DOCSLIB.ORG

Section 2.6.4 Pharmacokinetics Written Summary EMTRICITABINE

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Section 2.6.4 Pharmacokinetics Written Summary EMTRICITABINE SECTION 2.6 NONCLINICAL SUMMARY Section 2.6.4 Pharmacokinetics Written Summary EMTRICITABINE/ RILPIVIRINE/ TENOFOVIR DISOPROXIL FUMARATE FIXED-DOSE COMBINATION 17 August 2010 CONFIDENTIAL AND PROPRIETARY INFORMATION Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Section 2.6.4 Pharmacokinetics Written Summary Final TABLE OF CONTENTS SECTION 2.6 NONCLINICAL SUMMARY........................................................................................................1 TABLE OF CONTENTS .......................................................................................................................................2 GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ..............................................................5 2.6. NONCLINICAL SUMMARY.......................................................................................................................8 2.6.4. PHARMACOKINETICS WRITTEN SUMMARY .........................................................................8 2.6.4.1. Brief Summary................................................................................................................8 2.6.4.2. Methods of Analysis .....................................................................................................14 2.6.4.2.1. Emtricitabine............................................................................................14 2.6.4.2.2. Rilpivirine ................................................................................................14 2.6.4.2.3. Tenofovir Disoproxil Fumarate ...............................................................16 2.6.4.3. Absorption.....................................................................................................................17 2.6.4.3.1. In Vitro Absorption Studies for Rilpivirine .............................................17 2.6.4.3.2. In Vitro Absorption Studies for Tenofovir DF ........................................17 2.6.4.3.3. Single-Dose Studies for Emtricitabine, Rilpivirine, and Tenofovir DF...18 2.6.4.3.4. Repeat Dose Studies for Emtricitabine, Rilpivirine, and Tenofovir DF ............................................................................................................24 2.6.4.3.5. Emtricitabine/Tenofovir DF: Absorption.................................................39 2.6.4.3.6. Emtricitabine/Rilpivirine/Tenofovir DF: Absorption ..............................39 2.6.4.4. Distribution ...................................................................................................................39 2.6.4.4.1. Plasma Protein Binding for Emtricitabine, Rilpivirine, and Tenofovir DF ............................................................................................................39 2.6.4.4.2. Tissue Distribution Studies for Emtricitabine, Rilpivirine, and Tenofovir DF ...........................................................................................41 2.6.4.4.3. Studies in Pregnant or Nursing Animals for Emtricitabine, Rilpivirine, and Tenofovir DF .................................................................49 2.6.4.4.4. Emtricitabine/Tenofovir DF: Distribution ...............................................51 2.6.4.4.5. Emtricitabine/Rilpivirine/Tenofovir DF: Distribution.............................51 2.6.4.5. Metabolism....................................................................................................................52 2.6.4.5.1. Metabolism In Vitro for Emtricitabine, Rilpivirine, and Tenofovir DF...52 2.6.4.5.2. Metabolism In Vivo for Emtricitabine, Rilpivirine, and Tenofovir DF...61 2.6.4.5.3. Possible Metabolic Pathways for Emtricitabine, Rilpivirine, and Tenofovir DF ...........................................................................................69 2.6.4.5.4. Emtricitabine/Tenofovir DF: Metabolism................................................72 2.6.4.5.5. Emtricitabine/Rilpivirine/Tenofovir DF: Metabolism .............................72 2.6.4.6. Excretion .......................................................................................................................73 2.6.4.6.1. Route and Extent of Excretion of Emtricitabine, Rilpivirine, and Tenofovir DF ...........................................................................................73 2.6.4.6.2. Excretion into Bile...................................................................................75 2.6.4.6.3. Excretion into Milk..................................................................................76 2.6.4.6.4. Emtricitabine/Tenofovir DF: Excretion ...................................................77 2.6.4.6.5. Emtricitabine/Rilpivirine/Tenofovir