DOCSLIB.ORG

(12) Patent Application Publication (10) Pub. No.: US 2006/0205789 A1 Lobl Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) Patent Application Publication (10) Pub. No.: US 2006/0205789 A1 Lobl Et Al US 20060205789A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0205789 A1 LObl et al. (43) Pub. Date: Sep. 14, 2006 (54) GACYCLIDINE FORMULATIONS (22) Filed: Mar. 6, 2006 (75) Inventors: Thomas Jay Lobl, Valencia, CA (US); Related U.S. Application Data John Vinton Schloss, Valencia, CA (US); Stephen Joseph McCormack, (60) Provisional application No. 60/658.207, filed on Mar. Claremont, CA (US); Anna Imola 4, 2005. Nagy, Valencia, CA (US); Jacob E. Pananen, Los Angeles, CA (US) Publication Classification Correspondence Address: (51) Int. Cl. BANNER & WTCOFF A6II 3 L/453 (2006.01) 1001 G STREET NW (52) U.S. Cl. .............................................................. S14/326 SUTE 11 OO WASHINGTON, DC 20001 (US) (57) ABSTRACT (73) Assignee: NeuroSystec Corporation, Valencia, CA Improved formulations of gacyclidine for direct administra (21) Appl. No.: 11/367,720 tion to the inner or middle ear. Patent Application Publication Sep. 14, 2006 Sheet 1 of 5 US 2006/0205789 A1 1 OOO V Excipients at 0.1 % by weight an room temperature in glass s N-1 100 CD S S Soluphor P O > 10 Solutol HS 15 8 O Tween 80 Captisol 1 FIG. 1 1 OOO Excipients at 0.1 % by weight 37°C in polypropylene 1 OO ss Ne/ S.CD no excipientA 8 s 10 Soluphor P > Soluto HS 15 O Tween 80 1 Captisol FIG. 2 Patent Application Publication Sep. 14, 2006 Sheet 2 of 5 US 2006/0205789 A1 100 37°C, polypropylene VWR # 20170-710, 2 mL 0.15 MNaCl 25 uMgacyclidine 60 40 0.1% Solutol, 1 day No excipient, 1 day 2O 0.1% Solutol, 3 days No excipient, 3 days O 1 2 3 4. 5 6 Time (days) FIG. 4. Patent Application Publication Sep. 14, 2006 Sheet 3 of 5 US 2006/0205789 A1 O 23 to 56°C 0. 1 est. 5 °C O.O1 0.001 OOOO1 O 10 20 30 40 50 60 Temperature (C) Initial Gacyclidine = 100 uM O 2 4 6 8 10 12 14 16 Time (days) Patent Application Publication Sep. 14, 2006 Sheet 4 of 5 US 2006/0205789 A1 1 OO NO EXCIPIENT - 80 gacyclidine + piperidine >s N-1 60 "C 92 8 40 iš - piperidine 20 gacyclidine O FIG. 7. 1 OO 0.3% POLYSORBATE 80 s 80 gacyclidine + piperidine N-s 60 g o re gacyclidine CAS 40 X t 2 O piperidine FIG. 8. Patent Application Publication Sep. 14, 2006 Sheet 5 of 5 US 2006/0205789 A1 1 no excipient -o- plus 0.3% polysorbate 80 O. O 1 6.5 7 7.5 8 8.5 FIG. 9. US 2006/0205789 A1 Sep. 14, 2006 GACYCLIDINE FORMULATIONS active agent reaches the CSF it may have undesirable side effects because it could act on nerve cells which are not its 0001. This application claims the benefit of Ser. No. target. Thus, there may be unintended effects on the brain 60/658,207 filed Mar. 4, 2005. Ser. No. 60/658,207 is and spinal cord. Damage to any of these cells and tissues incorporated herein by reference in its entirety. would cause severe consequences to important senses Such as hearing. In addition, compounds delivered to the middle FIELD OF THE INVENTION ear in addition to the desired delivery of drug through the 0002 The invention relates to improved formulations of round window may also be absorbed partially into the gacyclidine and other therapeutic agents useful for treating exposed vascular system and get out into the general circu disorders of the middle and inner ear. lation or travel down the Eustachian tube to be absorbed in the mouth, throat, stomach or GI tract. BACKGROUND OF THE INVENTION 0006. Accordingly, the administration method, location, 0003. Many therapeutics when given systemically (i.e., device and formulation are all important for achieving a per-orally, intravenously, or intramuscularly) have side desirable outcome without undesirable side effects. Thus, effects which prevent an optimal dose from being delivered. there is a continuing need in the art for improved formula This is due to other body and nervous system cells being tions of therapeutic agents that are specifically designed for exposed to a full dose of the therapeutic obtained from the delivery to the middle and inner ear or to other specific sites circulation while the targeted cells do not receive an optimal in need of therapy. This invention addresses this need. dose because of the systemic side effects elsewhere. When formulated correctly for tissue-specific drug delivery, a BRIEF DESCRIPTION OF THE DRAWINGS potent therapeutic, so