Pharmacologically Active Metabolites of Currently Marketed Drugs: Potential Resources for New Drug Discovery and Development

Total Page:16

File Type:pdf, Size:1020Kb

Pharmacologically Active Metabolites of Currently Marketed Drugs: Potential Resources for New Drug Discovery and Development hon p.1 [100%] YAKUGAKU ZASSHI 130(10) 1325―1337 (2010) 2010 The Pharmaceutical Society of Japan 1325 ―Review― Pharmacologically Active Metabolites of Currently Marketed Drugs: Potential Resources for New Drug Discovery and Development Myung Joo KANG, Woo Heon SONG, Byung Ho SHIM, Seung Youn OH, Hyun Young LEE, Eun Young CHUNG, Yesung SOHN,andJaehwiLEE Division of Pharmaceutical Sciences, College of Pharmacy, Chung-Ang University, 221 Heuksuk-dong, Dongjak-gu, Seoul 156756, South Korea (Received April 14, 2010; Accepted July 14, 2010) Biotransformation is the major clearance mechanism of therapeutic agents from the body. Biotransformation is known not only to facilitate the elimination of drugs by changing the molecular structure to more hydrophilic, but also lead to pharmacological inactivation of therapeutic compounds. However, in some cases, the biotransformation of drugs can lead to the generation of pharmacologically active metabolites, responsible for the pharmacological actions. This review provides an update of the kinds of pharmacologically active metabolites and some of their individual phar- macological and pharmacokinetic aspects, and describes their importance as resources for drug discovery and develop- ment. Key words―pharmacologically active metabolite; biotransformation; metabolism; drug discovery gents exhibited by biotransformation can sometimes INTRODUCTION lead to the generation of pharmacologically active Xenobiotics are chemical substances found in living metabolites, which can responsible for the pharmaco- being but not normally produced or present in body, logical responses.1,46) It has been reported that about including pollutants, dietary components and drugs. 22% of the top 50 drugs prescribed in the USA in To defense the body against xenobiotic substances, an 2003 undergo biotransformation into metabolites array of biotransformation reactions (or metabolic that play signiˆcant roles in the pharmacological ac- reactions) is undergone. Due to the biotransforma- tions of the corresponding drugs.6) Active metabolites tion, the molecular structure of a drug is commonly exerting improved pharmacological, pharmacokinetic changed to be more hydrophilic and the substances behaviors or lower toxicity than its parent drug were can be readily eliminated from the body.1) already developed as new drugs in some cases. Biotransformation reactions are usually divided In this regard, recognizing the pharmacologically into two broad categories known as phase I and phase active metabolites as signiˆcant resources for drug de- II reactions. In the phase I reaction mediated by en- velopment would be beneˆcial. This paper provides zymes such as cytochrome P450 (CYP), ‰avin-con- an update on pharmacological active metabolites with taining monooxygenase, esterases and amidases, po- their pharmacological and pharmacokinetic aspects, lar functional groups are introduced into the molec- and further describes their values as resources for ules, aŠording it a suitable substrate for direct excre- drug discovery and development. tion. On the other hand, the phase II metabolism, FORMATION OF PHARMACOLOGICALLY AC- mediated by enzymes such as glucuronosyltrans- TIVE METABOLITES ferase, sulfotransferase and N-acetyltransferase, causes conjugation of phase I metabolites or xeno- Pharmacologically active metabolites are generated biotics with highly water-soluble endogenous materi- through mainly primary and/or secondary, and ter- als such as glucuronic acid, sulfate, amino acids or tiary metabolism by phase I and phase II reactions. glutathione.2) After this metabolic process, the drugs Although metabolites are chemical structurally diŠer- are excreted through the bile route.1,3) ent from the parent drug, if they have structural However, the structural alteration of therapeutic a- similarities to the parent molecules, they might attain biological activities similar to the parent drug in some e-mail: jaehwi@cau.ac.kr cases.6) Table 1 lists the active metabolites produced hon p.2 [100%] 1326 Vol. 130 (2010) from currently marketed drugs. As shown in Table 1, metabolites have more hydrophilic property and bet- simple reactions mediated