DF: Excretion.................................77 2.6.4.7. Pharmacokinetic Drug Interactions...............................................................................77 2.6.4.7.1. Emtricitabine: Pharmacokinetic Drug Interactions..................................77 2.6.4.7.2. Rilpivirine: Pharmacokinetic Drug Interactions ......................................77 2.6.4.7.3. Tenofovir DF: Pharmacokinetic Drug Interactions..................................78 2.6.4.7.4. Emtricitabine/Tenofovir DF: Pharmacokinetic Drug Interactions...........79 2.6.4.7.5. Emtricitabine/Rilpivirine/Tenofovir DF: Pharmacokinetic Drug Interactions...............................................................................................79 2.6.4.8. Other Pharmacokinetic Studies .....................................................................................79 CONFIDENTIAL Page 2 17 August 2010 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Section 2.6.4 Pharmacokinetics Written Summary Final 2.6.4.8.1. Emtricitabine/Rilpivirine/Tenofovir DF ..................................................79 2.6.4.9. Discussion and Conclusions..........................................................................................79 2.6.4.10. Summary Tables............................................................................................................90 2.6.4.10. References.....................................................................................................................95 LIST OF IN-TEXT TABLES Table 1. Pharmacokinetic Parameters of TMC278 After Single or Repeated Administration by Oral Gavage of TMC278 in Mice .....................................................27 Table 2. Pharmacokinetic Parameters of TMC278 After Single or Repeated Administration by Oral Gavage of TMC278 Base or TMC278 in Sprague Dawley Rats ....................................................................................................................31 Table 3. Pharmacokinetic Parameters of TMC278 After Single or Repeated Administration by Oral Gavage of TMC278 Base in Beagle Dogs.................................34 Table 4. Pharmacokinetic Parameters of TMC278 After Single or Repeated Administration by Oral Gavage of TMC278 in Female Cynomolgus Monkeys.............36 Table 5. Plasma Protein Binding and Blood Distribution of TMC278 at 1 μg/mL (Various Species) or 2.5 μg/mL (Guinea pig and Monkey) ............................................40 Table 6. Percentage of Testosterone 6ȕ-hydroxylase, Lauric Acid 12-hydroxylase and UDP-GT Activities Relative to Control Values in Hepatic Microsomal Fractions of CD-1 Mouse, Sprague Dawley Rat and Beagle Dog After Repeated Administration of TMC278 or TMC278 Base ................................................58 Table 7. Interaction of TMC278 With Human CYP450 In Vitro..................................................59 Table 8. Total Percentage of the Administered Dose Metabolized per Major Pathways in Man and its Corresponding Percentages in Mice, Rats, and Dogs After Oral Administration of [14C]TMC278.....................................................................................70 Table 9. Urinary and Fecal Excretion of the Radioactivity Following a Single Oral Dose of 14C-TMC278 base in Mouse and Rat at 96 Hours After Dosing and in Dog and Human at 168 Hours After Dosing...........................................................................74 Table 10. Summary of Pharmacokinetics Parameters for Emtricitabine After Single Dose Administration.................................................................................................................91 Table 11. Disposition of Radioactivity after Oral Single Dose Administration of Radiolabeled Emtricitabine in Animals...........................................................................92 Table 12. Comparison of Tenofovir Non-Compartmental Pharmacokinetic Parameters Between Species Following Single Dose Oral Administration of TDF ..........................93 Table 13. Comparison of Tenofovir Non-Compartmental Pharmacokinetic Parameters Between Species Following IV Administration of Tenofovir .........................................94 LIST OF IN-TEXT FIGURES Figure 1. Structural Formula of [14C]TMC278 (Left) and [3H]TMC278 (Right) ...........................14 Figure 2. Plasma Concentrations of TMC278 in CD-1 Mice After Repeated Administration of TMC278 by Oral Gavage Once Daily for 28 Weeks in the Carcinogenicity Study .....................................................................................................28 Figure 3. Plasma Concentrations of TMC278 in Sprague Dawley Rats After Repeated Administration of TMC278 Base by Gavage Once Daily for 6 Months (Day 175) ........................................................................................................................32 Figure 4. Plasma