delivered, will have minimal side 0007 FIG. 1. Graph showing a decrease in solution effects and still be effective on the target nerve tissue. concentration of gacyclidine as a function of pH and the 0004 As currently understood, tinnitus is frequently a increase in Solution concentration afforded by selected symptom of a variety of neurological disorders, including excipients at room temperature in glass vials. damage to dental or facial nerves, temporomandibular joint 0008 FIG. 2. Graph showing adsorption of gacyclidine (TMJ) disease, hypersensitivity to smell, taste and touch and to polypropylene vials as a function of pH at 37° C. and the damage to the auditory cortex or inferior colliculus. Tinnitus moderating effects of selected excipients (1 mM total gacy is also frequently comorbid with other manifestations of these underlying neurological disorders, such as Meniere's clidine present; excess). Disease, pain, anxiety, depression, and migraine headaches. 0009 FIG. 3. Graph showing loss of 25 uMgacyclidine As such, it is desirable to treat the precise location where the in a polypropylene vial as a function of pH with and without underlying neurological disorder occurs, which is not SOLUTOL(R) (no excess gacyclidine). restricted to, but can include, the cochlea, auditory nerve, 0010 FIG. 4. Graph showing chemical stability of gacy dental or facial nerves, and auditory cortex or inferior clidine base form and the chemical instability of the acid colliculus of the central nervous system. A patient recog form at 54° C. or 56° C. nizes tinnitus as an internal Sound when there is no external sound. Clinically, the desirable treatment is to suppress the 0011 FIG. 5. Graph showing increased chemical stabil perception of inappropriate sound without side effects that ity of gacyclidine acid form (pH 2) at lower temperatures. prevent normal functioning at work and daily life. Note the Surprisingly large temperature dependence of the 0005 Accordingly, the appropriate treatment necessarily decomposition rate. will require the administration of a potent CNS active drug 0012 FIG. 6. Graph showing that decomposition of to quiet the inappropriate firing of the associated nerves that gacyclidine is slower at pH 7.4 than at pH 5.5 or 6.0 in report the sound percept into the auditory cortex. Potent Ringer's Lactate at 37° C. CNS active drugs that act to quiet the spontaneous and 0013 FIG. 7. Graph showing declining solution concen perhaps the tonic firing of specific nervous tissue without tration of gacyclidine as the pH increases between pH 7.3 turning off other essential functions such as hearing or and 8.1 in Ringer's solution at 55° C. and decreased pro balance may be given for treatment of middle and inner ear duction of piperidine at higher pH. disorders such as tinnitus. These drugs have specific limi tations when given systemically because of their general 0014 FIG. 8. Graph showing enhanced solution concen activity on the entire nervous system. To overcome these tration of gacyclidine and chemical stability of gacyclidine systemic side effects and to get an improved therapeutic by 0.3% polysorbate 80 in Ringer's solution at 55° C. outcome while minimizing side effects, it is desirable to between pH 6.7 and 7.2. administer the drug into the site of tinnitus origin Such as the 0015 FIG. 9. Graph showing decreasing decomposition middle or inner ear. Direct administration to the middle or inner ear allows the healthcare provider to optimize the rate of gacyclidine at 55° C. in Ringer's solution with 0.3% therapeutic program to avoid or minimize tissue damage and polysorbate 80 added as pH increases between 6.7 and 7.2. side effects. Consequences of tissue damage in this organ DETAILED DESCRIPTION OF THE resulting from an inappropriate dosing regimen are serious INVENTION to the senses of hearing and balance and could include irreversible damage to the hearing related hair cells or the 0016. The invention provides formulations of gacyclidine nerves, spiral ganglion, or vestibular system. In some cases, and other drugs which are suitable for administration to the compounds administered into the inner ear or cochlea can middle and inner ear. Such formulations can be used to treat drain into the cerebral spinal fluid (CSF). If a potent CNS disorders such as tinnitus, Meniere's disease, vertigo, US 2006/0205789 A1 Sep. 14, 2006 middle and inner ear inflammation and