DOCSLIB.ORG

Istanbul Technical University Graduate School of Science

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Istanbul Technical University Graduate School of Science ISTANBUL TECHNICAL UNIVERSITY GRADUATE SCHOOL OF SCIENCE ENGINEERING AND TECHNOLOGY IN SILICO DESIGN OF HERG NON-BLOCKER COMPOUNDS WITH RETAINED PHARMACOLOGICAL ACTIVITY USING MULTI-SCALE MOLECULAR MODELING APPLICATIONS Ph.D. THESIS Gülru KAYIK Chemistry Department Chemistry Programme DECEMBER 2017 ISTANBUL TECHNICAL UNIVERSITY GRADUATE SCHOOL OF SCIENCE ENGINEERING AND TECHNOLOGY IN SILICO DESIGN OF HERG NON-BLOCKER COMPOUNDS WITH RETAINED PHARMACOLOGICAL ACTIVITY USING MULTI-SCALE MOLECULAR MODELING APPLICATIONS Ph.D. THESIS Gülru KAYIK (509112008) Chemistry Department Chemistry Programme Thesis Advisor: Prof. Dr. Nurcan TÜZÜN Thesis Co-Advisor: Assoc. Prof. Dr. Serdar DURDAĞI DECEMBER 2017 İSTANBUL TEKNİK ÜNİVERSİTESİ FEN BİLİMLERİ ENSTİTÜSÜ HERG BLOKER OLMAYAN FARMAKOLOJİK AKTİVİTESİ KORUNMUŞ BİLEŞİKLERİN ÇOK BOYUTLU MOLEKÜLER MODELLEME UYGULAMALARI İLE İN SİLİKO TASARIMI DOKTORA TEZİ Gülru KAYIK (509112008) Kimya Anabilim Dalı Kimya Programı Tez Danışmanı: Prof. Dr. Nurcan TÜZÜN Eş Danışman: Doç. Dr. Serdar DURDAĞI ARALIK 2017 Gülru KAYIK, a Ph.D. student of İTU Graduate School of Science Engineering and Technology student ID 509112008, successfully defended the thesis entitled “IN SILICO DESIGN OF HERG NON-BLOCKER COMPOUNDS WITH RETAINED PHARMACOLOGICAL ACTIVITY USING MULTI-SCALE MOLECULAR MODELING APPLICATIONS”, which she prepared after fulfilling the requirements specified in the associated legislations, before the jury whose signatures are below. Thesis Advisor : Prof. Dr. Nurcan TÜZÜN .............................. Istanbul Technical University Co-advisor : Assoc. Prof. Dr. Serdar DURDAĞI .............................. Bahçeşehir University Jury Members : Prof. Dr. Mine YURTSEVER ............................. Istanbul Technical University Prof. Dr. Kemal YELEKÇİ .............................. Kadir Has University Assis. Prof. Dr. Bülent BALTA .............................. Istanbul Technical University Assoc. Prof. Dr. Fethiye Aylin SUNGUR .............................. Istanbul Technical University Prof. Dr. Safiye ERDEM .............................. Marmara University Date of Submission : 26 October 2017 Date of Defense : 01 December 2017 v vi FOREWORD First of all, I would like to thank my Ph.D. thesis advisor Prof. Dr. Nurcan Tüzün and co-advisor Assoc. Prof. Dr. Serdar Durdağı for their kind concern, recommendations and supports during the course of my Ph.D. studies. I would like to present my acknowledgements to Istanbul Technical University Research Fund BAP (Project numbers: 38208 and 30492) and the National Center for High Performance Computing of Turkey (UHEM) under Grant 10982010 for supporting this thesis and providing the related computer resources. The numerical calculations reported in this thesis were partially performed at TUBITAK ULAKBIM, High Performance and Grid Computing Center (TRUBA resources). I would also like to thank The Scientific and Technological Research Council of Turkey (TUBITAK) for granting me the 2214-A Research Grant and providing financial support during the course of my Ph.D. thesis. December 2017 Gülru KAYIK (Chemical Engineer) vii viii TABLE OF CONTENTS Page FOREWORD ............................................................................................................ vii TABLE OF CONTENTS .......................................................................................... ix ABBREVIATIONS ................................................................................................. xiii SYMBOLS ................................................................................................................ xv LIST OF TABLES ................................................................................................. xvii LIST OF FIGURES ................................................................................................ xix SUMMARY ............................................................................................................ xxv ÖZET......... ............................................................................................................ xxvii 1. INTRODUCTION .................................................................................................. 1 2. IN SILICO DESIGN OF NOVEL HERG-NEUTRAL SILDENAFIL LIKE PDE5 INHIBITORS ............................................................................... 3 2.1 Introduction ........................................................................................................ 3 2.2 Methods .............................................................................................................. 5 2.2.1 Molecular docking simulations ................................................................... 6 2.2.2 Fragment-based de novo drug design & virtual screening .......................... 