DOCSLIB.ORG

Pjp6'2003.Vp:Corelventura

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Pjp6'2003.Vp:Corelventura Copyright © 2003 by Institute of Pharmacology Polish Journal of Pharmacology Polish Academy of Sciences Pol. J. Pharmacol., 2003, 55, 1045–1053 ISSN 1230-6002 EFFECTS OF CLASSIC AND NEWER ANTIDEPRESSANTS ON THE OXIDATION PATHWAYS OF CAFFEINE IN RAT LIVER. IN VITRO STUDY W³adys³awa A. Daniel#, Marta Kot, Jacek Wójcikowski Department of Pharmacokinetics and Drug Metabolism, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland Effects of classic and newer antidepressants on the oxidation pathways of caffeine in rat liver. In vitro study. W.A. DANIEL, M. KOT, J. WÓJ- CIKOWSKI. Pol. J. Pharmacol., 2003, 55, 1045–1053. Caffeine undergoes 3-N-demethylation via CYP1A2, as well as 1-N- demethylation, 7-N-demethylation and 8-hydroxylation, which may involve other CYP isoenzymes. The aim of the present study was to investigate the influence of clomipramine, desipramine, sertraline, nefazodone and mirtaza- pine on cytochrome P-450 activity measured by caffeine oxidation in rat liver microsomes. The obtained results showed that all the investigated anti- depressants, with an exception of mirtazapine, added in vitro to liver micro- somes had an inhibitory effect on caffeine metabolism (via competitive or mixed mechanism), though their potency towards particular metabolic path- ways was different. Dixon analysis of caffeine metabolism carried out in the control liver microsomes, in the absence and presence of the antidepressant drugs showed that desipramine and clomipramine exerted the most potent inhibitory effect on caffeine metabolism. Desipramine decreased the rates of 1-N-, 3-N- and 7-N-demethylations, and 8-hydroxylation of caffeine (Ki = 23.3, 36.6, 23.3 and 63.3 mM, respectively), the effect on 1-N- and 7-N-de- methylation being the most pronounced. Clomipramine showed distinct ini- bition of 1-N- and 3-N-demethylation and 8-hydroxylation of caffeine, the effects on N-demethylations being the most pronounced (Ki = 38.6, 34.8, m 45.6 M, respectively). Its effect on 7-N-demethylation was rather weak (Ki = 97.8 mM). Sertraline decreased significantly the rate of 1-N- and 3-N-de- m methylation and 8-hydroxylation (Ki = 37.3, 69.3 and 64 M, respectively), while its effect on 7-N-demethylation of caffeine was less pronounced (Ki = 92.1 mM). Nefazodone displayed clear effect on 3-N- and 7-N-demethyla- m tion (Ki = 68.8 and 66.4 M, respectively), but was weak in inhibiting 1-N- m demethylation and 8-hydroxylation of caffeine (Ki = 110 and 186 M, re- spectively). In contrast to the above-tested antidepressants, mirtazapine did not decrease significantly the oxidation rates of 3-N-demethylation or 8-hy- m droxylation (Ki = 264 and 455 M, respectively) and had no effect on other oxidation pathways of caffeine. In summary, we have observed intra- and inter-drug differences in the inhibitory effects of the antidepressants on the four oxidation pathways of caffeine in rat liver microsomes. The tested anti- depressants (with an exception of mirtazapine) may lead to drug-drug meta- bolic interactions at a level of a few CYP isoforms. The obtained results pro- vide further indirect evidence that apart from CYP1A2, other CYP isoforms are also important for the metabolism of caffeine. Key words: caffeine metabolism, rat, cytochrome P-450 activity, clomi- pramine, desipramine, sertraline, nefazodone, mirtazapine # correspondence W.A. Daniel, M. Kot, J. Wójcikowski INTRODUCTION 1-N- and 3-N-demethylation, while fluoxetine was effective in this respect towards 8-hydroxylation Caffeine (1,3,7-trimethylxanthine), a purine al- and 7-N-demethylation of caffeine. kaloid and a component of coffee, tea and many The aim of our present study was to estimate an drugs, has some essential pharmacological proper- influence of two other tricyclic antidepressant ties, e.g. stimulation of the central nervous system, drugs, clomipramine and desipramine, one selec- diuretic and biochemical effects based on inhibition tive serotonin reuptake inhibitor (SSRI), sertraline, of phosphodiestrerase leading to the accumulation and two new antidepressants, nefazodone and mir- of cAMP and cGMP in the cells. A number of stud- tazapine, on 1-N-, 3-N- and 7-N-demethylations ies have indicated that phase I of caffeine biotrans- and 8-hydroxylation of caffeine in vitro in rat liver formation in the liver