infection, hearing nitrogen. See Geneste et al., Eur J Med 14, 301-08, 1979). loss induced by noise or certain kinds of trauma, and Gacyclidine derivatives and analogs containing a thiophen neurological damage resulting from physical (e.g., Surgery) 2-yl ring would be enhanced by the formulation invention or chemical trauma. described herein. Definitions 0025 Acid and base forms of gacyclidine can be pre 0017 (a) A “carrier molecule' as used herein is a pared according to U.S. Pat. No. 6,107,495. The chloride salt molecule which helps to retain an active agent in of the acid form of gacyclidine is very soluble in water or Solution or Suspension. Surfactants (amphipathic mol unbuffered physiologically acceptable solutions such as ecules which form a complex with water-insoluble or Ringer's Solution and will form solutions containing up to poorly soluble molecules and render the complex water 150 mg/ml of the chloride salt with a pH of about 4.4.
Load more

Recommended publications
  • RR5211-Front Cover-TB.Pmd
    Morbidity and Mortality Weekly Report Recommendations and Reports June 20, 2003 / Vol. 52 / No. RR-11 Treatment of Tuberculosis American Thoracic Society, CDC, and Infectious Diseases Society of America INSIDE: Continuing Education Examination department of health and human services Centers for Disease Control and Prevention MMWR CONTENTS The MMWR series of publications is published by the Purpose ............................................................................... 1 Epidemiology Program Office, Centers for Disease What’s New In This Document ............................................. 1 Control and Prevention (CDC), U.S. Department of Health and Human Services, Atlanta, GA 30333. Summary ............................................................................. 1 1. Introduction and Background ......................................... 13 SUGGESTED CITATION 2. Organization and Supervision of Treatment ................... 15 Centers for Disease Control and Prevention. 3. Drugs in Current Use ..................................................... 19 Treatment of Tuberculosis, American Thoracic 4. Principles of Antituberculosis Chemotherapy .................. 32 Society, CDC, and Infectious Diseases Society of America. MMWR 2003;52(No. RR-11):[inclusive 5. Recommended Treatment Regimens .............................. 36 page numbers]. 6. Practical Aspects of Treatment........................................ 42 7. Drug Interactions ........................................................... 45 8. Treatment in Special Situations
    [Show full text]
  • Tinnitus Hopes Put to Sleep by Latest Auris Failure
    March 14, 2018 Tinnitus hopes put to sleep by latest Auris failure Madeleine Armstrong Ketamine is best known as a horse tranquiliser or a recreational drug, but it has also been proposed as a treatment for various disorders from depression to Alzheimer’s. Hopes of developing the drug in tinnitus have been dashed by the failure of Auris’s Keyzilen in a second phase III trial. As well as leaving Auris’s future looking bleak – Keyzilen is the second of its phase III candidates to flunk in four months – the setback could also be bad news for the sparse tinnitus pipeline. According to EvaluatePharma there is only one other candidate in active clinical development, Otonomy’s OTO-313, and this uses the same mechanism of action as Keyzilen (see table below). Tinnitus pipeline Generic Project Company Pharma class Trial(s) Notes name Phase III Auris Esketamine TACTT2 Keyzilen NMDA antagonist Failed Aug 2016 Medical hydrochloride (NCT01803646) TACTT3 Failed Mar 2018 (NCT02040194) Phase I OTO- Phase I/II trial to OTO-311 abandoned in Otonomy NMDA antagonist Gacyclidine 313 start H1 2019 favour of this formulation Preclinical Auris AM-102 Undisclosed - - Medical KCNQ2 Knopp Kv7 potassium - - Program Biosciences channel modulator Source: EvaluatePharma. Both projects are psychoactive drugs targeting the NMDA receptor. Tinnitus is commonly caused by loud noise and resulting damage to the sensory hair cells in the cochlea. Initial trauma to the inner ear has been shown to trigger excess production of glutamate, which leads to the hyperactivation of NMDA receptors and, in turn, cell death. Blocking the NMDA receptor could therefore have a protective effect – but it is unclear how this mechanism would work once the damage to hair cells had been done.