7 2.2.3 MD simulations and post-processing MD analyses .................................... 8 2.2.4 MD simulations of the target receptor: PDE5 in its apo state and bound with its inhibitors ................................................................................................. 8 2.2.5 MD simulations of hERG K+ ion channel: Apo state and bound with PDE5 inhibitors .................................................................................................... 9 2.2.6 Molecular Mechanics/Generalized Born surface area (MM/GBSA) calculations ......................................................................................................... 11 2.3 Results and Discussion ..................................................................................... 11 2.3.1 Analysis of the key interactions of sildenafil with the target receptor (PDE5) ............................................................................................................... 13 2.3.2 Comparison of used docking tools in terms of predicting the binding positions of “Sildenafil” in the central cavities of hERG1 channel ................... 15 2.3.2.1 GOLD ................................................................................................. 16 2.3.2.2 AutoDock ........................................................................................... 21 2.3.2.3 MOE ................................................................................................... 24 2.3.3 In silico Alanine mutagenesis study .......................................................... 25 2.3.4 General statements on the binding energy predictions derived from GOLD, AutoDock and MOE ............................................................................. 27 2.3.5 Binding interactions of Vardenafil and Tadalafil with the hERG K+ ion channel ............................................................................................................... 27 2.3.6 Virtual screening results ............................................................................ 29 2.3.7 MM/GBSA analyses ................................................................................. 30 2.4 Conclusions ...................................................................................................... 30 3. INVESTIGATION OF PDE5/PDE6 AND PDE5/PDE11 SELECTIVE POTENT TADALAFIL-LIKE PDE5 INHIBITORS USING COMBINATION OF MOLECULAR MODELING APPROACHES, MOLECULAR FINGERPRINT-BASED VIRTUAL SCREENING ix PROTOCOLS AND STRUCTURE-BASED PHARMACOPHORE DEVELOPMENT ................................................................................. 37 3.1 Introduction ...................................................................................................... 37 3.2 Methods ............................................................................................................ 41 3.2.1 Ligand and protein preparations ................................................................ 41 3.2.2 Virtual library screening............................................................................ 41 3.2.3 Flexible molecular docking simulations ................................................... 41 3.2.4 Molecular Dynamics simulations .............................................................. 42 3.2.5 Molecular Mechanics Generalized Born Solvation (MM/GBSA) Calculations ........................................................................................................ 42 3.3 Results and discussion ...................................................................................... 43 3.3.1 Validation of the docking methodology .................................................... 43 3.3.2 Constructing the homology models of the catalytic domains of PDE6 (amino acid residues: 482-816) and PDE11 (amino acid residues: 587-910) .... 43 3.3.3 Binding affinity and binding pattern analysis of the hit compounds and tadalafil with PDE5, PDE6 and PDE11 ............................................................. 47 3.3.4 MD simulations of apo and holo states of PDE5, PDE6 and PDE11 bound with the selected hit compounds (ZINC02120502 and ZINC16031243) and tadalafil ............................................................................................................... 59 3.3.5 MM-GBSA calculations ............................................................................ 62 3.3.6 hERG K+ ion channel activity of the compounds ..................................... 63 3.3.7 E-Pharmacophore studies .......................................................................... 65 3.4 Conclusions ...................................................................................................... 68 4. STRUCTURAL
Load more

Recommended publications
  • The Postmortem Distribution of Vardenafil (Levitra | in an Aviation