Load more

Recommended publications
  • Steroid Recognition and Regulation of Hormone Action: Crystal
    Research Article 799 Steroid recognition and regulation of hormone action: crystal structure of testosterone and NADP+ bound to 3a-hydroxysteroid/ dihydrodiol dehydrogenase Melanie J Bennett1†, Ross H Albert1, Joseph M Jez1, Haiching Ma2, Trevor M Penning2 and Mitchell Lewis1* Background: Mammalian 3a-hydroxysteroid dehydrogenases (3a-HSDs) Addresses: 1Department of Biochemistry and modulate the activities of steroid hormones by reversibly reducing their C3 Biophysics, The Johnson Research Foundation, 37th and Hamilton Walk, Philadelphia, PA 19104- ketone groups. In steroid target tissues, 3a-HSDs act on 5a-dihydrotestosterone, 6059, USA and 2Department of Pharmacology, a potent male sex hormone (androgen) implicated in benign prostate hyperplasia University of Pennsylvania School of Medicine, 37th and prostate cancer. Rat liver 3a-HSD belongs to the aldo-keto reductase (AKR) and Hamilton Walk, Philadelphia, PA 19104-6084, superfamily and provides a model for mammalian 3a-, 17b- and 20a-HSDs, USA. which share > 65% sequence identity. The determination of the structure of 3a- †Present address: Division of Biology, California + HSD in complex with NADP and testosterone (a competitive inhibitor) will help Institute of Technology, 1200 E California Blvd., to further our understanding of steroid recognition and hormone regulation by Pasadena, CA 91125, USA. mammalian HSDs. *Corresponding author. E-mail: [email protected] Results: We have determined the 2.5 Å resolution crystal structure of recombinant rat liver 3a-HSD complexed with NADP+ and testosterone. The Key words: aldo-keto reductase, crystal structure, structure provides the first picture of an HSD ternary complex in the AKR 3a-hydroxysteroid/dihydrodiol dehydrogenase, superfamily, and is the only structure to date of testosterone bound to a protein.
    [Show full text]
  • WO 2018/005909 Al 04 January 2018 (04.01.2018) W !P O PCT
    (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 2018/005909 Al 04 January 2018 (04.01.2018) W !P O PCT (51) International Patent Classification: A61P 31/12 (2006 .01) A61K 31/505 (2006 .0 1) A61K 31/4985 (2006.01) (21) International Application Number: PCT/US20 17/040 175 (22) International Filing Date: 30 June 2017 (30.06.2017) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/357,458 0 1 July 2016 (01 .07.2016) US (71) Applicant: VIIV HEALTHCARE COMPANY [US/US]; 25 1 Little Falls Drive, Wilmington, DE 19808 (US). (72) Inventor: SPREEN, William, R.; 5 Moore Drive, Re search Triangle Park, NC 27709-3398 (US). (74) Agent: HAN, William, T. et al; Glaxosmithkline, Glob al Patents, UW2220, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PA 19406-0939 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
    [Show full text]
  • CASODEX (Bicalutamide)
    HIGHLIGHTS OF PRESCRIBING INFORMATION • Gynecomastia and breast pain have been reported during treatment with These highlights do not include all the information needed to use CASODEX 150 mg when used as a single agent. (5.3) CASODEX® safely and effectively. See full prescribing information for • CASODEX is used in combination with an LHRH agonist. LHRH CASODEX. agonists have been shown to cause a reduction in glucose tolerance in CASODEX® (bicalutamide) tablet, for oral use males. Consideration should be given to monitoring blood glucose in Initial U.S. Approval: 1995 patients receiving CASODEX in combination with LHRH agonists. (5.4) -------------------------- RECENT MAJOR CHANGES -------------------------- • Monitoring Prostate Specific Antigen (PSA) is recommended. Evaluate Warnings and Precautions (5.2) 10/2017 for clinical progression if PSA increases. (5.5) --------------------------- INDICATIONS AND USAGE -------------------------- ------------------------------ ADVERSE REACTIONS ----------------------------- • CASODEX 50 mg is an androgen receptor inhibitor indicated for use in Adverse reactions that occurred in more than 10% of patients receiving combination therapy with a luteinizing hormone-releasing hormone CASODEX plus an LHRH-A were: hot flashes, pain (including general, back, (LHRH) analog for the treatment of Stage D2 metastatic carcinoma of pelvic and abdominal), asthenia, constipation, infection, nausea, peripheral the prostate. (1) edema, dyspnea, diarrhea, hematuria, nocturia, and anemia. (6.1) • CASODEX 150 mg daily is not approved for use alone or with other treatments. (1) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca Pharmaceuticals LP at 1-800-236-9933 or FDA at 1-800-FDA-1088 or ---------------------- DOSAGE AND ADMINISTRATION ---------------------- www.fda.gov/medwatch The recommended dose for CASODEX therapy in combination with an LHRH analog is one 50 mg tablet once daily (morning or evening).