via CYP generate active ter in vivo metabolic stability compared to their cor- metabolites in many cases such as aromatic or responding parent molecules.1,5,6) Although active aliphatic hydroxylation, O-orN-dealkylation, and metabolites have structural similarities to the parent dehydrogenation or in combinations.1,46) drugs, their protein binding, membrane permeability, Many of the pharmacologically active metabolites tissue distribution, and pharmacological potency are generated via hydroxylation or dealkylation reac- might be diŠerent from those of the parent com- tions. For instance, atorvastatin (Fig. 1(a)),7) pro- pounds. paferone,8) alprazolam,9) atomoxetine,10) ‰utamide,11) The degrees of pharmacological activities of nefazodone,12) acetohexamide,13) cyclosporine,14) metabolites compared to parent drugs are diŠerent propranolol,15) risperidone,16) itraconazole,17) and from each other, but in most cases, metabolites are bupropion (Fig. 1(b))18) generate their active meta- less potent than parent drugs. For instance, 3-hydr- bolites via aromatic or aliphatic hydroxylations. oxyquinidine,37) hydroxymetronidazole,38) (R)-nor- Bupropion also forms two other active metabolites, ‰uoxetine,22,23) norverapamil,39) hydroxycyclospo- namely threohydrobupropion and erythrohydro- rine,14) N-desmethylazonaˆde,26) hydroxybupropion bupropion through carbonyl reduction.18) O-Deme- and threohydrobupropion,18) and many active meta- thylation of venlafaxine (Fig. 1(c)), ivabradine and bolites have weaker activities than their parents. But, artemether gives pharmacologically active O-des- in some cases, metabolites are more potent or have methylvenlafaxine, O-desmethylivabradine and dihy- similar biological activities to parent drugs. 2- or droartemisinin, respectively.1921) Ivabradine also 4-Hydroxyatorvastatin,7) 2-hydroxy‰utamide,11) hy- forms active metabolite by N-demethylation.20) N- droxynefazodone,40) hydroxyacetohexamide,41) 5-hy- Demethylation signiˆcantly contributes to produce droxypropafenone,8) minoxidil sulfate,34) desme- active metabolites in cases of ‰uoxetine (Fig. 1 thylclomipramine,42) mesoridazine,27) (S)-nor‰uoxe- (d)),22,23) sibutramine,24) ferroquine25) and azonaˆde.26) tine,22,23) O-desmethylvenlafaxine19) and S-hydrox- S-Oxidation of thioridazine and epoxidation of car- yrisperidone16) showed comparable activities with bamazepine lead to the formation of mesoridazine27) parent drugs in vitro or vivo experiments. and carbamazepine-10, 11-epoxide,28) respectively. In this part, pharmacological activities and phar- There are also numerous examples of active macokinetic behaviors of active metabolites were il- metabolites that are produced by phase II enzymes. lustrated as follows. Glucuronidation is normally considered to be detox- Acebutolol Acebutolol is a cardioselective be- ifying process, because glucuronides usually possess ta-adrenoreceptor blocking agent. The major meta- less intrinsic biological or chemical activity than their bolite, N-acetyl derivative, diacetolol is pharmacolog- parent forms and exhibit higher polarity and ex- ically active. This metabolite was reported to be e- cretability.29) However, some glucuronide conjugates quipotent to acebutolol in cats and is more cardio- are active and may contribute to pharmacological ac- selective than acebutolol.35) tivities. The N, O-glucuronides of hydroxamic acid30) Acetohexamide Acetohexamide is an oral anti- and the acylglucuronides of carboxylic acids form ac- diabetic drug possessing a moderate duration of ac- tive metabolites.31,32) Particularly, the 6-O-glu- tion. S-Hydroxyacetohexamide and R-hydroxyaceto- curonide of morphine constitutes the most well- hexamide exhibit similar hypoglycemic eŠects in rats. known example of a glucuronide possessing phar- Particularly, S-hydroxyacetohexamide demonstrated macological activity greater than the parent drug.33) a more potent hypoglycemic activity than acetohex- And, the sulfation of minoxidil (Fig. 1(e)), N-acety- amide, implying that S-hydroxyacetohexamide plays lation of acebutol or procainamide has also contribut- an important role in overall hypoglycemic eŠect.13,41) ed the production of the pharmacologically active Both acetohexamide and S-hydroxyacetohexamide metabolites.3436) are rapidly eliminated from the body.43) Alprazolam Alprazolam is a benzodiazepine, PHARMACOLOGICALLY ACTIVE METABO- which is used for the treatment of anxiety, panic dis- LITES OF MARKETED DRUGS orders, depression