    Journal of Analytical Toxicology, Vol. 31, July/August 2007 The Postmortem Distribution of Vardenafil (Levitra| in an Aviation Accident Victim with an Unusually High Blood Concentration* Robert D. Johnson ~, Russell J. Lewis, and Mike K. Angler Downloaded from https://academic.oup.com/jat/article/31/6/328/682815 by guest on 27 September 2021 Civil Aerospace Medical Institute, Federal Aviation Administration, Analytical Toxicology and Accident Research Laboratory, AAM-610, CAMI Building, 6500 S. MacArthur Blvd., Oklahoma City, Oklahoma 73169-6901 I Abstract phodiesterase type 5 enzyme (PDE5) found predominantly in the penile corpus cavernosum (2-7). Vardenafil (tevitra) is one of the most widely prescribed Vardenafil undergoes hepatic metabolism, producing the treatments for erectile dysfunction. This report presents a active desethyl metabolite M1. M1 contributes to the ob- rapid and reliable method for the identification and quantification served pharmacological effects provided by vardenafil, as M1 of vardenafil in postmortem fluids and tissues, applies this method exhibits approximately 30% of the potency of the parent to a postmortem case, and describes the distribution of vardenafil in various fluids and tissues.This procedure utilizes sildenafil-d8, drug (1). Under steady-state conditions, the plasma concen- which is structurally closely related to vardenafil, as an tration of M1 is approximately 26% of that seen for vardenafil internal standard for more accurate and reliable quantitation. (1). After oral administration of vardenafil, peak plasma con- The method incorporates solid-phaseextraction and liquid centrations are obtained within 30-60 min (1). Vardenafil chromatography-tandem mass spectrometry (MS) and and its active metabolite have a terminal half-life of approx- MS-MS-MS utilizing an atmospheric pressure chemical imately 4-5 h (1).
    [Show full text]
  • Vardenafil Better Choice for Premature Ejaculation
    August 15, 2005 • www.familypracticenews.com Men’s Health 47 Vardenafil Better Choice for Premature Ejaculation BY ROBERT FINN (24%) of the men and was secondary (in On a self-rating scale of 0-8, where 0 Center but is now at the University of San Francisco Bureau most cases to erectile dysfunction) in the means PE almost never, 4 means PE about Hamburg. remaining 26 men (77%). half the time, and 8 means PE almost al- Self-ratings of sexual satisfaction, on a 0- S AN A NTONIO — Vardenafil improved After a 4-week run-in period, 17 men ways, the mean score was 6.14 at baseline, 5 scale, where 0 means not at all satisfied premature ejaculation more than sertra- were given 10-mg vardenafil 10 minutes 4.28 with sertraline, and 3.2 with varde- and 5 means extremely satisfied, averaged line, Frank Sommer, M.D., reported at the before intercourse for 6 weeks. The other nafil. 1.4 at baseline, 3.2 with sertraline, and 4.2 annual meeting of the American Urolog- 17 received 50 mg of sertraline 4 hours be- IVELT, as measured by a stopwatch, with vardenafil. In addition, the partners’ ical Association. fore intercourse. averaged 0.54 minutes at baseline, 2.87 sexual satisfaction showed significant in- Both vardenafil (Levitra), a phosphodi- After a 1-week washout period, the men minutes with sertraline, and 5.23 minutes creases for sertraline and even more so for esterase-5 inhibitor, and sertraline (Zoloft), who had been receiving sertraline with vardenafil, reported Dr. Sommer, vardenafil.
    [Show full text]
  • LEVITRA (Vardenafil Hcl) Tablets
    LEVITRA (vardenafil HCl) Tablets DESCRIPTION LEVITRA® is an oral therapy for the treatment of erectile dysfunction. This monohydrochloride salt of vardenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Vardenafil HCl is designated chemically as piperazine, 1-[[3-(1,4-dihydro-5- methyl-4-oxo-7-propylimidazo[5,1-f][1,2,4]triazin-2-yl)-4- ethoxyphenyl]sulfonyl]-4-ethyl-, monohydrochloride and has the following structural formula: O O HN N x HCl x 3H2O N N O S O N N Vardenafil HCl is a nearly colorless, solid substance with a molecular weight of 579.1 g/mol and a solubility of 0.11 mg/mL in water. LEVITRA is formulated as orange, round, film-coated tablets with "BAYER" cross debossed on one side and "2.5", "5", "10", and "20" on the other side corresponding to 2.5 mg, 5 mg, 10 mg, and 20 mg of vardenafil, respectively. In addition to the active ingredient, vardenafil HCl, each tablet contains microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate, hypromellose, polyethylene glycol, titanium dioxide, yellow ferric oxide, and red ferric oxide. CLINICAL PHARMACOLOGY Mechanism of Action Penile erection is a hemodynamic process initiated by the relaxation of smooth muscle in the corpus cavernosum and its associated arterioles. During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells in the corpus cavernosum. Nitric oxide activates the enzyme guanylate cyclase resulting in increased synthesis of cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum. The cGMP in turn triggers smooth muscle relaxation, allowing increased blood flow into the penis, resulting in erection.