    [Show full text]
  • PENTOBARBITAL SODIUM- Pentobarbital Sodium Injection Akorn, Inc
    PENTOBARBITAL SODIUM- pentobarbital sodium injection Akorn, Inc. ---------- Nembutal® Sodium Solution CII (pentobarbital sodium injection, USP) + novaplus TM Rx only Vials DO NOT USE IF MATERIAL HAS PRECIPITATED DESCRIPTION The barbiturates are nonselective central nervous system depressants which are primarily used as sedative hypnotics and also anticonvulsants in subhypnotic doses. The barbiturates and their sodium salts are subject to control under the Federal Controlled Substances Act (See “Drug Abuse and Dependence” section). The sodium salts of amobarbital, pentobarbital, phenobarbital, and secobarbital are available as sterile parenteral solutions. Barbiturates are substituted pyrimidine derivatives in which the basic structure common to these drugs is barbituric acid, a substance which has no central nervous system (CNS) activity. CNS activity is obtained by substituting alkyl, alkenyl, or aryl groups on the pyrimidine ring. NEMBUTAL Sodium Solution (pentobarbital sodium injection) is a sterile solution for intravenous or intramuscular injection. Each mL contains pentobarbital sodium 50 mg, in a vehicle of propylene glycol, 40%, alcohol, 10% and water for injection, to volume. The pH is adjusted to approximately 9.5 with hydrochloric acid and/or sodium hydroxide. NEMBUTAL Sodium is a short-acting barbiturate, chemically designated as sodium 5-ethyl-5-(1- methylbutyl) barbiturate. The structural formula for pentobarbital sodium is: The sodium salt occurs as a white, slightly bitter powder which is freely soluble in water and alcohol but practically insoluble in benzene and ether. CLINICAL PHARMACOLOGY Barbiturates are capable of producing all levels of CNS mood alteration from excitation to mild sedation, to hypnosis, and deep coma. Overdosage can produce death. In high enough therapeutic doses, barbiturates induce anesthesia.
    [Show full text]
  • Download Article PDF/Slides
    Kan Lu, PharmD New Antiretrovirals for Based on a presentation at prn by Roy M. Gulick, md, mph the Treatment of HIV: Kan Lu, PharmD | Drug Development Fellow University of North Carolina School of Pharmacy Chapel Hill, North Carolina The View in 2006 Roy M. Gulick, md, mph Reprinted from The prn Notebook® | october 2006 | Dr. James F. Braun, Editor-in-Chief Director, Cornell Clinical Trials Unit | Associate Professor of Medicine, Meri D. Pozo, PhD, Managing Editor. Published in New York City by the Physicians’ Research Network, Inc.® Weill Medical College of Cornell University | New York, New York John Graham Brown, Executive Director. For further information and other articles available online, visit http://www.prn.org | All rights reserved. ©october 2006 substantial progress continues to be made in the arena of cokinetics and a long extracellular half-life of approximately 10 hours antiretroviral drug development. prn is again proud to present its annual (Zhu, 2003). During apricitabine’s development, a serious drug interac- review of the experimental agents to watch for in the coming months and tion with lamivudine (Epivir) was noted. Although the plasma years. This year’s review is based on a lecture by Dr. Roy M. Gulick, a long- concentrations of apricitabine were unaffected by coadministration of time friend of prn, and no stranger to the antiretroviral development lamivudine, the intracellular concentrations of apricitabine were reduced pipeline. by approximately sixfold. Additionally, the 50% inhibitory concentration To date, twenty-two antiretrovirals have been approved by the Food (ic50) of apricitabine against hiv with the M184V mutation was increased and Drug Administration (fda) for the treatment of hiv infection.