and sleeping disorders. It is meta- Generally, most of the pharmacologically active bolized to 4-hydroxyalprazolam and 4a-hydroxyal- hon p.3 [100%] No. 10 1327 Table 1. Pharmacologically Active Metabolites of Currently Marketed Drugs Drug Active metabolites Biotransformation Therapeutic actions Atomoxetine 10) 4-Hydroxyatomoxetine Treatment of attention-deˆcit hyperactivity disorder Atorvastatin 7) 2- or 4-Hydroxyatorvastatin Anti-hypercholesterolemia Chlorpromazine 119) 7-Hydroxychlorpromazine Anti-depressive Clomiphene 120) 4-Hydroxyclomiphene Anti-uterotrophic Aromatic hydroxylation Granisetron 121) 7-Hydroxygranisetron Anti-nausea Indapamide 122) 5-Hydroxyindapamide Anti-hypertensive Levamisole 82) 4-Hydroxylevamisole Anthelmintic Propafenone 8) 5-Hydroxypropafenone Anti-arrhythmic Propranolol 15) 4-Hydroxypropranolol Anti-arrhythmic Alprazolam 9) 4-Hydroxyalprazolam Anti-depressant
Recommended publications
  • Impact of CYP2C19 Genotype on Sertraline Exposure in 1200 Scandinavian Patients
    www.nature.com/npp ARTICLE Impact of CYP2C19 genotype on sertraline exposure in 1200 Scandinavian patients Line S. Bråten 1,2, Tore Haslemo1,2, Marin M. Jukic3,4, Magnus Ingelman-Sundberg 3, Espen Molden1,5 and Marianne K. Kringen1,2 Sertraline is an (SSRI-)antidepressant metabolized by the polymorphic CYP2C19 enzyme. The aim of this study was to investigate the impact of CYP2C19 genotype on the serum concentrations of sertraline in a large patient population. Second, the proportions of patients in the various CYP2C19 genotype-defined subgroups obtaining serum concentrations outside the therapeutic range of sertraline were assessed. A total of 2190 sertraline serum concentration measurements from 1202 patients were included retrospectively from the drug monitoring database at Diakonhjemmet Hospital in Oslo. The patients were divided into CYP2C19 genotype-predicted phenotype subgroups, i.e. normal (NMs), ultra rapid (UMs), intermediate (IMs), and poor metabolisers (PMs). The differences in dose-harmonized serum concentrations of sertraline and N-desmethylsertraline-to-sertraline metabolic ratio were compared between the subgroups, with CYP2C19 NMs set as reference. The patient proportions outside the therapeutic concentration range were also compared between the subgroups with NMs defined as reference. Compared with the CYP2C19 NMs, the sertraline serum concentration was increased 1.38-fold (95% CI 1.26–1.50) and 2.68-fold (95% CI 2.16–3.31) in CYP2C19 IMs and PMs, respectively (p < 0.001), while only a marginally lower serum concentration (−10%) was observed in CYP2C19 UMs (p = 0.012). The odds ratio for having a sertraline concentration above the therapeutic reference range was 1.97 (95% CI 1.21–3.21, p = 0.064) and 8.69 (95% CI 3.88–19.19, p < 0.001) higher for IMs and PMs vs.
    [Show full text]
  • ZOLOFT® 50 Mg and 100 Mg Tablets
    NEW ZEALAND DATA SHEET 1. PRODUCT NAME ZOLOFT® 50 mg and 100 mg tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each 50 mg tablet contains sertraline hydrochloride equivalent to 50 mg sertraline. Each 100 mg tablet contains sertraline hydrochloride equivalent to 100 mg sertraline. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM ZOLOFT 50 mg tablets: white film-coated tablets marked with the Pfizer logo on one side and “ZLT” scoreline “50” on the other. Approximate tooling dimensions are 1.03 cm x 0.42 cm x 0.36 cm. ZOLOFT 100 mg tablets: white film-coated tablets marked with the Pfizer logo on one side and “ZLT-100” or “ZLT 100” on the other. Approximate tooling dimensions are 1.31 cm x 0.52 cm x 0.44 cm. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Adults ZOLOFT is indicated for the treatment of symptoms of depression, including depression accompanied by symptoms of anxiety, in patients with or without a history of mania. Following satisfactory response, continuation with ZOLOFT therapy is effective in preventing relapse of the initial episode of depression or recurrence of further depressive episodes. ZOLOFT is indicated for the treatment of obsessive compulsive disorder (OCD). Following initial response, sertraline has been associated with sustained efficacy, safety and tolerability in up 2 years of treatment of OCD. ZOLOFT is indicated for the treatment of panic disorder, with or without agoraphobia. ZOLOFT is indicated for the treatment of post-traumatic stress disorder (PTSD). ZOLOFT is indicated for the treatment of social phobia (social anxiety disorder).