    [Show full text]
  • Phosphodiesterase (PDE)
    Phosphodiesterase (PDE) Phosphodiesterase (PDE) is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases, as well as numerous less-well-characterized small-molecule phosphodiesterases. The cyclic nucleotide phosphodiesterases comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP. They regulate the localization, duration, and amplitude of cyclic nucleotide signaling within subcellular domains. PDEs are therefore important regulators ofsignal transduction mediated by these second messenger molecules. www.MedChemExpress.com 1 Phosphodiesterase (PDE) Inhibitors, Activators & Modulators (+)-Medioresinol Di-O-β-D-glucopyranoside (R)-(-)-Rolipram Cat. No.: HY-N8209 ((R)-Rolipram; (-)-Rolipram) Cat. No.: HY-16900A (+)-Medioresinol Di-O-β-D-glucopyranoside is a (R)-(-)-Rolipram is the R-enantiomer of Rolipram. lignan glucoside with strong inhibitory activity Rolipram is a selective inhibitor of of 3', 5'-cyclic monophosphate (cyclic AMP) phosphodiesterases PDE4 with IC50 of 3 nM, 130 nM phosphodiesterase. and 240 nM for PDE4A, PDE4B, and PDE4D, respectively. Purity: >98% Purity: 99.91% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 1 mg, 5 mg Size: 10 mM × 1 mL, 10 mg, 50 mg (R)-DNMDP (S)-(+)-Rolipram Cat. No.: HY-122751 ((+)-Rolipram; (S)-Rolipram) Cat. No.: HY-B0392 (R)-DNMDP is a potent and selective cancer cell (S)-(+)-Rolipram ((+)-Rolipram) is a cyclic cytotoxic agent. (R)-DNMDP, the R-form of DNMDP, AMP(cAMP)-specific phosphodiesterase (PDE) binds PDE3A directly.
    [Show full text]
  • Use of Sildenafil in Patients with Cardiovascular Disease
    Arq Bras Cardiol GuimarãesReview et al volume 73, (nº6), 1999 Sildenafil in patients with cardiovascular disease Use of Sildenafil in Patients with Cardiovascular Disease Armênio Costa Guimarães, Marcus Vinícius Bolívar Malachias, Otávio Rizzi Coelho, Emílio Cesar Zilli, Rafael Leite Luna Introduction of phosphodiesterase inhibitors. The erectile action of sildenafil combines increase in arterial flow with reduction Erectile dysfunction, formerly called impotence, is the in the venous flow of cavernous body of penis. Sildenafil inability of the male to achieve or maintain penile erection and leads to relaxation of smooth muscle of penile arteries and thus engage in coitus1. It is common among patients with trabeculae surrounding the sinusoidal spaces, resulting in cardiovascular diseases or their risk factors. This dysfunc- a greater engorgement of cavernous body. The trabeculae tion occurs mainly among individuals with coronary artery of engorged sinusoidal spaces compress the penile disease, after episodes of acute ischemic syndrome, hyper- venules against the tunica albuginea, reducing venous tensive patients underpharmacologic treatment, and among flow, contributing to maintenance of engorgement of patients with heart failure. In approximately 85% of these ca- cavernous body8. Relaxation of this smooth muscle ses, the fear of a cardiac event during coitus constitutes an results from a decrease in intracellular calcium mediated important factor for erectile dysfunction 2-4. by accumulation of the second messenger, the cyclic Discovery of sildenafil citrate has represented a great de- guanosine monophosphate (cGMP), whose production velopment in the treatment of erectile dysfunction; it may results from activation of guanyl cyclase by nitric oxide benefit, among many others, those patients with cardiovascu- produced by the stimulus of endothelial cells generated lar diseases or with their risk factors 5.