proceeds mainly via mono- microsomes. The direct inhibitory effect of those oxygenases, but its particular metabolic pathways antidepressant drugs on CYP (via binding to en- are not well characterized in respect of contribution zyme protein) has not been thoroughly studied in of cytochrome P-450 (CYP) isoenzymes. Because humans and laboratory animals as yet. While their of its natural character, caffeine is used as a test direct effects on CYP2D are relatively well known substance for estimation of phenotype with regard [5, 7], their interactions with other CYP isoforms to the activity of N-acetyltransferase NAT2 and have not been fully tested. CYP1A2 (3-N-demethylation to paraxanthine is a specific, marker reaction for CYP1A2) in humans MATERIALS and METHODS and rats [4, 16, 18]. However, caffeine is oxidized in a few positions Chemicals of its structure. Apart from 3-N-demethylation cata- lyzed by CYP1A2, the compound undergoes 1-N- Clomipramine hydrochloride was provided by demethylation, 7-N-demethylation and 8-hydroxy- RBI (Natick, MA, USA) and desipramine hydro- lation. The literature data suggest that the last three chloride by Ciba-Geigy (Wehr, Germany). Sertra- oxidation pathways of caffeine may be mediated by line hydrochloride was obtained from Pfizer Corp. CYP isoenzymes other than CYP1A2, both in hu- (Brussels, Belgium). Mirtazapine hydrochloride was mans [1, 12, 13, 21] and rats [2, 3, 4, 17]. It seems donated by Organon (The Netherlands) and nefazo- that the CYP3A subfamily is the main isoenzyme done by Bristol-Meyers Squibb International, Ltd. catalyzing 8-hydroxylation to 1,3,7-trimethyluric (Uxbridge, UK). Caffeine and its metabolites, NADP, acid [17, 21]. Moreover, there are some suggestions DL-isocitric acid (trisodium salt) and isocitric de- that 1-N-demethylation and in particular 7-N-de- hydrogenase were purchased from Sigma (St. Louis, methylation leading to the formation of theobro- USA). All organic solvents with HPLC purity were mine and theophylline (respectively) engage proba- supplied by Merck (Darmstadt, Germany). bly isoenzymes CYP2B and/or CYP2E1 [2, 21]. Animals However, the relative contribution of CYP iso- forms to the catalysis of the four oxidation path- The experiment was carried out on male Wistar ways of caffeine still requires investigation, since rats (230–260 g) kept under standard laboratory no detailed, comprehensive comparative studies conditions. Liver microsomes were prepared by concerning individual CYP isoforms have been differential centrifugation in 20 mM Tris/KCl buffer carried out so far. (pH = 7.4) including washing with 0.15 M KCl, ac- Our earlier results on the influence of psycho- cording to a conventional method. tropic drugs on the rate of caffeine oxidation in the In vitro studies into caffeine metabolism in rat liver showed distinct, but differential changes in liver microsomes the rates of individual oxidation reactions, which additionally confirmed the possibility of engage- Pooled liver microsomes from six control rats ment of different CYP isoenzymes in caffeine me- were used. Each sample was prepared in duplicate. tabolism [8, 9]. Out of the antidepressants studied The caffeine metabolism in liver microsomes was (imipramine, amitriptyline and fluoxetine), imi- studied at linear dependence of the product forma- pramine distinctly inhibited the four oxidation tion on time, and protein and substrate concentra- pathways, amitriptyline exerted such an effect on tions. The rates of 1-N-, 3-N- and 7-N-demethyla- 1046 Pol. J. Pharmacol., 2003, 55, 1045–1053 INHIBITION OF CAFFEINE METABOLISM BY ANTIDEPRESSANTS tions and 8-hydroxylation of caffeine (caffeine con- The intra- and inter-assay coefficients of variance centrations: 100–800 nmol/ml) were assessed in were below 4% and 6%, respectively. The results of the absence and presence of one of the antidepres- the above measurements were evaluated using sants added in vitro (antidepressant concentrations: Dixon and Lineweaver-Burk analysis. The values 50–800 nmol/ml). Incubations were carried out in of Ki,Km and Vmax were obtained graphically. a system containing liver microsomes (ca. 1 mg of protein/ml), phosphate buffer (0.1 M, pH = 7.4), RESULTS and DISCUSSION MgCl2 ×6H2O (6 mM), NADP (1.2 mM), DL-iso- citric acid (6 mM) and isocitric dehydrogenase (1.2 The obtained results showed intra- and inter- U/ml). The final incubation volume was 0.5 ml. drug differences