    [Show full text]
  • Medical Review Officer Manual
    Department of Health and Human Services Substance Abuse and Mental Health Services Administration Center for Substance Abuse Prevention Medical Review Officer Manual for Federal Agency Workplace Drug Testing Programs EFFECTIVE OCTOBER 1, 2010 Note: This manual applies to Federal agency drug testing programs that come under Executive Order 12564 dated September 15, 1986, section 503 of Public Law 100-71, 5 U.S.C. section 7301 note dated July 11, 1987, and the Department of Health and Human Services Mandatory Guidelines for Federal Workplace Drug Testing Programs (73 FR 71858) dated November 25, 2008 (effective October 1, 2010). This manual does not apply to specimens submitted for testing under U.S. Department of Transportation (DOT) Procedures for Transportation Workplace Drug and Alcohol Testing Programs (49 CFR Part 40). The current version of this manual and other information including MRO Case Studies are available on the Drug Testing page under Medical Review Officer (MRO) Resources on the SAMHSA website: http://www.workplace.samhsa.gov Previous Versions of this Manual are Obsolete 3 Table of Contents Chapter 1. The Medical Review Officer (MRO)........................................................................... 6 Chapter 2. The Federal Drug Testing Custody and Control Form ................................................ 7 Chapter 3. Urine Drug Testing ...................................................................................................... 9 A. Federal Workplace Drug Testing Overview..................................................................
    [Show full text]
  • And N-Demethylation of Venlafaxine in Vitro by Human Liver Microsomes
    O- and N-demethylation of Venlafaxine In Vitro by Human Liver Microsomes and by Microsomes from cDNA-Transfected Cells: Effect of Metabolic Inhibitors and SSRI Antidepressants Steven M. Fogelman, Jürgen Schmider, Karthik Venkatakrishnan, Lisa L. von Moltke, Jerold S. Harmatz, Richard I. Shader, and David J. Greenblatt The biotransformation of venlafaxine (VF) into its two to the formation of NDV for all four livers tested. major metabolites, O-desmethylvenlafaxine (ODV) and Parameters determined by applying a single-enzyme model 5 / / 5 N-desmethylvenlafaxine (NDV) was studied in vitro with were Vmax 2.14 nmol min mg protein, and Km 2504 human liver microsomes and with microsomes containing mM. Ketoconazole was a potent inhibitor of NDV individual human cytochromes from cDNA-transfected production, although its inhibitory activity was not as great human lymphoblastoid cells. VF was coincubated with as observed with pure 3A substrates. NDV formation was selective cytochrome P450 (CYP) inhibitors and several also reduced by 42% by a polyclonal rabbit antibody against selective serotonin reuptake inhibitors (SSRIs) to assess rat liver CYP3A1. Studies using expressed cytochromes their inhibitory effect on VF metabolism. Formation rates showed that NDV was formed by CYP2C9, 22C19, and for ODV incubated with human microsomes were 23A4. The highest intrinsic clearance was attributable to consistent with Michaelis-Menten kinetics for a single- CYP2C19 and the lowest to CYP3A4. However the high in enzyme mediated reaction with substrate inhibition. Mean vivo abundance of 3A isoforms will magnify the 5 parameters determined by non-linear regression were: Vmax importance of this cytochrome. Fluvoxamine (FX), at a / / 5 m m 0.36 nmol min mg protein, Km 41 M, and Ks 22901 concentration of 20 M, decreased NDV production by m M (Ks represents a constant which reflects the degree of 46% consistent with the capacity of FX to inhibit CYP3A, substrate inhibition).