    [Show full text]
  • Guideline for Preoperative Medication Management
    Guideline: Preoperative Medication Management Guideline for Preoperative Medication Management Purpose of Guideline: To provide guidance to physicians, advanced practice providers (APPs), pharmacists, and nurses regarding medication management in the preoperative setting. Background: Appropriate perioperative medication management is essential to ensure positive surgical outcomes and prevent medication misadventures.1 Results from a prospective analysis of 1,025 patients admitted to a general surgical unit concluded that patients on at least one medication for a chronic disease are 2.7 times more likely to experience surgical complications compared with those not taking any medications. As the aging population requires more medication use and the availability of various nonprescription medications continues to increase, so does the risk of polypharmacy and the need for perioperative medication guidance.2 There are no well-designed trials to support evidence-based recommendations for perioperative medication management; however, general principles and best practice approaches are available. General considerations for perioperative medication management include a thorough medication history, understanding of the medication pharmacokinetics and potential for withdrawal symptoms, understanding the risks associated with the surgical procedure and the risks of medication discontinuation based on the intended indication. Clinical judgement must be exercised, especially if medication pharmacokinetics are not predictable or there are significant risks associated with inappropriate medication withdrawal (eg, tolerance) or continuation (eg, postsurgical infection).2 Clinical Assessment: Prior to instructing the patient on preoperative medication management, completion of a thorough medication history is recommended – including all information on prescription medications, over-the-counter medications, “as needed” medications, vitamins, supplements, and herbal medications. Allergies should also be verified and documented.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8,894,970 B2 Tomczuk Et Al
    US008894970B2 (12) United States Patent (10) Patent No.: US 8,894,970 B2 Tomczuk et al. (45) Date of Patent: Nov. 25, 2014 (54) ARGINASE INHIBITORS AND METHODS OF 546/184, 133, 138, 139, 152; 548/560; USE THEREOF 540/484 See application file for complete search history. (75) Inventors: Bruce Edward Tomczuk, Collegeville, PA (US); Gary Lee Olson, (56) References Cited Mountainside, NJ (US); Richard Scott Pottorf, Belle Mead, NJ (US); Lijuan U.S. PATENT DOCUMENTS Jane Wang, Wildwood, MO (US); Bhask Rao Nall h 4.483,853. A 11/1984 Collins et al. naskara Kao Nalagancnu, 5,792,769 A * 8/1998 Lu et al. ...... 514,252.12 Hillsborough, NJ (US); Yanqun Zhang, 5,891,909 A * 4/1999 Soll et al. ...................... 514/517 East Brunswick, NJ (US) 6,037,356 A * 3/2000 Lu et al. ...... ... 514,349 6,133,315 A * 10/2000 Lu et al. ...... 514/517 6,204.263 B1* 3/2001 Lu et al. ...... 514,235.8 (73) Assignee: Corridor Pharmaceuticals, Inc., 6,225,302 B1* 5/2001 Lu et al. ......... ... 514, 183 Towson, MD (US) 6,235,778 B1* 5/2001 Tomczuk et al. 514/517 6,245,763 B1* 6/2001 Lu et al. ......... ... 514,247 (*) Notice: Subject to any disclaimer, the term of this 6,281.206 B1 : 8/2001 Lu et al. ...... ... 514, 183 patent is extended or adjusted under 35 6,326,492 B1* 12/2001 Wang et al. ..................... 544, 63 6,344,466 B2 * 2/2002 Soll et al. ....... ... 514,331 U.S.C. 154(b) by 356 days.