    [Show full text]
  • An Unexpected Target for Androgen Deprivation Therapy with Prognosis and Diagnostic Implications
    Author Manuscript Published OnlineFirst on October 11, 2013; DOI: 10.1158/0008-5472.CAN-13-1462 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Androgen glucuronidation: an unexpected target for androgen deprivation therapy with prognosis and diagnostic implications. Laurent Grosse1, Sophie Pâquet1, Patrick Caron1, Ladan Fazli2, Paul S. Rennie2, Alain Bélanger3 and Olivier Barbier1 1Laboratory of Molecular Pharmacology, CHU-Québec Research Centre and Faculty of Pharmacy, Laval University, Québec, Canada 2 Vancouver Prostate Centre at VGH, University of British Columbia, Vancouver, British Columbia, Canada. 3CHU-Québec Research Centre and Faculty of Medicine, Laval University, Québec, Canada Running title: Ablation therapy improves androgen glucuronidation in PCa Keywords: Prostate cancer, androgen ablation therapy, glucuronidation, biomarker, drug target. Financial support: This study was supported by grants from the Canadian Institutes of Health Research (CIHR), the Terry Fox foundation and the Canadian Foundation for Innovation. S. Pâquet is holder of scholarships from CIHR and the Fonds pour la Recherche en Santé du Québec (FRSQ). L. Grosse is supported by a scholarship from the Fonds pour l’Enseignement et la Recherche (FER) from the Faculty of Pharmacy, Laval University (Québec). O. Barbier is holder of salary grants from the CIHR (New Investigator Award #MSH95330) and FRSQ (Junior 2 Scholarship). Address correspondence to: Olivier Barbier, Ph.D. Laboratory of Molecular Pharmacology CHU-Québec Research Centre 2705, boulevard Laurier Québec (QC) G1V 4G2, Canada Phone: 418 654 2296 Fax: 418 654 2769 Email: [email protected] Conflict of interests: Authors have nothing to disclose. Downloaded from cancerres.aacrjournals.org on September 26, 2021.
    [Show full text]
  • Ep 2531027 B1
    (19) TZZ ¥_Z _T (11) EP 2 531 027 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/4985 (2006.01) A61K 31/52 (2006.01) 06.05.2015 Bulletin 2015/19 A61K 31/536 (2006.01) A61K 31/513 (2006.01) A61K 38/55 (2006.01) A61P 31/18 (2006.01) (21) Application number: 11737484.3 (86) International application number: (22) Date of filing: 24.01.2011 PCT/US2011/022219 (87) International publication number: WO 2011/094150 (04.08.2011 Gazette 2011/31) (54) Therapeutic combination comprising dolutegravir, abacavir and lamivudine Therapeutische Zusammensetzung enthaltend Dolutegravir, Abacavir und Lamivudine Combinaison thérapeutique comprenant du dolutégravir, de l’abacavir et de la lamivudine (84) Designated Contracting States: (74) Representative: Gladwin, Amanda Rachel AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GlaxoSmithKline GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Global Patents (CN925.1) PL PT RO RS SE SI SK SM TR 980 Great West Road Designated Extension States: Brentford, Middlesex TW8 9GS (GB) BA ME (56) References cited: (30) Priority: 27.01.2010 US 298589 P WO-A1-2010/011812 WO-A2-2009/148600 US-A1- 2006 084 627 US-A1- 2006 084 627 (43) Date of publication of application: US-A1- 2008 076 738 US-A1- 2009 318 421 12.12.2012 Bulletin 2012/50 US-A1- 2009 318 421 US-B1- 6 544 961 (73) Proprietor: VIIV Healthcare Company • SONG1 et al: "The Effect of Ritonavir-Boosted Research Triangle Park, NC 27709 (US) ProteaseInhibitors on the HIV Integrase Inhibitor, S/GSK1349572,in Healthy Subjects", INTERNET , (72) Inventor: UNDERWOOD, Mark, Richard 15 September 2009 (2009-09-15), XP002697436, Research Triangle Park Retrieved from the Internet: URL:http: North Carolina 27709 (US) //www.natap.org/2009/ICCAC/ICCAC_ 52.htm [retrieved on 2013-05-21] Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations.
