DOCSLIB.ORG

Inhibitory Effects of Antipsychotics on the Contractile Response To

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Inhibitory Effects of Antipsychotics on the Contractile Response To ←確認用doi （左上Y座標：－17.647 pt） 1140 Biol. Pharm. Bull. 44, 1140–1150 (2021) Vol. 44, No. 8 Regular Article Inhibitory Effects of Antipsychotics on the Contractile Response to Acetylcholine in Rat Urinary Bladder Smooth Muscles Keisuke Obara,*,a Yuka Matsuoka,a Naoya Iwata,a Yukako Abe, a Yohei Ikegami,a Nanako Shioda,a Yume Hattori,a Shoko Hamamatsu,a Kento Yoshioka, a Fumiko Yamaki,a,b Kazuhiro Matsuo,c Takashi Yoshio,c and Yoshio Tanakaa a Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Toho University; 2–2–1 Miyama, Funabashi, Chiba 274–8510, Japan: b Department of Pharmacy, Faculty of Pharmacy, Musashino University; 1–1–20 Shinmachi, Nishitokyo, Tokyo 202–8585, Japan: and c Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Toho University; 2–2–1 Miyama, Funabashi, Chiba 274–8510, Japan. Received April 24, 2021; accepted May 27, 2021 The clinical applications of antipsychotics for symptoms unrelated to schizophrenia, such as behavioral and psychological symptoms, in patients with Alzheimer’s disease, and the likelihood of doctors prescrib- ing antipsychotics for elderly people are increasing. In elderly people, drug-induced and aging-associated urinary disorders are likely to occur. The most significant factor causing drug-induced urinary disorders is a decrease in urinary bladder smooth muscle (UBSM) contraction induced by the anticholinergic action of therapeutics. However, the anticholinergic action-associated inhibitory effects of antipsychotics on UBSM contraction have not been sufficiently assessed. In this study, we examined 26 clinically available antipsychot- ics to determine the extent to which they inhibit acetylcholine (ACh)-induced contraction in rat UBSM to predict the drugs that should not be used by elderly people to avoid urinary disorders. Of the 26 antipsychot- ics, six (chlorpromazine, levomepromazine (phenothiazines), zotepine (a thiepine), olanzapine, quetiapine, clozapine (multi-acting receptor targeted antipsychotics (MARTAs))) competitively inhibited ACh-induced contractions at concentrations corresponding to clinically significant doses. Further, 11 antipsychotics (per- phenazine, fluphenazine, prochlorperazine (phenothiazines), haloperidol, bromperidol, timiperone, spiperone (butyrophenones), pimozide (a diphenylbutylpiperidine), perospirone, blonanserin (serotonin–dopamine antagonists; SDAs), and asenapine (a MARTA)) significantly suppressed ACh-induced contraction; however, suppression occurred at concentrations substantially exceeding clinically achievable blood levels. The re- maining nine antipsychotics (pipamperone (a butyrophenone), sulpiride, sultopride, tiapride, nemonapride (benzamides), risperidone, paliperidone (SDAs), aripiprazole, and brexpiprazole (dopamine partial agonists)) did not inhibit ACh-induced contractions at concentrations up to 105 M. These findings suggest that chlor- promazine, levomepromazine, zotepine, olanzapine, quetiapine, and clozapine should be avoided by elderly people with urinary disorders. Key words antipsychotics; rat urinary bladder smooth muscle; anticholinergic effect; urinary disorder INTRODUCTION cause of age-related changes in pharmacokinetics and pharma- codynamics, current medical conditions, polypharmacy, and Antipsychotics are mainly utilized to treat schizophrenia; potential drug interactions.13) The U.S. Food and Drug Ad- however, in recent years, its application has extended to other ministration (FDA) issued an advisory and a subsequent black mental disorders, such as depression, behavioral and psycho- box warning regarding the risks of atypical antipsychotic use logical symptoms of dementia (BPSD), and gastrointestinal among elderly patients with dementia.14) Owing to the issu- symptoms associated with