in the inhibitory effects of the in- After a 2-min preincubation, the reaction was initi- vestigated antidepressants on the four oxidation ated by adding NADPH generating system and the pathways of caffeine in rat liver microsomes. The incubation lasted for 50 min. Afterwards, the reac- tricyclic antidepressants clomipramine and desi- m tion was stopped by adding 350 lof2%ZnSO4 pramine displayed distinct inhibitory effects on caf- and 25 mlof2MHCl. feine metabolism via competitive or mixed mecha- Determination of caffeine and its metabolites nisms, but their potency towards particular meta- bolic pathways was different. Dixon analysis of Caffeine and its four primary metabolites were caffeine metabolism carried out on control liver mi- assessed using the HPLC method with UV detec- crosomes, in the absence and presence of the anti- tion as described previously [9]. After incubation, depressants showed that desipramine exerted the samples were centrifuged for 10 min at 2000 × g. most potent inhibitory effect on caffeine metabo- A water phase containing caffeine and its metabo- lism. Desipramine decreased the rate of both the lites was extracted with 6 ml of organic mixture three N-demethylations and 8-hydroxylation of caf- consisting of ethyl acetate and 2-propanol (8:1, feine (Fig.
Load more

Recommended publications
  • T.C. Süleyman Demirel Üniversitesi Fen Bilimleri Enstitüsü Bazi Antidepresan Ilaç Numunelerinin Pcr Ve Pls
    T.C. SÜLEYMAN DEMİREL ÜNİVERSİTESİ FEN BİLİMLERİ ENSTİTÜSÜ BAZI ANTİDEPRESAN İLAÇ NUMUNELERİNİN PCR VE PLS İLE SPEKTROFOTOMETRİK TAYİNLERİ Nuray AYTEKİN Danışman Prof. Dr. Ahmet Hakan AKTAŞ YÜKSEK LİSANS TEZİ KİMYA ANABİLİM DALI ISPARTA - 2014 2 © 2014 [Nuray AYTEKİN] TAAHHÜTNAME Bu tezin akademik ve etik kurallara uygun olarak yazıldığını ve kullanılan tüm literatür bilgilerinin referans gösterilerek tezde yer aldığını beyan ederim. Nuray AYTEKİN ii İÇİNDEKİLER Sayfa İÇİNDEKİLER ......................................................................................................................... i ÖZET ......................................................................................................................................... iii ABSTRACT .............................................................................................................................. iv TEŞEKKÜR .............................................................................................................................. v ŞEKİLLER DİZİNİ ................................................................................................................. vi ÇİZELGELER DİZİNİ ............................................................................................................ vii SİMGELER VE KISALTMALAR DİZİNİ .......................................................................... viii 1. GİRİŞ..................................................................................................................................... 1 1.1. Sertralinenin
    [Show full text]
  • WO 2012/068516 A2 24 May 20 12 (24.05.2012) W P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/068516 A2 24 May 20 12 (24.05.2012) W P O P C T (51) International Patent Classification: (72) Inventors; and A61K 31/352 (2006.01) A61P 25/24 (2006.01) (75) Inventors/Applicants (for US only): LETENDRE, Peter A61K 9/48 (2006.01) A61P 25/22 (2006.01) [US/US]; 2389 Indian Peaks Trail, Lafayette, Colorado A61K 9/20 (2006.01) A61P 25/00 (2006.01) 80026 (US). CARLEY, David [US/US]; 2457 Pioneer Rd., Evanston, Illinois 60201 (US). (21) International Application Number: PCT/US201 1/061490 (74) Agents: FEDDE, Kenton et al; 18325 AUenton Woods Ct, Wildwood, Missouri 63069 (US). (22) International Filing Date: 18 November 201 1 (18.1 1.201 1) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (25) Language: English Filing AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (26) Publication Language: English CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (30) Priority Data: HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, 61/415,33 1 18 November 2010 (18. 11.2010) US KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (71) Applicant (for all designated States except US): PIER MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PHARMACEUTICALS [US/US]; 901 Front St., Suite OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, 201, Louisville, Colorado 80027 (US).