    [Show full text]
  • Pharmaceuticals and Endocrine Active Chemicals in Minnesota Lakes
    Pharmaceuticals and Endocrine Active Chemicals in Minnesota Lakes May 2013 Authors Mark Ferrey Contributors/acknowledgements The MPCA is reducing printing and mailing costs This report contains the results of a study that by using the Internet to distribute reports and characterizes the presence of unregulated information to wider audience. Visit our website contaminants in Minnesota’s lakes. The study for more information. was made possible through funding by the MPCA reports are printed on 100 percent post- Minnesota Clean Water Fund and by funding by consumer recycled content paper manufactured the U.S. Environmental Protection Agency without chlorine or chlorine derivatives. (EPA), which facilitated the sampling of lakes for this study. The Minnesota Pollution Control Agency (MPCA) thanks the following for assistance and advice in designing and carrying out this study: Steve Heiskary, Pam Anderson, Dereck Richter, Lee Engel, Amy Garcia, Will Long, Jesse Anderson, Ben Larson, and Kelly O’Hara for the long hours of sampling for this study. Cynthia Tomey, Kirsten Anderson, and Richard Grace of Axys Analytical Labs for the expert help in developing the list of analytes for this study and logistics to make it a success. Minnesota Pollution Control Agency 520 Lafayette Road North | Saint Paul, MN 55155-4194 | www.pca.state.mn.us | 651-296-6300 Toll free 800-657-3864 | TTY 651-282-5332 This report is available in alternative formats upon request, and online at www.pca.state.mn.us. Document number: tdr-g1-16 Contents Contents ...........................................................................................................................................
    [Show full text]
  • Determination of Sertraline and Its Metabolite by High-Pressure Liquid Chromatography in Plasma
    ACADEMIA ROMÂNĂ Rev. Roum. Chim., Revue Roumaine de Chimie 2015, 60(5-6), 543-548 http://web.icf.ro/rrch/ DETERMINATION OF SERTRALINE AND ITS METABOLITE BY HIGH-PRESSURE LIQUID CHROMATOGRAPHY IN PLASMA Nazan YUCE-ARTUN,a Erguvan Tuğba ÖZEL KIZIL,b Bora BASKAK,b Halise Devrimci ÖZGÜVEN,b Yalçın DUYDUc and Halit Sinan SUZENc,* aBiotechnology Institute, Ankara University, Golbasi, Ankara, Turkey bDepartment of Psychiatry, School of Medicine, Ankara University, Dikimevi, Ankara, Turkey cDepartment of Toxicology, Faculty of Pharmacy, Ankara University, Tandogan, Ankara, Turkey Received November 10, 2014 A fast, simple and sensitive high-pressure liquid chromatography (HPLC) method with UV detection was developed for frequently prescribed antidepressant, sertraline (SERT) and its main B metabolite N-desmethylsertraline (DSERT), in human plasma. SERT and DSERT were extracted by an optimized solid phase chromatographic (SPE) method using C-18 cartridges and DSE SER Clomipramine was used as external standard (ES). The analytes ES were separated on C18, 4.6 mm × 150 mm, 5 µm column at 50 °C with a mobile phase of 45% acetonitrile + 55% NaH2PO4 at a flow rate of 0.4 mL/min. Detector responses monitored at 4 different wave-lengths; 200-205-210-215 nm. The method proved to be rapid and effective for the plasma sample analyses of therapeutic drug monitoring for sertraline treated patients. INTRODUCTION* depression, panic disorder, generalised anxiety disorder, and social phobia.2 Like other SSRIs, it High rates of poor compliance, considerable has a wide therapeutic index and seems to be better genetic variability in metabolism, and the clinical tolerated than tricyclic antidepressants.3 The drug heterogeneity of depression are the main problems is slowly absorbed with a time to peak plasma for the practical application of selective serotonin concentration of approximately 4–8 h and an reuptake inhibitors (SSRI).1 Therapeutic drug elimination half life of 22–35 h.