chemotherapy.1–5) As a result, the ance of this black box warning, many clinical studies on the prescription of antipsychotics has been increasing world- serious side effects of antipsychotics have been carried out.13) wide.6–8) Owing to the increase in human life span, elderly However, little information is available on the side effects that patients with mental disorders, Alzheimer's dementia, and clearly lead to poorer QOL for patients but are not recognized cancer have also been increasing.9–11) Thus, the prescription as severe. Urinary disorders are one of the such side effects of antipsychotics for elderly patients is expected to rapidly induced by antipsychotics.15) In elderly people, drug-induced increase in the future. In support of this speculation, the pre- as well as aging-associated urinary disorders are likely to scription rate of antipsychotics for elderly patients in Japan occur.16) Drug-induced urinary disorders affect patient adher- was found to increase by ≥10% between 2006 and 2012.6) ence,17) and thus should be avoided. In general, elderly patients are more likely to develop ad- The most significant factor for drug-induced urinary disor- verse effects than middle-age patients are. For example, elder- ders is a decrease in urinary bladder smooth muscle (UBSM) ly patients are more prone to antipsychotic-induced movement contraction due to anticholinergic actions.18) Among antipsy- disorders12) and are at an increased risk of adverse events due chotics, there is no significant difference in the rate of side to the intake of atypical antipsychotics (serotonin–dopamine effects caused by anticholinergic actions between patients antagonists (SDAs), multi-acting receptor targeted antipsychot- taking typical antipsychotics and those taking atypical anti- ics (MARTAs), dopamine partial agonists (DPAs)); this is be- psychotics.15) However, little information is available on which * To whom correspondence should be addressed. e-mail: [email protected] © 2021 The Pharmaceutical Society of Japan Vol. 44, No. 8 (2021) Biol. Pharm. Bull. 1141 antipsychotics inhibit UBSM contractility through their pos- to the bath medium. After a 30 min equilibration period, to sible anticholinergic actions. produce sustained contractions, the strip was contracted with In this study, we determined the potential inhibitory effects 80 mM high-KCl solution (containing atropine, prazosin, and of 26 clinically available antipsychotics on acetylcholine propranolol) comprising (mM): NaCl, 79.6; KCl, 80; CaCl2, (ACh)-induced contractions in rat UBSM. We then compared 2.2; MgCl2, 2.1; NaHCO3, 5.9; and glucose, 2.8. When the the drug concentrations required to produce inhibitory effects contractile response reached a steady state, each antipsychotic against ACh-induced contractions with their clinically achiev- was incrementally applied to the bath medium. At the end of able concentration ranges to predict the antipsychotics that the experiment, the UBSM preparations were treated with should be avoided in elderly patients with urinary disorders. verapamil (10−5 M). We considered that rat UBSM is suitable for evaluating the Drugs The 26 antipsychotics tested in this study were: le- anticholinergic potencies of drugs for the following reasons: 1) vomepromazine maleate, fluphenazine dimaleate, haloperidol, ACh-induced contractions in both rat and human UBSMs are sultopride hydrochloride, and perospirone hydrochloride dihy- mediated through M3 receptors, although the expression level drate (FUJIFILM Wako Pure Chemical Corporation, Osaka, of M2 receptors is higher than that of M3 receptors in their Japan); chlorpromazine hydrochloride, prochlorperazine di- UBSMs19); 2) The binding properties of various muscarinic maleate, pipamperone, (±)-sulpiride, tiapride hydrochloride, receptor antagonists (such as M1 receptor antagonist, pirenz- paliperidone, blonanserin, olanzapine, and aripiprazole (Tokyo epine; M2 receptor antagonist, AF-DX 