 48: 289–298, morphology and pulmonary hypertension, as assessed by right 2000) ventricular hypertrophy, after a 14-d exposure to 60% O2.
    [Show full text]
  • Basic Concepts in Medicinal Chemistry, 2Nd Edition
    APP ANSWERS TO CHAPTER QUESTIONS CHAPTER 2 STRUCTURE ANALYSIS CHECKPOINT Checkpoint Drug 1: Venetoclax 1. Answers provided in table below. Functional Group Name Contribution to Water and/or Lipid Solubility A Halogen (chlorine atom) Lipid Solubility B Alicyclic ring, alkyl ring, cycloalkane Lipid Solubility C Tertiary amine (piperazine) Water Solubility D Heterocyclic ring system (pyrrolopyridine) Hydrocarbons: Lipid Solubility Nitrogen atoms: Water Solubility E Aromatic ring; phenyl ring; aromatic hydrocarbon Lipid Solubility F Sulfonamide Water Solubility G Secondary aromatic amine/aniline Water Solubility H Ether Hydrocarbons: Lipid Solubility Oxygen atom: Water Solubility 2. The sulfonamide and tertiary amine will be primarily ionized in most physiological environments and can participate in ion-dipole interactions (as the ion) with water. In the event that they are unionized, they could participate in hydrogen bonding interactions with water. The nitrogen atoms of the heterocyclic ring system, as well as the secondary aromatic amine, and the oxygen atom of the ether will not be appreciably ionized, but can participate in hydrogen bonding interactions with water. Thus, all of these functional groups contribute to the water solubility of venetoclax. The halogen as well as the hydrocarbon chains and rings are not able to ionize or form hydrogen bonds with water and thus contribute to the lipid solubility of venetoclax. 477 Unauthenticated | Downloaded 09/26/21 09:50 PM UTC 478 BASIC CONCEPTS IN MEDICINAL CHEMISTRY 3. Answers provided in table below. Electron Donating or Withdrawing Resonance or Induction A Electron Withdrawing Induction B Both Donates electrons into the aromatic ring through resonance. Withdraws electrons from adjacent methylene groups through induction.
    [Show full text]
  • Convergent Pharmacological Mechanisms in Impulsivity And
    British Journal of DOI:10.1111/bph.12787 www.brjpharmacol.org BJP Pharmacology Themed Section: Animal Models in Psychiatry Research Correspondence Jeffrey W Dalley, Department of Psychology, University of REVIEW Cambridge, Downing St, Cambridge CB2 3EB, UK. E-mail: [email protected] Convergent ---------------------------------------------------------------- Received 20 February 2014 pharmacological Revised 2 May 2014 Accepted mechanisms in impulsivity 12 May 2014 and addiction: insights from rodent models B Jupp1,2 and J W Dalley1,3 1Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK, 2Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia, and 3Department of Psychiatry, University of Cambridge, Cambridge, UK Research over the last two decades has widely demonstrated that impulsivity, in its various forms, is antecedent to the development of drug addiction and an important behavioural trait underlying the inability of addicts to refrain from continued drug use. Impulsivity describes a variety of rapidly and prematurely expressed behaviours that span several domains from impaired response inhibition to an intolerance of delayed rewards, and is a core symptom of attention deficit hyperactivity disorder (ADHD) and other brain disorders. Various theories have been advanced to explain how impulsivity interacts with addiction both causally and as a consequence of chronic drug abuse; these acknowledge the strong overlaps in neural circuitry and mechanisms between impulsivity and addiction and the seemingly paradoxical treatment of ADHD with stimulant drugs with high abuse potential. Recent years have witnessed unprecedented progress in the elucidation of pharmacological mechanisms underpinning impulsivity. Collectively, this work has significantly improved the prospect for new therapies in ADHD as well as our understanding of the neural mechanisms underlying the shift from recreational drug use to addiction.