    [Show full text]
  • Drug-Facilitated Sexual Assault Panel, Blood
    DRUG-FACILITATED SEXUAL ASSAULT PANEL, BLOOD Blood Specimens (Order Code 70500) Alcohols Analgesics, cont. Anticonvulsants, cont. Antihistamines, cont. Ethanol Phenylbutazone Phenytoin Cyclizine Amphetamines Piroxicam Pregabalin Diphenhydramine Amphetamine Salicylic Acid* Primidone Doxylamine BDB Sulindac* Topiramate Fexofenadine Benzphetamine Tapentadol Zonisamide Guaifenesin Ephedrine Tizanidine Antidepressants Hydroxyzine MDA Tolmetin Amitriptyline Loratadine MDMA Tramadol Amoxapine Oxymetazoline* Mescaline* Anesthetics Bupropion Pyrilamine Methcathinone Benzocaine Citalopram Tetrahydrozoline Methamphetamine Bupivacaine Clomipramine Triprolidine Phentermine Etomidate Desipramine Antipsychotics PMA Ketamine Desmethylclomipramine 9-hydroxyrisperidone Phenylpropanolamine Lidocaine Dosulepin Aripiprazole Pseudoephedrine Mepivacaine Doxepin Buspirone Analgesics Methoxetamine Duloxetine Chlorpromazine Acetaminophen Midazolam Fluoxetine Clozapine Baclofen Norketamine Fluvoxamine Fluphenazine Buprenorphine Pramoxine* Imipramine Haloperidol Carisoprodol Procaine 1,3-chlorophenylpiperazine (mCPP) Mesoridazine Cyclobenzaprine Rocuronium Mianserin* Norclozapine Diclofenac Ropivacaine Mirtazapine Olanzapine Etodolac Antibiotics Nefazodone Perphenazine Fenoprofen Azithromycin* Nordoxepin Pimozide Hydroxychloroquine Chloramphenicol* Norfluoxetine Prochlorperazine Ibuprofen Ciprofloxacin* Norsertraline Quetiapine Ketoprofen Clindamycin* Nortriptyline Risperidone Ketorolac Erythromycin* Norvenlafaxine Thioridazine Meclofenamic Acid* Levofloxacin* Paroxetine
    [Show full text]
  • General Pharmacology
    GENERAL PHARMACOLOGY Winners of “Nobel” prize for their contribution to pharmacology Year Name Contribution 1923 Frederick Banting Discovery of insulin John McLeod 1939 Gerhard Domagk Discovery of antibacterial effects of prontosil 1945 Sir Alexander Fleming Discovery of penicillin & its purification Ernst Boris Chain Sir Howard Walter Florey 1952 Selman Abraham Waksman Discovery of streptomycin 1982 Sir John R.Vane Discovery of prostaglandins 1999 Alfred G.Gilman Discovery of G proteins & their role in signal transduction in cells Martin Rodbell 1999 Arvid Carlson Discovery that dopamine is neurotransmitter in the brain whose depletion leads to symptoms of Parkinson’s disease Drug nomenclature: i. Chemical name ii. Non-proprietary name iii. Proprietary (Brand) name Source of drugs: Natural – plant /animal derivatives Synthetic/semisynthetic Plant Part Drug obtained Pilocarpus microphyllus Leaflets Pilocarpine Atropa belladonna Atropine Datura stramonium Physostigma venenosum dried, ripe seed Physostigmine Ephedra vulgaris Ephedrine Digitalis lanata Digoxin Strychnos toxifera Curare group of drugs Chondrodendron tomentosum Cannabis indica (Marijuana) Various parts are used ∆9Tetrahydrocannabinol (THC) Bhang - the dried leaves Ganja - the dried female inflorescence Charas- is the dried resinous extract from the flowering tops & leaves Papaver somniferum, P album Poppy seed pod/ Capsule Natural opiates such as morphine, codeine, thebaine Cinchona bark Quinine Vinca rosea periwinkle plant Vinca alkaloids Podophyllum peltatum the mayapple
    [Show full text]
  • Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0192440 A1
    US 20190192440A1 (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0192440 A1 LI (43 ) Pub . Date : Jun . 27 , 2019 ( 54 ) ORAL DRUG DOSAGE FORM COMPRISING Publication Classification DRUG IN THE FORM OF NANOPARTICLES (51 ) Int . CI. A61K 9 / 20 (2006 .01 ) ( 71 ) Applicant: Triastek , Inc. , Nanjing ( CN ) A61K 9 /00 ( 2006 . 01) A61K 31/ 192 ( 2006 .01 ) (72 ) Inventor : Xiaoling LI , Dublin , CA (US ) A61K 9 / 24 ( 2006 .01 ) ( 52 ) U . S . CI. ( 21 ) Appl. No. : 16 /289 ,499 CPC . .. .. A61K 9 /2031 (2013 . 01 ) ; A61K 9 /0065 ( 22 ) Filed : Feb . 28 , 2019 (2013 .01 ) ; A61K 9 / 209 ( 2013 .01 ) ; A61K 9 /2027 ( 2013 .01 ) ; A61K 31/ 192 ( 2013. 01 ) ; Related U . S . Application Data A61K 9 /2072 ( 2013 .01 ) (63 ) Continuation of application No. 16 /028 ,305 , filed on Jul. 5 , 2018 , now Pat . No . 10 , 258 ,575 , which is a (57 ) ABSTRACT continuation of application No . 15 / 173 ,596 , filed on The present disclosure provides a stable solid pharmaceuti Jun . 3 , 2016 . cal dosage form for oral administration . The dosage form (60 ) Provisional application No . 62 /313 ,092 , filed on Mar. includes a substrate that forms at least one compartment and 24 , 2016 , provisional application No . 62 / 296 , 087 , a drug content loaded into the compartment. The dosage filed on Feb . 17 , 2016 , provisional application No . form is so designed that the active pharmaceutical ingredient 62 / 170, 645 , filed on Jun . 3 , 2015 . of the drug content is released in a controlled manner. Patent Application Publication Jun . 27 , 2019 Sheet 1 of 20 US 2019 /0192440 A1 FIG .