116; and M3 receptor Chemical Industry Co., Ltd., Tokyo, Japan); perphenazine, antagonist, darifenacin) to rat UBSM are almost identical spiperone hydrochloride, quetiapine hemifumarate, clozapine, to their binding properties to human UBSM, although the brexpiprazole, and pimozide (Cayman Chemical, Ann Arbor, binding properties of β3-adrenoceptor agonists/antagonists MI, U.S.A.); bromperidol (MedChemExpress Co., Ltd., Mon- to rat UBSM differ from their binding properties to human mouth Junction, NJ, U.S.A.); timiperone (Toronto Research UBSM.20) Chemicals, Toronto, ON, Canada); nemonapride, and zotepine (Santa Cruz Biotechnology Inc., Dallas, TX, U.S.A.); risperi- MATERIALS AND METHODS done (Acros Organics, Geel, Belgium); and asenapine maleate (AdooQ BioScience LLC, Irvine, CA, U.S.A.). ACh chloride Animals Male Wistar rats (age, 8–10 weeks old; weight, was purchased from Daiichi Sankyo Co., Ltd. (Tokyo, Japan). 175–280 g; Japan SLC, Hamamatsu, Japan) were housed under Atropine sulfate, indomethacin, propranolol hydrochloride, controlled conditions (21–22°C, relative air humidity 50 ± 5%) and (±)-verapamil were purchased from Sigma-Aldrich Co. and a fixed 12–12 h light–dark cycle (08 : 00–20 : 00), with food (St. Louis, MO, U.S.A.). All other chemicals were commer- and water available ad libitum. This study was approved by cially available and of reagent grade. the Toho University Animal Care and Use Committee (Ap- Fluphenazine and clozapine were dissolved in 0.1 N HCl to proval Nos. 17-53-294, 18-54-294, 19-55-294) and was con- create a stock solution of 2 × 10−2 M. Thereafter, the stock so- ducted in accordance with the guidelines of the Laboratory lutions were further diluted with distilled water to the desired Animal Center of Faculty of Pharmaceutical Sciences, Toho concentrations. The other antipsychotics
Load more

Recommended publications
  • Treatment of Psychosis: 30 Years of Progress
    Journal of Clinical Pharmacy and Therapeutics (2006) 31, 523–534 REVIEW ARTICLE Treatment of psychosis: 30 years of progress I. R. De Oliveira* MD PhD andM.F.Juruena MD *Department of Neuropsychiatry, School of Medicine, Federal University of Bahia, Salvador, BA, Brazil and Department of Psychological Medicine, Institute of Psychiatry, King’s College, University of London, London, UK phrenia. Thirty years ago, psychiatrists had few SUMMARY neuroleptics available to them. These were all Background: Thirty years ago, psychiatrists had compounds, today known as conventional anti- only a few choices of old neuroleptics available to psychotics, and all were liable to cause severe extra them, currently defined as conventional or typical pyramidal side-effects (EPS). Nowadays, new antipsychotics, as a result schizophrenics had to treatments are more ambitious, aiming not only to suffer the severe extra pyramidal side effects. improve psychotic symptoms, but also quality of Nowadays, new treatments are more ambitious, life and social reinsertion. We briefly but critically aiming not only to improve psychotic symptoms, outline the advances in diagnosis and treatment but also quality of life and social reinsertion. Our of schizophrenia, from the mid 1970s up to the objective is to briefly but critically review the present. advances in the treatment of schizophrenia with antipsychotics in the past 30 years. We conclude DIAGNOSIS OF SCHIZOPHRENIA that conventional antipsychotics still have a place when just the cost of treatment, a key factor in Up until the early 1970s, schizophrenia diagnoses poor regions, is considered. The atypical anti- remained debatable. The lack of uniform diagnostic psychotic drugs are a class of agents that have criteria led to relative rates of schizophrenia being become the most widely used to treat a variety of very different, for example, in New York and psychoses because of their superiority with London, as demonstrated in an important study regard to extra pyramidal symptoms.