    [Show full text]
  • (19) United States (12) Patent Application Publication (10) Pub
    US 20130289061A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0289061 A1 Bhide et al. (43) Pub. Date: Oct. 31, 2013 (54) METHODS AND COMPOSITIONS TO Publication Classi?cation PREVENT ADDICTION (51) Int. Cl. (71) Applicant: The General Hospital Corporation, A61K 31/485 (2006-01) Boston’ MA (Us) A61K 31/4458 (2006.01) (52) U.S. Cl. (72) Inventors: Pradeep G. Bhide; Peabody, MA (US); CPC """"" " A61K31/485 (201301); ‘4161223011? Jmm‘“ Zhu’ Ansm’ MA. (Us); USPC ......... .. 514/282; 514/317; 514/654; 514/618; Thomas J. Spencer; Carhsle; MA (US); 514/279 Joseph Biederman; Brookline; MA (Us) (57) ABSTRACT Disclosed herein is a method of reducing or preventing the development of aversion to a CNS stimulant in a subject (21) App1_ NO_; 13/924,815 comprising; administering a therapeutic amount of the neu rological stimulant and administering an antagonist of the kappa opioid receptor; to thereby reduce or prevent the devel - . opment of aversion to the CNS stimulant in the subject. Also (22) Flled' Jun‘ 24’ 2013 disclosed is a method of reducing or preventing the develop ment of addiction to a CNS stimulant in a subj ect; comprising; _ _ administering the CNS stimulant and administering a mu Related U‘s‘ Apphcatlon Data opioid receptor antagonist to thereby reduce or prevent the (63) Continuation of application NO 13/389,959, ?led on development of addiction to the CNS stimulant in the subject. Apt 27’ 2012’ ?led as application NO_ PCT/US2010/ Also disclosed are pharmaceutical compositions comprising 045486 on Aug' 13 2010' a central nervous system stimulant and an opioid receptor ’ antagonist.
    [Show full text]
  • Salicylate Induces Tinnitus Through Activation of Cochlear NMDA Receptors
    3944 • The Journal of Neuroscience, May 1, 2003 • 23(9):3944–3952 Salicylate Induces Tinnitus through Activation of Cochlear NMDA Receptors Matthieu J. Guitton,1 Jean Caston,2 Je´roˆme Ruel,1 Randolph M. Johnson,3 Re´my Pujol,1 and Jean-Luc Puel1 1Institut National de la Sante´ et de la Recherche Me´dicale UR-254, Laboratoire de Neurobiologie de l’Audition–Plasticite´ Synaptique, Faculte´deMe´decine, Universite´ de Montpellier 1, 34090 Montpellier, France, 2 Unite´ Propre de Recherche et de l’Enseignement Supe´rieur 1780, Laboratoire de Neurobiologie de l’Apprentissage, Universite´ de Rouen, 76821 Mont-Saint-Aignan, France, and 3DURECT Corporation, Cupertino, California 95014 Salicylate, the active component of aspirin, is known to induce tinnitus. However, the site and the mechanism of generation of tinnitus induced by salicylate remains unclear. Here, we developed a behavioral procedure to measure tinnitus in rats. The behavioral model was based on an active avoidance paradigm in which rats had to display a motor task (i.e., to jump on a climbing pole when hearing a sound). Giving salicylate led to a decrease in the percentage of correct responses (score) and a drastic increase in the number of false positive responses (i.e., animals execute the motor task during a silent period). Presentation of the sound at a constant perceptive level prevents decrease of the score, leading to the proposal that score is related to hearing performance. In contrast, the increase of false positive responses remained unchanged. In fact, animals behaved as if they hear a sound, indicating that they are experiencing tinnitus.