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 6,333,354 B1 Schudt (45) Date of Patent: Dec
    USOO6333354B1 (12) United States Patent (10) Patent No.: US 6,333,354 B1 Schudt (45) Date of Patent: Dec. 25, 2001 (54) SYNERGISTIC COMBINATION OF PDE Buerke et al.: “Synergistic platelet inhibitory effect of the INHIBITORS AND ADENYLATE CYCLASE phosphodiesterase inhibitor piroximone and iloprost: Pros AGONSTS OR GUANYL CYCLYSE taglandins in the Cardiovascular System, 1992, 37/suppl. AGONSTS (71–77).* (75) Inventor: Christian Schudt, Constance (DE) O'Grady et al. “A chemically stable analot 9-beta methyl carbacyclin with Similar effects to epoprostenol proStacyclin (73) Assignee: Byk Gulden Lomberg Chemische prostaglandin in I-2 in man” Br J Clin Pharmacol, 18(6). Fabrik GmbH, Constance (DE) 1984 (921-934).* (*) Notice: Subject to any disclaimer, the term of this Crutchley et al. “Effects of Prostacyclin Analogs on the patent is extended or adjusted under 35 Synthesis of Tissue Factor, Tumor Necrosis Facotr-alpha U.S.C. 154(b) by 0 days. and Interleukin-1beta in Human Monocytic THP-1 Cells”, J Pharmacol and Experimental Therapeutics, 271 (1). 1994. (21) Appl. No.: 09/367,850 446-451. (22) PCT Filed: Feb. 24, 1998 Crutchley et al. “Prostacyclin Analogues Inhibit Tissue (86) PCT No.: PCT/EP98/O1047 Factor Expression in the Human Monocytic Cell Line THP-1 Via a Cyclic AMP-Dependent Mechanism” Arterio S371 Date: Aug. 27, 1999 scler. Thromb, 12(6), 1992. 664-670.* S 102(e) Date: Aug. 27, 1999 Turner et al., Br. J. Pharmacol., “Pulmonary effects of type V cyclic GMP specific phosphodiesterase inhibition in the (87) PCT Pub. No.: WO98/37894 anaesthetized guinea-pig", (1994), 111, pp.
    [Show full text]
  • Mechanism of Drug-Induced Qt Interval Prolongation
    ABSTRACT Torsades de pointes (TdP) is a polymorphic ventricular tachycardia characterized by a distinctive pattern of undulating QRS complexes that twist around the isoelectric line. TdP is usually self-terminating or can subsequently degenerate into ventricular fibrillation, syncope, and sudden death. TdP has been associated with QT interval prolongation of the electrocardiogram; therefore, the QT interval has come to be recognized as a surrogate marker for the risk of TdP. International guidelines have been developed to harmonize both the preclinical and clinical studies for the evaluation of drug-induced TdP. However, currently preclinical in vitro and in vivo methods as well as biomarkers for proarrhythmias have been imperfect in predicting drug-induced TdP in humans. It is clear that relevant biomarkers together with appropriate models are needed to assess the arrhythmic risk of new chemical entities. The goal of the present dissertation is to create rabbit with myocardial failing heart as an in vivo animal model to predict TdP in humans and to determine mechanism(s) underlying TdP in this model. Electrocardiograms were recorded from bipolar transthoracic leads in 7 conscious healthy rabbits previously trained to rest quietly in slings. The RR and QT relationship, ii QT=2.4RR0.72 (r2=0.79, p < 0.001) was obtained by slowed the heart rate with 2.0 mg/kg zatebradine, and the algorithm for removing effect of heart rate on QT is QTc = QT/(RR)0.72. QTc lengthened significantly in all conscious rabbits given intravenous cisapride, dofetilide or haloperidol (p < 0.05), and QTc did not change with DMSO (vehicle control), propranolol or enalaprilat.
    [Show full text]