    [Show full text]
  • Quantitative Resting State Electroencephalography in Patients with Schizophrenia Spectrum Disorders Treated with Strict Monotherapy Using Atypical Antipsychotics
    Original Article https://doi.org/10.9758/cpn.2021.19.2.313 pISSN 1738-1088 / eISSN 2093-4327 Clinical Psychopharmacology and Neuroscience 2021;19(2):313-322 Copyrightⓒ 2021, Korean College of Neuropsychopharmacology Quantitative Resting State Electroencephalography in Patients with Schizophrenia Spectrum Disorders Treated with Strict Monotherapy Using Atypical Antipsychotics Takashi Ozaki1,2, Atsuhito Toyomaki1, Naoki Hashimoto1, Ichiro Kusumi1 1Department of Psychiatry, Graduate School of Medicine, Hokkaido University, 2Department of Psychiatry, Hokkaido Prefectural Koyogaoka Hospital, Sapporo, Japan Objective: The effect of antipsychotic drugs on quantitative electroencephalography (EEG) has been mainly examined by the administration of a single test dose or among patients using combinations of other psychotropic drugs. We therefore investigated the effects of strict monotherapy with antipsychotic drugs on quantitative EEG among schizophrenia patients. Methods: Data from 2,364 medical reports with EEG results from psychiatric patients admitted to the Hokkaido University Hospital were used. We extracted EEG records of patients who were diagnosed with schizophrenia spectrum disorders and who were either undergoing strict antipsychotic monotherapy or were completely free of psychotropic drugs. The spectral power was compared between drug-free patients and patients using antipsychotic drugs. We also performed multiple regression analysis to evaluate the relationship between spectral power and the chlorpromazine equivalent daily dose of antipsychotics in all the patients. Results: We included 31 monotherapy and 20 drug-free patients. Compared with drug-free patients, patients receiving antipsychotic drugs demonstrated significant increases in theta, alpha and beta power. When patients taking different types of antipsychotics were compared with drug-free patients, we found no significant change in any spectrum power for the aripiprazole or blonanserin groups.
    [Show full text]
  • Steven, Stacy (2012) the Pharmacology of the 5-HT2A Receptor and the Difficulty Surrounding Single Taret Models
    Steven, Stacy (2012) The pharmacology of the 5-HT2A receptor and the difficulty surrounding single taret models. MSc(R) thesis. http://theses.gla.ac.uk/3636/ Copyright and moral rights for this thesis are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the Author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the Author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Glasgow Theses Service http://theses.gla.ac.uk/ [email protected] The pharmacology of the 5-HT2A receptor and the difficulty surrounding functional studies with single target models A thesis presented for the degree of Master of Science by research Stacy Steven April 2012 Treatment of many disorders can be frequently problematic due to the relatively non selective nature of many drugs available on the market. Symptoms can be complex and expansive, often leading to symptoms representing other disorders in addition to the primary reason for treatment. In particular mental health disorders fall prey to this situation. Targeting treatment can be difficult due to the implication of receptors in more than one disorder, and more than one receptor in a single disorder. In the instance of GPCRs, receptors such as the serotonin receptors (and in particular the 5-HT2A for the interest of this research) belong to a large family of receptors, the GPCR Class A super family.
    [Show full text]
  • Selective Labeling of Serotonin Receptors Byd-[3H]Lysergic Acid
    Proc. Nati. Acad. Sci. USA Vol. 75, No. 12, pp. 5783-5787, December 1978 Biochemistry Selective labeling of serotonin receptors by d-[3H]lysergic acid diethylamide in calf caudate (ergots/hallucinogens/tryptamines/norepinephrine/dopamine) PATRICIA M. WHITAKER AND PHILIP SEEMAN* Department of Pharmacology, University of Toronto, Toronto, Canada M5S 1A8 Communicated by Philip Siekevltz, August 18,1978 ABSTRACT Since it was known that d-lysergic acid di- The objective in this present study was to improve the se- ethylamide (LSD) affected catecholaminergic as well as sero- lectivity of [3H]LSD for serotonin receptors, concomitantly toninergic neurons, the objective in this study was to enhance using other drugs to block a-adrenergic and dopamine receptors the selectivity of [3HJISD binding to serotonin receptors in vitro by using crude homogenates of calf caudate. In the presence of (cf. refs. 36-38). We then compared the potencies of various a combination of 50 nM each of phentolamine (adde to pre- drugs on this selective [3H]LSD binding and compared these clude the binding of [3HJLSD to a-adrenoceptors), apmo ie, data to those for the high-affinity binding of [3H]serotonin and spiperone (added to preclude the binding of [3H[LSD to (39). dopamine receptors), it was found by Scatchard analysis that the total number of 3H sites went down to 300 fmol/mg, compared to 1100 fmol/mg in the absence of the catechol- METHODS amine-blocking drugs. The IC50 values (concentrations to inhibit Preparation of Membranes. Calf brains were obtained fresh binding by 50%) for various drugs were tested on the binding of [3HLSD in the presence of 50 nM each of apomorphine (A), from the Canada Packers Hunisett plant (Toronto).