    [Show full text]
  • Deliberate Self-Poisoning with a Lethal Dose of Pentobarbital: Survival with Supportive Care
    Deliberate self-poisoning with a lethal dose of pentobarbital: Survival with supportive care. (1) (1,2) Santosh Gone , Andis Graudins (1) Clinical Toxicology Service, Program of Emergency Medicine, Monash Health (2) Monash Emergency Research Collaboration, Clinical Sciences at Monash Health, Monash University Abstract 84 INTRODUCTION CASE REPORT (continued) DISCUSSION Pentobarbital (Nembutal) is short acting In the ED: Pentobarbital has been a banned substance for barbiturate sedative-hypnotic, currently widely GCS: 3/15, fixed dilated pupils, apnoeic and human use in Australia since 1998. However, it can used in veterinary practice for anesthesia and ventilated. be procured overseas or bought on the internet. euthanasia. Pulse: 116 bpm sinus tachycardia BP: 115/60 on epinephrine infusion. Pentobarbital is recommended as an effective It is also commonly recommended as a VBG: pH 7.03 pCO2 77 mmHg Bicarb 19 mmol/L agent for use in euthanasia due to its apparently euthanasia drug for assisted suicide and it is Lactate 8.8 mmol/L peaceful transition to death. unlikely that any resuscitative measures will be Activated charcoal (50g) given via an NG tube. attempted in such cases. Course in the Intensive Care Department: In a case series of 150 assisted suicides in Day-1 post-OD: Sweden, a 100% success rate was seen with Intentional overdose results in depression of - Absent brain stem reflexes and fixed dilated pupils for ingestion of 9 grams. Cardiovascular collapse was brain stem function and rapid onset respiratory five days. seen within 15 minutes in 30% of patients. It is rare depression and apnoea. Hypotension also - Diabetes insipidus developed with urine output of to see survival after intentional ingestion for develops, followed by cardiovascular collapse 300ml/hour.
    [Show full text]
  • Pentobarbital Sodium
    PENTobarbital Sodium Brand names Nembutal Sodium Medication error Look-alike, sound-alike drug names. Tall man letters (not FDA approved) are recommended potential to decrease confusion between PENTobarbital and PHENobarbital.(1,2) ISMP recommends the following tall man letters (not FDA approved): PENTobarbital.(30) Contraindications Contraindications: In patients with known hypersensitivity to barbiturates or any com- and warnings ponent of the formulation.(2) If an allergic or hypersensitivity reaction or a life-threatening adverse event occurs, rapid substitution of an alternative agent may be necessary. If pentobarbital is discontinued due to development of a rash, an anticonvulsant that is structurally dissimilar should be used (i.e., nonaromatic). (See Rare Adverse Effects in the Comments section.) Also contraindicated in patients with a history of manifest or latent porphyria.(2) Warnings: Rapid administration may cause respiratory depression, apnea, laryngospasm, or vasodilation with hypotension.(2) Should be withdrawn gradually if large doses have been used for prolonged periods.(2) Paradoxical excitement may occur or important symptoms could be masked when given to patients with acute or chronic pain.(2) May be habit forming. Infusion-related Respiratory depression and arrest requiring mechanical ventilation may occur. Monitor cautions oxygen saturation. If hypotension occurs, the infusion rate should be decreased and/or the patient should be treated with IV fluids and/or vasopressors. Pentobarbital is an alkaline solution (pH = 9–10.5); therefore, extravasation may cause tissue necrosis.(2) (See Appendix E for management.) Gangrene may occur following inadvertent intra-arterial injection.(2) Dosage Medically induced coma (for persistently elevated intracranial pressure (ICP) or refractory status epilepticus): Patient should be intubated and mechanically ventilated.
    [Show full text]
  • PHARMACEUTICAL APPENDIX to the TARIFF SCHEDULE 2 Table 1
    Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names INN which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service CAS registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known.