    [Show full text]
  • Antidepressants, Other Review 04/14/2009
    Antidepressants, Other Review 04/14/2009 Copyright © 2004 - 2009 by Provider Synergies, L.L.C. All rights reserved. Printed in the United States of America. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, digital scanning, or via any information storage and retrieval system without the express written consent of Provider Synergies, L.L.C. All requests for permission should be mailed to: Attention: Copyright Administrator Intellectual Property Department Provider Synergies, L.L.C. 5181 Natorp Blvd., Suite 205 Mason, Ohio 45040 The materials contained herein represent the opinions of the collective authors and editors and should not be construed to be the official representation of any professional organization or group, any state Pharmacy and Therapeutics committee, any state Medicaid Agency, or any other clinical committee. This material is not intended to be relied upon as medical advice for specific medical cases and nothing contained herein should be relied upon by any patient, medical professional or layperson seeking information about a specific course of treatment for a specific medical condition. All readers of this material are responsible for independently obtaining medical advice and guidance from their own physician and/or other medical professional in regard to the best course of treatment for their specific medical condition. This publication, inclusive of all forms contained herein, is intended to be
    [Show full text]
  • Toxic, and Comatose-Fatal Blood-Plasma Concentrations (Mg/L) in Man
    Therapeutic (“normal”), toxic, and comatose-fatal blood-plasma concentrations (mg/L) in man Substance Blood-plasma concentration (mg/L) t½ (h) Ref. therapeutic (“normal”) toxic (from) comatose-fatal (from) Abacavir (ABC) 0.9-3.9308 appr. 1.5 [1,2] Acamprosate appr. 0.25-0.7231 1311 13-20232 [3], [4], [5] Acebutolol1 0.2-2 (0.5-1.26)1 15-20 3-11 [6], [7], [8] Acecainide see (N-Acetyl-) Procainamide Acecarbromal(um) 10-20 (sum) 25-30 Acemetacin see Indomet(h)acin Acenocoumarol 0.03-0.1197 0.1-0.15 3-11 [9], [3], [10], [11] Acetaldehyde 0-30 100-125 [10], [11] Acetaminophen see Paracetamol Acetazolamide (4-) 10-20267 25-30 2-6 (-13) [3], [12], [13], [14], [11] Acetohexamide 20-70 500 1.3 [15] Acetone (2-) 5-20 100-400; 20008 550 (6-)8-31 [11], [16], [17] Acetonitrile 0.77 32 [11] Acetyldigoxin 0.0005-0.00083 0.0025-0.003 0.005 40-70 [18], [19], [20], [21], [22], [23], [24], [25], [26], [27] 1 Substance Blood-plasma concentration (mg/L) t½ (h) Ref. therapeutic (“normal”) toxic (from) comatose-fatal (from) Acetylsalicylic acid (ASS, ASA) 20-2002 300-3502 (400-) 5002 3-202; 37 [28], [29], [30], [31], [32], [33], [34] Acitretin appr. 0.01-0.05112 2-46 [35], [36] Acrivastine -0.07 1-2 [8] Acyclovir 0.4-1.5203 2-583 [37], [3], [38], [39], [10] Adalimumab (TNF-antibody) appr. 5-9 146 [40] Adipiodone(-meglumine) 850-1200 0.5 [41] Äthanol see Ethanol -139 Agomelatine 0.007-0.3310 0.6311 1-2 [4] Ajmaline (0.1-) 0.53-2.21 (?) 5.58 1.3-1.6, 5-6 [3], [42] Albendazole 0.5-1.592 8-992 [43], [44], [45], [46] Albuterol see Salbutamol Alcuronium 0.3-3353 3.3±1.3 [47] Aldrin -0.0015 0.0035 50-1676 (as dieldrin) [11], [48] Alendronate (Alendronic acid) < 0.005322 -6 [49], [50], [51] Alfentanil 0.03-0.64 0.6-2.396 [52], [53], [54], [55] Alfuzosine 0.003-0.06 3-9 [8] 2 Substance Blood-plasma concentration (mg/L) t½ (h) Ref.