    [Show full text]
  • Appendix 13C: Clinical Evidence Study Characteristics Tables
    APPENDIX 13C: CLINICAL EVIDENCE STUDY CHARACTERISTICS TABLES: PHARMACOLOGICAL INTERVENTIONS Abbreviations ............................................................................................................ 3 APPENDIX 13C (I): INCLUDED STUDIES FOR INITIAL TREATMENT WITH ANTIPSYCHOTIC MEDICATION .................................. 4 ARANGO2009 .................................................................................................................................. 4 BERGER2008 .................................................................................................................................... 6 LIEBERMAN2003 ............................................................................................................................ 8 MCEVOY2007 ................................................................................................................................ 10 ROBINSON2006 ............................................................................................................................. 12 SCHOOLER2005 ............................................................................................................................ 14 SIKICH2008 .................................................................................................................................... 16 SWADI2010..................................................................................................................................... 19 VANBRUGGEN2003 ....................................................................................................................
    [Show full text]
  • Revision of Precautions Asenapine Maleate, Aripiprazole, Olanzapine
    Published by Translated by Ministry of Health, Labour and Welfare Pharmaceuticals and Medical Devices Agency This English version is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Revision of Precautions Asenapine maleate, aripiprazole, olanzapine, quetiapine fumarate, clocapramine hydrochloride hydrate, chlorpromazine hydrochloride, chlorpromazine hydrochloride/promethazine hydrochloride/phenobarbital, chlorpromazine phenolphthalinate, spiperone, zotepine, timiperone, haloperidol, paliperidone, pipamperone hydrochloride, fluphenazine decanoate, fluphenazine maleate, brexpiprazole, prochlorperazine maleate, prochlorperazine mesilate, Pharmaceuticals and Medical Devices Agency Office of Safety I 3-3-2 Kasumigaseki, Chiyoda-ku, Tokyo 100-0013 Japan E-mail: [email protected] Published by Translated by Ministry of Health, Labour and Welfare Pharmaceuticals and Medical Devices Agency This English version is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. propericiazine, bromperidol, perphenazine, perphenazine hydrochloride, perphenazine fendizoate, perphenazine maleate, perospirone hydrochloride hydrate, mosapramine hydrochloride, risperidone (oral drug), levomepromazine hydrochloride, levomepromazine maleate March 27, 2018 Non-proprietary name Asenapine maleate,
    [Show full text]
  • Antipsychotics (Part-4) FLUOROBUTYROPHENONES
    Antipsychotics (Part-4) FLUOROBUTYROPHENONES The fluorobutyrophenones belong to a much-studied class of compounds, with many compounds possessing high antipsychotic activity. They were obtained by structure variation of the analgesic drug meperidine by substitution of the N-methyl by butyrophenone moiety to produce the butyrophenone analogue which has similar activity as chlorpromazine. COOC2H5 N H3C Meperidine COOC2H5 N O Butyrophenone analog The structural requirements for antipsychotic activity in the group are well worked out. General features are expressed in the following structure. F AR Y O N • Optimal activity is seen when with an aromatic with p-fluoro substituent • When CO is attached with p-fluoroaryl gives optimal activity is seen, although other groups, C(H)OH and aryl, also give good activity. • When 3 carbons distance separates the CO from cyclic N gives optimal activity. • The aliphatic amino nitrogen is required, and highest activity is seen when it is incorporated into a cyclic form. • AR is an aromatic ring and is needed. It should be attached directly to the 4-position or occasionally separated from it by one intervening atom. • The Y group can vary and assist activity. An example is the hydroxyl group of haloperidol. The empirical SARs suggest that the 4-aryl piperidino moiety is superimposable on the 2-- phenylethylamino moiety of dopamine and, accordingly, could promote affinity for D2 receptors. The long N-alkyl substituent could help promote affinity and produce antagonistic activity. Some members of the class are extremely potent antipsychotic agents and D2 receptor antagonists. The EPS are extremely marked in some members of this class, which may, in part, be due to a potent DA block in the striatum and almost no compensatory striatal anticholinergic block.