    [Show full text]
  • Stems for Nonproprietary Drug Names
    USAN STEM LIST STEM DEFINITION EXAMPLES -abine (see -arabine, -citabine) -ac anti-inflammatory agents (acetic acid derivatives) bromfenac dexpemedolac -acetam (see -racetam) -adol or analgesics (mixed opiate receptor agonists/ tazadolene -adol- antagonists) spiradolene levonantradol -adox antibacterials (quinoline dioxide derivatives) carbadox -afenone antiarrhythmics (propafenone derivatives) alprafenone diprafenonex -afil PDE5 inhibitors tadalafil -aj- antiarrhythmics (ajmaline derivatives) lorajmine -aldrate antacid aluminum salts magaldrate -algron alpha1 - and alpha2 - adrenoreceptor agonists dabuzalgron -alol combined alpha and beta blockers labetalol medroxalol -amidis antimyloidotics tafamidis -amivir (see -vir) -ampa ionotropic non-NMDA glutamate receptors (AMPA and/or KA receptors) subgroup: -ampanel antagonists becampanel -ampator modulators forampator -anib angiogenesis inhibitors pegaptanib cediranib 1 subgroup: -siranib siRNA bevasiranib -andr- androgens nandrolone -anserin serotonin 5-HT2 receptor antagonists altanserin tropanserin adatanserin -antel anthelmintics (undefined group) carbantel subgroup: -quantel 2-deoxoparaherquamide A derivatives derquantel -antrone antineoplastics; anthraquinone derivatives pixantrone -apsel P-selectin antagonists torapsel -arabine antineoplastics (arabinofuranosyl derivatives) fazarabine fludarabine aril-, -aril, -aril- antiviral (arildone derivatives) pleconaril arildone fosarilate -arit antirheumatics (lobenzarit type) lobenzarit clobuzarit -arol anticoagulants (dicumarol type) dicumarol
    [Show full text]
  • Guadinomines, Type III Secretion System Inhibitors, Produced by Streptomyces Sp
    J. Antibiot. 61(4): 222–229, 2008 THE JOURNAL OF ORIGINAL ARTICLE ANTIBIOTICS Guadinomines, Type III Secretion System Inhibitors, Produced by Streptomyces sp. K01-0509 I. Taxonomy, Fermentation, Isolation and Biological Properties Masato Iwatsuki, Ryuji Uchida, Hitomi Yoshijima, Hideaki Ui, Kazuro Shiomi, Atsuko Matsumoto, Yoko Takahashi, Akio Abe, Hiroshi Tomoda, Satoshi O¯ mura Dedicated to the late Prof. Shigeo Iwasaki Received: January 22, 2008 / Accepted: April 4, 2008 © Japan Antibiotics Research Association Abstract Enteropathogenic Escherichia coli (EPEC) Chlamydia spp. [4]. These bacteria use TTSS to deliver expressing the Type III secretion system (TTSS) induced effector proteins into the cytosol of the eukaryotic target hemolysis of sheep blood cells. Using this assay, six cell and depend on their respective TTSS to invade the structurally related compounds designated as guadinomines host, resist phagocytosis, grow in deep tissues, and cause were isolated as inhibitors of TTSS-induced hemolysis by disease [5]. Recent studies have revealed that TTSS is not ion exchange column chromatography and HPLC from the essential for the survival of bacteria and is not found in culture broth of Streptomyces sp. K01-0509. Guadinomines non-pathogenic Gram-negative bacteria except for some A and B showed potent inhibition with IC50 values of 0.02 kinds of symbiotic bacteria. and 0.007 mg/ml, respectively, guadinomine D showed Based on the new concept of “anti-infective drugs” ¯ moderate activity (IC50: 8.5 mg/ml), while guadinomines C1 developed by Omura [6], we have focused on TTSS as a and C2 and guadinomic acid had no activity. new target for anti-infective drugs.
    [Show full text]
  • Autonomic Nervous System Activity Changes in Patients with Hypertension and Overweight: Role and Therapeutic Implications Paul Valensi*
    Valensi Cardiovasc Diabetol (2021) 20:170 https://doi.org/10.1186/s12933-021-01356-w Cardiovascular Diabetology REVIEW Open Access Autonomic nervous system activity changes in patients with hypertension and overweight: role and therapeutic implications Paul Valensi* Abstract The incidence and prevalence of hypertension is increasing worldwide, with approximately 1.13 billion of people currently afected by the disease, often in association with other diseases such as diabetes mellitus, chronic kidney disease, dyslipidemia/hypercholesterolemia, and obesity. The autonomic nervous system has been implicated in the pathophysiology of hypertension, and treatments targeting the sympathetic nervous system (SNS), a key component of the autonomic nervous system, have been developed; however, current recommendations provide little guid‑ ance on their use. This review discusses the etiology of hypertension, and more specifcally the role of the SNS in the pathophysiology of hypertension and its associated disorders. In addition, the efects of current antihypertensive management strategies, including pharmacotherapies, on the SNS are examined, with a focus on imidazoline recep‑ tor agonists. Keywords: Autonomic nervous system, Hypertension, Obesity, Type 2 diabetes, Selective imidazoline receptor agonists Introduction 6]. Te prevalence of hypertension is higher in low- and Hypertension is one of the leading causes of premature middle-income countries [5] and increases with age [1]. death worldwide with 1.13 billion people having hyper- Te autonomic nervous system has been implicated tension. It is associated with an increased risk of cardio- in the pathophysiology of hypertension [7, 8] and treat- vascular diseases (CVD; e.g., stroke, angina, myocardial ments targeting the sympathetic nervous system (SNS) infarction, heart failure, peripheral artery disease, and have been developed [9, 10] although largely forgotten or abdominal aortic aneurysm) as well as end-stage renal ruled out in international recommendations [1, 2].