    [Show full text]
  • Non-Alcohol Sedative Hypnotics
    Tom Fowlkes, MD Director of Professional & Medical Relations American Addiction Centers Oxford Treatment Center More Accurately We Will Talk About: Non-alcohol Sedative Hypnotics Objectives To review the history & pharmacology of benzodiazepines and other sedative-hypnotics To educate prescribers about the indications for the proper use of benzodiazepines To educate prescribers about the indications for discontinuation of therapy and tapering strategies To review recent information about benzodiazepine use and abuse Disclosures I have nothing to disclose. Except perhaps that I make my living treating people with substance abuse disorders and as a result I have not become the biggest advocate for widespread benzodiazepine use. Most of the information in this talk is taken from the medical literature. Some of the information is my own medical opinion. I have tried to point out when information is my opinion. What we are going to cover 2 Case studies What are Sedative Hypnotics/How they work History – Older Sedative-Hypnotics>BZ>Newer Drugs Pharmacology Differences in benzodiazepines (=benzo’s, = BZ) Clinical Use Safe Prescribing Abuse & Dependence Sedative-Hypnotics Suppress CNS activity Pharmacologically diverse Cause effects along a continuum of: calming> sleep >unconsciousness > coma > death Uses: Anxiolytics Hypnotics Anti-convulsants Muscle relaxants Anesthesia induction (Olkkola, 2008) GABA System Most all of these sedative hypnotics act on this GABA system. Gamma-aminobutyric acid is the primary inhibitory neurotransmitter system in the CNS. There are GABA receptors with multiple sub-types in different regions, etc. GABA binds to these receptor sites causing a chloride ion channel to open and then all of these inhibitory things take place.
    [Show full text]
  • LEGISLATIVE ASSEMBLY Question on Notice
    LEGISLATIVE ASSEMBLY Question On Notice Thursday, 15 February 2018 2560. Ms M. M Quirk to the Minister for Police; I refer to the commencement of operation of the Road Traffic Amendment Act 2016 in March 2017 which introduced compulsory blood or urine samples to be taken from drivers involved in serious crashes, and I ask: (a) since March 2017 how many such samples have been taken; (b) for what specific substances are those blood or urine samples tested; (c) what are the results of those tests to date; and (d) what percentage of drivers have been found to have ingested more than one substance capable of impairing driving skills? Answer (a) The compulsory taking of blood from all drivers involved in serious crashes commenced on 10 March 2017. Between 10 March 2017 and 22 February 2018 (inclusive) a total of 398 blood test samples have been collected under the provision of the Road Traffic Amendment Act 2016. There have been no urine tests collected. (b) Please see attached table for a list of substances in blood sample that are identifiable in ChemCentre toxicology analysis (Paper Number). (c) Of the 398 blood samples collected, 48 are pending results of ChemCentre analysis. Of the 350 analysed, 259 samples had a specific substance(s) detected and 91 samples had no specific substance detected. d) Of the 259 samples with specific substance(s) detected, 92% were found to have multiple substances (more than one). Detectable Substances in Blood Samples capable of identification by the ChemCentre WA. ACETALDEHYDE AMITRIPTYLINE/NORTRIPTYLINE
    [Show full text]
  • Sertraline in Children and Adolescents with Obsessive-Compulsive Disorder a Multicenter Randomized Controlled Trial
    Sertraline in Children and Adolescents With Obsessive-Compulsive Disorder A Multicenter Randomized Controlled Trial John S. March, MD, MPH; Joseph Biederman, MD; Robert Wolkow, MD; Allan Safferman, MD; Jack Mardekian, PhD; Edwin H. Cook, MD; Neal R. Cutler, MD; Roberto Dominguez, MD; James Ferguson, MD; Betty Muller, MD; Robert Riesenberg, MD; Murray Rosenthal, DO; Floyd R. Sallee, MD, PhD; Hans Steiner, MD; Karen D. Wagner, MD, PhD Context.—The serotonin reuptake inhibitors are the treatment of choice for pa- APPROXIMATELY 1 in 200 young per- tients with obsessive-compulsive disorder; however, empirical support for this as- sons has obsessive-compulsive disorder sertion has been weaker for children and adolescents than for adults. (OCD),1 which many believe to be the 2 Objective.—To evaluate the safety and efficacy of the selective serotonin reup- paradigmatic neuropsychiatric illness. take inhibitor sertraline hydrochloride in children and adolescents with obsessive- Individuals with OCD experience obses- sions, which are recurrent and persis- compulsive disorder. tent thoughts, images, or impulses that Design.—Randomized, double-blind, placebo-controlled trial. are egodystonic, intrusive, and, for the Patients.—One hundred eighty-seven patients: 107 children aged 6 to 12 years most part, acknowledged as senseless.3 and 80 adolescents aged 13 to 17 years randomized to receive either sertraline (53 children, 39 adolescents) or placebo (54 children, 41 adolescents). See also p 1784 and Patient Page. Setting.—Twelve US academic and community clinics with experience con- ducting randomized controlled trials. Intervention.—Sertraline hydrochloride was titrated to a maximum of 200 mg/d Common obsessions are generally ac- during the first 4 weeks of double-blind therapy, after which patients continued to companied by distressing negative af- fects, such as fear, disgust, doubt, or a receive this dosage of medication for 8 more weeks.