    [Show full text]
  • BIOANALYTICAL Methodsat
    HANDBOOK OF BIOANALYTICALEdition: METHODS January 2015at LAMBDA THERAPEUTIC RESEARCH Edition: FEBRUARY 2020 Bio-analytical Lambda is one of the most experienced Bioanalytical service providers in India. We provide these services from two different strategic locations - India and Canada. Our highly qualified and experienced scientists work 24x7 and have an accumulated global catalogue of more than 1200 validated methods. Our vast expertise and in-depth understanding of the stringent regulatory demands ensures each project is accomplished in rapid turn-around times. qualified (Ph. D, M. Pharm, M.Sc, B.Pharm) and experience team comprising of 150+ research professionals GLP certified Bioanalytical labs in India and Canada Capabilities of analyzing 90,000+ samples per month on 50+ LC-MS/MS 7-8 new methods in development/month with expertise in handling different matrices such as plasma, serum, urine, whole blood, milk, food, bone, stool and animal tissues Infrastructure Separate well equipped extraction labs and chromatography labs. Separate lab for photosensitive drug. Separate room for storage of standards / balance room. Low temperature storage (-22 ± 5 °C, -65 ± 10 °C) Biolyte (Chromatographic Data review and data printing software) Different types of 50+ LC-MS/MS systems (including API 6500 and Waters Xevo TQ-S) Regulatory Track Record Table of Contents Title Page Large Molecules / Therapeutic Proteins / Biosimilars ............... 1 Small Molecules ............... 2 New Chemical Entities ............... 71 In‐Vitro Studies ..............
    [Show full text]
  • Antidepressants, Other Therapeutic Class Review (TCR)
    Antidepressants, Other Therapeutic Class Review (TCR) January 9, 2020 No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, digital scanning, or via any information storage or retrieval system without the express written consent of Magellan Rx Management. All requests for permission should be mailed to: Magellan Rx Management Attention: Legal Department 6950 Columbia Gateway Drive Columbia, Maryland 21046 The materials contained herein represent the opinions of the collective authors and editors and should not be construed to be the official representation of any professional organization or group, any state Pharmacy and Therapeutics committee, any state Medicaid Agency, or any other clinical committee. This material is not intended to be relied upon as medical advice for specific medical cases and nothing contained herein should be relied upon by any patient, medical professional or layperson seeking information about a specific course of treatment for a specific medical condition. All readers of this material are responsible for independently obtaining medical advice and guidance from their own physician and/or other medical professional in regard to the best course of treatment for their specific medical condition. This publication, inclusive of all forms contained herein, is intended to be educational in nature and is intended to be used for informational purposes only. Send comments and suggestions to [email protected]. January
    [Show full text]
  • University of Groningen SSRI Augmentation Strategies Cremers
    University of Groningen SSRI augmentation strategies Cremers, Thomas Ivo Franciscus Hubert IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2002 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Cremers, T. I. F. H. (2002). SSRI augmentation strategies: pharmacodynamic and pharmacokinetic considerations. s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 01-10-2021 Clinical efficacy of antidepressants in depression Chapter 2 Clinical efficacy of antidepressants in depression 33 Chapter 2 Introduction History Once the therapeutic effects of iproniazid and imipramine in major depression were recognized, pharmaceutical companies intensified research programs to develop superior antidepressants.