    [Show full text]
  • Download Product Insert (PDF)
    PRODUCT INFORMATION Guanfacine (hydrochloride) Item No. 22907 CAS Registry No.: 29110-48-3 Formal Name: N-(aminoiminomethyl)-2,6-dichloro- Cl H benzeneacetamide, monohydrochloride N NH2 MF: C9H9Cl2N3O • HCl FW: 282.6 O NH Purity: ≥98% Supplied as: A crystalline solid Cl • HCl Storage: -20°C Stability: ≥2 years Information represents the product specifications. Batch specific analytical results are provided on each certificate of analysis. Laboratory Procedures Guanfacine (hydrochloride) is supplied as a crystalline solid. A stock solution may be made by dissolving the guanfacine (hydrochloride) in the solvent of choice. Guanfacine (hydrochloride) is soluble in organic solvents such as ethanol, DMSO, and dimethyl formamide (DMF), which should be purged with an inert gas. The solubility of guanfacine (hydrochloride) in ethanol is approximately 25 mg/ml and approximately 30 mg/ml in DMSO and DMF. Further dilutions of the stock solution into aqueous buffers or isotonic saline should be made prior to performing biological experiments. Ensure that the residual amount of organic solvent is insignificant, since organic solvents may have physiological effects at low concentrations. Organic solvent-free aqueous solutions of guanfacine (hydrochloride) can be prepared by directly dissolving the crystalline solid in aqueous buffers. The solubility of guanfacine (hydrochloride) in PBS, pH 7.2, is approximately 10 mg/ml. We do not recommend storing the aqueous solution for more than one day. Description Guanfacine is an α2-adrenergic receptor (α2-AR) agonist with Ki values of 93, 1,380, and 3,890 nM for α2A-, 1 α2B-, and α2C-ARs, respectively, in a radioligand binding assay. It has EC50 values of 52, 288, and 602 nM for 35 α2A-, α2B-, and α2C-ARs, respectively, for stimulated [ S]GTPγS binding.
    [Show full text]
  • Bioisosteric Replacement As a Tool in Anti-HIV Drug Design
    pharmaceuticals Review Bioisosteric Replacement as a Tool in Anti-HIV Drug Design Alexej Dick and Simon Cocklin * Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Rooms 10307, 10309, and 10315, 245 North 15th Street, Philadelphia, PA 19102, USA; [email protected] * Correspondence: [email protected]; Tel.: +215-762-7234 or +215-762-4979 Received: 3 February 2020; Accepted: 26 February 2020; Published: 28 February 2020 Abstract: Bioisosteric replacement is a powerful tool for modulating the drug-like properties, toxicity, and chemical space of experimental therapeutics. In this review, we focus on selected cases where bioisosteric replacement and scaffold hopping have been used in the development of new anti-HIV-1 therapeutics. Moreover, we cover field-based, computational methodologies for bioisosteric replacement, using studies from our group as an example. It is our hope that this review will serve to highlight the utility and potential of bioisosteric replacement in the continuing search for new and improved anti-HIV drugs. Keywords: bioisosteres; HIV-1; antiviral; computer-aided drug design; envelope; reverse transcriptase; protease; integrase; tat; Vif 1. Introduction The design and development of a lead compound into a drug is a laborious and often costly process, with most candidates failing due to metabolism and pharmacokinetics issues rather than potency. Bioisosteric replacement is a strategy used by medicinal chemists to address these limitations while still retaining the potency/efficacy of the initial lead compound. The use of bioisosteres and the introduction of structural changes to the lead compound allows the chemist to alter the compound’s size, shape, electronic distribution, polarizability, dipole, polarity, lipophilicity, and pKa, while still retaining potent target engagement.
    [Show full text]