    [Show full text]
  • 21-436/S-018
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 21-436/S-018 CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S) Clinical Pharmacology and Biopharmaceutics Review ______________________________________________________________________________ NDA: 21-436 S018, 21-713 S013, 21-729 S005, 21-866 S005 Generic Name: Aripiprazole Trade Name: Abilify™ Dosage Forms: Tablets, Oral Solution, ODT, IM Indication: Adjunctive treatment of Major Depressive Disorder Sponsor: Otsuka/Bristol Myer Squibb Submission Type: Efficacy Supplement Submission Date: 5/16/07 OCP Division: DCP1 (HFD-860) OND Division: DPP (HFD-130) Reviewer: Kofi A. Kumi, Ph.D. Secondary Reviewer: Andre Jackson, Ph.D. Team Leader: Raman Baweja, Ph.D. ______________________________________________________________________________ Table of Contents 1. EXECUTIVE SUMMARY .............................................................................................. 2 1.1. Recommendations ............................................................................................... 2 1.2. Phase IV Commitments ....................................................................................... 2 1.3. Comments to Medical Division............................................................................. 2 1.4. Comments to Sponsor ......................................................................................... 3 1.5. Summary of Clinical Pharmacology Findings....................................................... 3 1.5.1. Background.......................................................................................................................3
    [Show full text]
  • ZOLOFT ® (Sertraline Hydrochloride)
    ZOLOFT® (sertraline hydrochloride) Tablets and Oral Concentrate Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of ZOLOFT or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. ZOLOFT is not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD). (See Warnings: Clinical Worsening and Suicide Risk, Precautions: Information for Patients, and Precautions: Pediatric Use) DESCRIPTION ZOLOFT® (sertraline hydrochloride) is a selective serotonin reuptake inhibitor (SSRI) for oral administration. It has a molecular weight of 342.7. Sertraline hydrochloride has the following chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride. The empirical formula C17H17NCl2HCl is represented by the following structural formula: 1 Reference ID: 3536868 NHCH3 HCl Cl Cl Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and isopropyl alcohol, and sparingly soluble in ethanol.
    [Show full text]
  • Drug-Facilitated Sexual Assault in the U.S
    The author(s) shown below used Federal funds provided by the U.S. Department of Justice and prepared the following final report: Document Title: Estimate of the Incidence of Drug-Facilitated Sexual Assault in the U.S. Document No.: 212000 Date Received: November 2005 Award Number: 2000-RB-CX-K003 This report has not been published by the U.S. Department of Justice. To provide better customer service, NCJRS has made this Federally- funded grant final report available electronically in addition to traditional paper copies. Opinions or points of view expressed are those of the author(s) and do not necessarily reflect the official position or policies of the U.S. Department of Justice. AWARD NUMBER 2000-RB-CX-K003 ESTIMATE OF THE INCIDENCE OF DRUG-FACILITATED SEXUAL ASSAULT IN THE U.S. FINAL REPORT Report prepared by: Adam Negrusz, Ph.D. Matthew Juhascik, Ph.D. R.E. Gaensslen, Ph.D. Draft report: March 23, 2005 Final report: June 2, 2005 Forensic Sciences Department of Biopharmaceutical Sciences (M/C 865) College of Pharmacy University of Illinois at Chicago 833 South Wood Street Chicago, IL 60612 ABSTRACT The term drug-facilitated sexual assault (DFSA) has been recently coined to describe victims who were given a drug by an assailant and subsequently sexually assaulted. Previous studies that have attempted to determine the prevalence of drugs in sexual assault complainants have had serious biases. This research was designed to better estimate the rate of DFSA and to examine the social aspects surrounding it. Four clinics were provided with sexual assault kits and asked to enroll sexual assault complainants.
    [Show full text]