    [Show full text]
  • New Zealand Data Sheet 1. Product Name
    NEW ZEALAND DATA SHEET 1. PRODUCT NAME Norvir 100 mg tablets. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 100 mg ritonavir. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM White film-coated oval tablets debossed with the corporate Abbott "A" logo and the Abbott-Code “NK”. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications NORVIR is indicated for use in combination with appropriate antiretroviral agents or as monotherapy if combination therapy is inappropriate, for the treatment of HIV-1 infection in adults and children aged 12 years and older. For persons with advanced HIV disease, the indication for ritonavir is based on the results for one study that showed a reduction in both mortality and AIDS defining clinical events for patients who received ritonavir. Median duration of follow-up in this study was 6 months. The clinical benefit from ritonavir for longer periods of treatment is unknown. For persons with less advanced disease, the indication is based on changes in surrogate markers in controlled trials of up to 16 weeks duration (see section 5.1 Pharmacodynamic properties). 4.2 Dose and method of administration General Dosing Guidelines Prescribers should consult the full product information and clinical study information of protease inhibitors if they are co-administered with a reduced dose of ritonavir. The recommended dose of NORVIR is 600 mg (six tablets) twice daily by mouth, and should be given with food. NORVIR tablets should be swallowed whole and not chewed, broken or crushed. NORVIR DS 29 April 2020 Page 1 of 37 Version 35 Paediatric population Ritonavir has not been studied in patients below the age of 12 years; hence the safety and efficacy of ritonavir in children below the age of 12 have not been established.
    [Show full text]
  • A Study on the Efficacy and Safety of Blonanserin in Indian Patients in Ahmedabad: a Randomized, Active Controlled, Phase III Clinical Trial
    Lakdawala et al. : Efficacy and Safety of Blonanserin 359 Original Research Article A study on the efficacy and safety of Blonanserin in Indian patients in Ahmedabad: a randomized, active controlled, phase III clinical trial Bhavesh Lakdawala1, Mahemubin S. Lahori2, Ganpat K. Vankar3 1Associate Professor, Dept. of Psychiatry, AMC-MET Medical College and Sheth L.G. General Hospital, Ahmedabad, Gujarat, India. 2Assistant Professor, Dept. of Psychiatry, GMERS Medical College and General Hospital, Sola, Gujarat, India. 3Professor, Dept. of Psychiatry, Jawaharlal Nehru Medical College and Acharya Vinoba Bhave Rural Hospital Wardha, Maharashtra Corresponding author: Dr. Mahemubin Lahori Email – [email protected] ABSTRACT Introduction: Blonanserin is a novel atypical antipsychotic with higher dopamine D2 receptor occupancy and lower serotonin 5-HT2A receptor blocking activity as compared to the other atypical antipsychotics. The objective of this study was to compare the efficacy and safety of blonanserin with haloperidol in Indian patients with schizophrenia. Methodology: This was an 8 week, randomized, open label, active controlled, multicentre study. Patients diagnosed with schizophrenia according to the DSM-IV criteria were enrolled in the study. Patients were randomized to receive either blonanserin (16 mg/day) or haloperidol (4.5 mg/day). Patients were assessed on an out-patient basis after every 2 weeks for clinical efficacy [Positive and Negative Syndrome Scale (PANSS) total and factor scores], Clinical Global Impressions–severity CGI-S, Clinical Global Impressions–Improvement (CGI-I), Global Assessment of Efficacy (CGI-C), adverse events and drug compliance. Results: At our centre, total 60 patients were randomized in the study with 30 patients each in Blonanserin and Haloperidol group.