    [Show full text]
  • Drug Class Review
    Drug Class Review Miscellaneous and Serotonergic Agents 28:16.04.92 Antidepressants, Miscellaneous Bupropion (Wellbutrin®; Wellbutrin® SR; Wellbutrin® XL; Zyban®) Mirtazapine (Remeron®; Remeron® SolTab™) 28:16.04.24 Serotonin Modulators Nefazodone (Serzone®) Trazodone (Desyrel®) Vilazodone (Viibryd®) Vortioxetine (Trintellix®) 28:92 Central Nervous System Agents, Miscellaneous Atomoxetine (Strattera®) 28:28 Antimanic Agents Lithium (Eskalith CR®; Eskalith®; Lithobid® Slow-release) Final Report August 2016 Review prepared by: Melissa Archer, PharmD, Clinical Pharmacist Carin Steinvoort, PharmD, Clinical Pharmacist Vicki Frydrych, PharmD, Clinical Pharmacist Joanne LaFleur PharmD, MSPH, Associate Professor Gary Oderda, PharmD, MPH, Professor University of Utah College of Pharmacy Copyright © 2016 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved. 1 Contents Executive Summary ...................................................................................................................... 3 Introduction ................................................................................................................................... 6 Table 1. Comparison of the Miscellaneous and Serotonergic Agents ................................... 7 Table 2. Miscellaneous Serotonergic Agents FDA-Labeled Indications ............................. 10 Disease Overview ........................................................................................................................ 11 Table 3. Current Clinical Practice
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 6,469,008 B2 Currie Et Al
    USOO6469008B2 (12) United States Patent (10) Patent No.: US 6,469,008 B2 Currie et al. (45) Date of Patent: Oct. 22, 2002 (54) (R)-HYDROXYNEFAZODONE FOREIGN PATENT DOCUMENTS ANTIPSYCHOTIC THERAPY EP O769297 A1 4/1997 (75) Inventors: Mark G. Currie, Sterling, MA (US); OTHER PUBLICATIONS Thomas P. Jerussi, Framingham, MA (US); Paul D. Rubin, Sudbury, MA Green et al. “Clinical Pharmacokinetics of Nefazodone” (US) Clin. Pharmacokinet. 33, 260–275 (1997). Barbahaiya et al. “Single and Multiple Dose Pharmacoki (73) Assignee: Sepracor Inc., Marlborough, MA (US) netics of Nefazodone in Subjects Classified . .” Br. J. Clin. Pharm. 42,573–581 (1996). (*) Notice: Subject to any disclaimer, the term of this Cyr et al. “Nefazodone: Its Place Among Antidepressants' patent is extended or adjusted under 35 Ann. Pharmacother 30, 1006-12 (1996). U.S.C. 154(b) by 0 days. Malik “Nefazodone: structure, mode of action and pharma cokinetics”. J. Psychopharm. 10, 1-4 (1996). (21) Appl. No.: 09/992, 197 S.A. Montgomery “Efficacy of nefazodone in the treatment of depression” J. Psychopharm. 10, 5-10 (1996). (22) Filed: Nov. 14, 2001 Nacca et al. “Brain-to-blood partition and in vivo inhibition O O of 5-hydroxytryptamine reuptake . .” Br. J. Pharmac. 125, (65) Prior Publication Data 1617–1623 (1998). US 2002/0058675 A1 May 16, 2002 von Moltke et al. “Nefazodone, meta-chlorophenylpipera zine, and their metabolites . Psychopharma. 145, Related U.S. Application Data 113–122 (1999). Eison et a. “Nefazodone: Preclinical Pharmacology of a (63) Continuation-in-part of application No. 09/545,602, filed on New Antidepressant’ Psychopharma.