    [Show full text]
  • Apigenin-Loaded Solid Lipid Nanoparticle Attenuates Diabetic Nephropathy Induced by Streptozotocin Nicotinamide Through Nrf2/ HO-1/NF-Kb Signalling Pathway
    International Journal of Nanomedicine Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Apigenin-Loaded Solid Lipid Nanoparticle Attenuates Diabetic Nephropathy Induced by Streptozotocin Nicotinamide Through Nrf2/ HO-1/NF-kB Signalling Pathway This article was published in the following Dove Press journal: International Journal of Nanomedicine Pingping Li1 Background: Apigenin is known to have a broad-spectrum efficacy in oxidative stress and Syed Nasir Abbas Bukhari 2 conditions due to inflammation, although weak absorption, fast metabolic rate and a fast Tahseen Khan 3 elimination (systemic) limit the pharmacological efficacy of this drug. Hence, we propose the Renukaradhya Chitti4 usage of highly bioavailable Apigenin-solid lipid nanoparticles (SLNPs) to recognize such Davan B Bevoor5 limitations. The defensive function of Apigenin-SLNPs on renal damage induced by strep­ 6 tozotocin (STZ) in animals was studied. Anand R Hiremath −1 7 Materials and Methods: We initially injected the rats with 35 mg kg streptozocin intraper­ Nagaraja SreeHarsha −1 8 itoneally, and after 7 days, the rats were then injected 150 mg kg of metformin intragastrically Yogendra Singh followed by a once-daily intragastric dose of Apigenin-SLNP (25 or 50 mg kg−1) for 9 Kumar Shiva Gubbiyappa a continuous period of 30 days. We then measured the level of insulin and blood glucose, 1Department of Nephrology, Zhengzhou superoxide dismutase, catalase and malondialdehyde in the tissues of the kidney. We also Central Hospital Affiliated to Zhengzhou observed messenger-RNA expression of Interleukin-1β, Interleukin-6 and Tumor Necrosis University, Zhengzhou City, Henan Province 450007, People’s Republic of Factor-alpha in renal tissue through RT-PCR technique.
    [Show full text]
  • Calcium Current Block by (-)-Pentobarbital, Phenobarbital
    The Journal of Neuroscience, August 1993, 13(E): 321 l-3221 Calcium Current Block by (-)-Pentobarbital, Phenobarbital, and CHEB but not (+)-Pentobarbital in Acutely Isolated Hippocampal CA1 Neurons: Comparison with Effects on GABA-activated Cl- Current Jarlath M. H. ffrench-Mullen,’ Jeffery L. Barker,* and Michael A. Rogawski3 ‘Department of Pharmacology, Zeneca Pharmaceuticals Group, Zeneca Inc., Wilmington, Delaware 19897 and *Laboratory of Neurophysiology, and 3Neuronal Excitability Section, Epilepsy Research Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892 Block of a voltage-activated Ca*+ channel current by pheno- Ca*+ current, whereas the sedative effects that occur at high- barbital (PHB), 5-(2-cyclohexylideneethyl)-5-ethyl barbituric er concentrations could reflect stronger Ca2+ current block- acid (CHEB), and the optical R(-)- and S(+)-enantiomers of ade. The powerful sedative-hypnotic action of (-)-PB may pentobarbital (PB) was examined in freshly dissociated adult reflect greater maximal enhancement of GABA responses guinea pig hippocampal CA1 neurons; the effects of the in conjunction with strong inhibition of Ca2+ current. The barbiturates on GABA-activated Cl- current were also char- convulsant action of CHEB is unlikely to be related to its acterized in the same preparation. (-)-PB, PHB, and CHEB effects on the Ca*+ current. produced a reversible, concentration-dependent block of the [Key words: calcium channel, GABA receptor, (-)-pen- peak Ca*+ channel current (3 mM Ba2+ as the charge carrier) tobarbital, (+)-pentobarbital, phenobarbital, CHEB [S-(2-cy- evoked by depolarization from -80 to - 10 mV (I&,, values, clohexylideneethyl)-S-ethyl barbituric acid], CA 1 hippocam- 3.5, 72, and 118 PM, respectively).
    [Show full text]