    [Show full text]
  • Drug and Medication Classification Schedule
    KENTUCKY HORSE RACING COMMISSION UNIFORM DRUG, MEDICATION, AND SUBSTANCE CLASSIFICATION SCHEDULE KHRC 8-020-1 (11/2018) Class A drugs, medications, and substances are those (1) that have the highest potential to influence performance in the equine athlete, regardless of their approval by the United States Food and Drug Administration, or (2) that lack approval by the United States Food and Drug Administration but have pharmacologic effects similar to certain Class B drugs, medications, or substances that are approved by the United States Food and Drug Administration. Acecarbromal Bolasterone Cimaterol Divalproex Fluanisone Acetophenazine Boldione Citalopram Dixyrazine Fludiazepam Adinazolam Brimondine Cllibucaine Donepezil Flunitrazepam Alcuronium Bromazepam Clobazam Dopamine Fluopromazine Alfentanil Bromfenac Clocapramine Doxacurium Fluoresone Almotriptan Bromisovalum Clomethiazole Doxapram Fluoxetine Alphaprodine Bromocriptine Clomipramine Doxazosin Flupenthixol Alpidem Bromperidol Clonazepam Doxefazepam Flupirtine Alprazolam Brotizolam Clorazepate Doxepin Flurazepam Alprenolol Bufexamac Clormecaine Droperidol Fluspirilene Althesin Bupivacaine Clostebol Duloxetine Flutoprazepam Aminorex Buprenorphine Clothiapine Eletriptan Fluvoxamine Amisulpride Buspirone Clotiazepam Enalapril Formebolone Amitriptyline Bupropion Cloxazolam Enciprazine Fosinopril Amobarbital Butabartital Clozapine Endorphins Furzabol Amoxapine Butacaine Cobratoxin Enkephalins Galantamine Amperozide Butalbital Cocaine Ephedrine Gallamine Amphetamine Butanilicaine Codeine
    [Show full text]
  • Project of Japan Drug Information Institute in Pregnancy
    Pharmaceuticals and Medical Devices Safety Information No. 268 April 2010 Table of Contents 1. Manuals for Management of Individual Serious Adverse Drug Reactions ....................................................................................................... 4 2. Project of Japan Drug Information Institute in Pregnancy ........... 9 3. Important Safety Information ................................................................. 11 .1. Atorvastatin Calcium Hydrate, Simbastatin, Pitavastatin Calcium, Pravastatin Sodium, Fluvastatin Sodium, Rosuvastatin Calcium, Amlodipine Besilate/Atorvastatin Calcium Hydrate ·································································································· 11 .2. Cetuximab (Genetical Recombination) ·························································· 16 4. Revision of PRECAUTIONS (No. 215) Aripiprazole (and 6 others)........................................................................................22 5. List of products subject to Early Post-marketing Phase Vigilance ............................................... 25 This Pharmaceuticals and Medical Devices Safety Information (PMDSI) is issued based on safety information collected by the Ministry of Health, Labour and Welfare. It is intended to facilitate safer use of pharmaceuticals and medical devices by healthcare providers. PMDSI is available on the Pharmaceuticals and Medical Devices Agency website (http://www.pmda.go.jp/english/index.html) and on the MHLW website (http://www.mhlw.go.jp/, only available in Japanese
    [Show full text]
  • Pharmacology Review(S)
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 200603 PHARMACOLOGY REVIEW(S) Tertiary Pharmacology/Toxicology Review From: Paul C. Brown, Ph.D., ODE Associate Director for Pharmacology and Toxicology, OND IO NDA: 200603 Agency receipt date: 12/30/2009 Drug: Lurasidone hydrochloride Applicant: Sunovion Pharmaceuticals (Originally submitted by Dainippon Sumimoto Pharma America, Inc.) Indication: schizophrenia Reviewing Division: Division of Psychiatry Products Background: The pharm/tox reviewer and team leader concluded that the nonclinical data support approval of lurasidone for the indication listed above. Reproductive and Developmental Toxicity: Reproductive and developmental toxicity studies in rats and rabbits revealed no evidence of teratogenicity or embryofetal toxicity. The high doses in the rat and rabbit embryofetal toxicity studies were 3 and 12 times, respectively, the maximum recommended human dose (80 mg) based on a body surface area comparison. Carcinogenicity: Lurasidone was tested in 2 year rat and mouse carcinogenicity studies. These studies were reviewed by the division and the executive carcinogenicity assessment committee. The committee concluded that the studies were adequate and that there was a drug-related increase in mammary carcinomas in female rats at doses of 12 mg/kg and higher and a drug-related increase in mammary carcinomas and adenoacanthomas and pituitary pars distalis adenomas in female mice. The applicant also provided data from various studies showing that lurasidone significantly increases prolactin in several different species including rats and mice. Conclusions: I agree with the division pharm/tox conclusion that this application can be approved from a pharm/tox perspective. The division recommends that lurasidone be labeled with pregnancy category B.
    [Show full text]