    [Show full text]
  • Metabolic Activation 73 2-Allylisopropylacetamide (AIA) 117F
    j377 Index a – terminal 117ff. abacavir 369f. allele association ABT, see 1-aminobenzotriazole – HLA 370 acetaminophen 71, 273ff. allopurinol 373 – metabolic activation 73 2-allylisopropylacetamide (AIA) 117f. – metabolism 72 alpidem 304f., 336, 349 acetaminophen-like metabolite 276 amanitin 204 N-acetyl-p-benzoquinone imine (NAPQI) Ames assay 29 5, 73 AMG 458 139ff. N-acetylcysteine 275 a-amidoacetonitrile 324 N-acetyltransferase (NAT) 16, 283 amine 49 N-acetyltransferase-2 (NAT-2) 79, 283 – aromatic, see aromatic amine acute liver failure (ALF) 363 – carcinogenicity of aromatic and acylating agent 320 heteroaromatic amine 13 afatinib 319 – drug–drug interaction 51 affinity label 313 amineptine 196, 342ff. aflatoxin 214 2-amino-3,8-dimethylimidazo[4,5-f] fl a atoxin B1 (AFB1)2 quinoxaline (MeIQx) 216 – bioactivation 215 – bioactivation 218 AKT inhibitor, see protein kinase B inhibitor 2-amino-1-methyl-6-phenylimidazo[4,5-b] alanine transaminase (ALT) 363 pyridine (PhIP) 216 alclofenac – bioactivation 218 – metabolic activation 119 aminoazo dye 15 aldehyde oxidase 60 1-aminobenzotriazole (ABT) 58f. alendronic acid 290 aminoglutethimide 188 alkaloid 5-aminooxindole 253 – pyrrolizidine 210 – derivative 254 alkene ortho-aminophenol 101 – terminal 117f. para-aminophenol 101 3-alkyl pyrrole 112 2-aminothiazole 109 – activation 112 amitriptyline 282ff., 343f. alkylating species 173 – metabolism 287 2-alkylimidazole 57 amlodipine 274 3-alkylindole analogue 113 amodiaquine 252 3-alkylindole derivative 112 – metabolic activation 101 alkylpiperazine 258 amoxicillin 132, 273ff., 288 alkyne 56f. angiotensin converting enzyme – bioactivation 119f. inhibitor 294ff. – internal 120 angiotensin II receptor antagonist 298 Reactive Drug Metabolites, First Edition. Amit S. Kalgutkar, Deepak Dalvie, R. Scott Obach, and Dennis A.
    [Show full text]
  • WO 2009/049018 Al
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 16 April 2009 (16.04.2009) WO 2009/049018 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/33 (2006.01) C07D 213/00 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, (21) International Application Number: CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, PCT/US2008/079298 EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, (22) International Filing Date: 9 October 2008 (09.10.2008) IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY,MA, MD, ME, MG, MK, MN, MW, (25) Filing Language: English MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, (26) Publication Language: English RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (30) Priority Data: ZW 60/978,955 10 October 2007 (10.10.2007) US (71) Applicant (for all designated States except US): SYN- (84) Designated States (unless otherwise indicated, for every DAX PHARMACEUTICALS, INC. [US/US]; 11260 El kind of regional protection available): ARIPO (BW, GH, Camino Real, Suite 220, San Diego, CA 92130 (US). GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), (72) Inventors; and European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, (75) Inventors/Applicants (for US only): KEANNA, John, FR, GB, GR, HR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, F.W.
    [Show full text]
  • Depression Following Spinal Cord Injury: a Clinical Practice Guideline for Primary Care Physicians CLINICAL PRACTICE GUIDELINE: DEPRESSION
    SPINAL CORD MEDICINE Depression Following Spinal Cord Injury: A Clinical Practice Guideline for Primary Care Physicians CLINICAL PRACTICE GUIDELINE: DEPRESSION Administrative and financial support provided by Paralyzed Veterans of America CLINICAL PRACTICE GUIDELINES Spinal Cord Medicine Depression Following Spinal Cord Injury: A Clinical Practice Guideline for Primary Care Physicians Consortium for Spinal Cord Medicine Administrative and financial support provided by Paralyzed Veterans of America © Copyright 1998, Paralyzed Veterans of America August 1998 This guide has been prepared based on scientific and professional information known about depression following spinal cord injury/dysfunction, its causes, and its treatments, in 1998. Users of this guide should periodically review this material to ensure that the advice herein is consistent with current reasonable clinical practice. CLINICAL PRACTICE GUIDELINES iii Contents v Foreword vii Preface ix Acknowledgments x Panel Members xi Contributors 1 Summary of Recommendations 3 The Spinal Cord Medicine Consortium GUIDELINES DEVELOPMENT PROCESS DEPRESSION GUIDELINES METHODOLOGY STRENGTH OF EVIDENCE 6 Treatment Recommendations ASSESSMENT DIAGNOSIS TREATMENT PSYCHOPHARMACOLOGICAL AGENTS PSYCHOPHARMACOLOGICAL GUIDELINES ANTIDEPRESSANT PHARMACOTHERAPY ENVIRONMENTAL AND SOCIAL FACTORS AND SOCIAL SUPPORT SYSTEMS CONSUMER AND FAMILY EDUCATION EVALUATION AND MODIFICATION OF TREATMENT PLAN 28 Directions for Future Research 30 Reference Section A 32 Reference Section B 34 Index CLINICAL PRACTICE
    [Show full text]