    [Show full text]
  • Customs Tariff - Schedule
    CUSTOMS TARIFF - SCHEDULE 99 - i Chapter 99 SPECIAL CLASSIFICATION PROVISIONS - COMMERCIAL Notes. 1. The provisions of this Chapter are not subject to the rule of specificity in General Interpretative Rule 3 (a). 2. Goods which may be classified under the provisions of Chapter 99, if also eligible for classification under the provisions of Chapter 98, shall be classified in Chapter 98. 3. Goods may be classified under a tariff item in this Chapter and be entitled to the Most-Favoured-Nation Tariff or a preferential tariff rate of customs duty under this Chapter that applies to those goods according to the tariff treatment applicable to their country of origin only after classification under a tariff item in Chapters 1 to 97 has been determined and the conditions of any Chapter 99 provision and any applicable regulations or orders in relation thereto have been met. 4. The words and expressions used in this Chapter have the same meaning as in Chapters 1 to 97. Issued January 1, 2020 99 - 1 CUSTOMS TARIFF - SCHEDULE Tariff Unit of MFN Applicable SS Description of Goods Item Meas. Tariff Preferential Tariffs 9901.00.00 Articles and materials for use in the manufacture or repair of the Free CCCT, LDCT, GPT, UST, following to be employed in commercial fishing or the commercial MT, MUST, CIAT, CT, harvesting of marine plants: CRT, IT, NT, SLT, PT, COLT, JT, PAT, HNT, Artificial bait; KRT, CEUT, UAT, CPTPT: Free Carapace measures; Cordage, fishing lines (including marlines), rope and twine, of a circumference not exceeding 38 mm; Devices for keeping nets open; Fish hooks; Fishing nets and netting; Jiggers; Line floats; Lobster traps; Lures; Marker buoys of any material excluding wood; Net floats; Scallop drag nets; Spat collectors and collector holders; Swivels.
    [Show full text]
  • D-Cycloserine
    D-Cycloserine Catalog Numbers: C6880, C3909, C7670 Storage Temperature –20°C CAS #: 68-41-7 Reagents Synonyms: D-4-amino-3-isoxazolidone, D-oxamycin, These products are supplied as powders. Seromycin, K300, NJ-21 C7670 is convenience packaged for use in molecular Product Description biology; it is pre-weighed in quantities to give typical Appearance: White powder working concentrations when the entire package is Molecular Formula: C3H6N2O2 added to 1 L of agar preparations (for 50 plates of 20 ml Molecular Weight: 102.09 per plate). Furthermore, C 7670 is g-irradiated for E 1% = 402 (226 nm) sterility and septum-capped for ease in injecting sterile 23 1 [a]D = +115° (c=1.0%, water) diluent. C 7670 is also USP tested for potency following g-irradiation to assure full biological activity. D-Cycloserine, a structural analog of D-alanine, is a broad spectrum antibiotic produced by certain strains of Preparation Instructions Streptomyces orchidaceus or S. garphalus.1-5 D-cyclo- D-cycloserine is soluble in deionized water up to serine (at 100-200 mg/ml) inhibits the synthesis of 100 mg/ml. A solution of 50 mg/ml cycloserine in water bacterial cell walls (involving peptidoglycan synthesis) is clear and colorless or very faintly yellow. by preventing formation of D-alanine from L-alanine and D-cycloserine is also soluble at 1 in 50 parts of 96% hence the formation of peptide bonds involving ethanol, but practically insoluble in chloroform and D-alanine.4 D-cycloserine has antibiotic activity in vitro ether. It is also slightly soluble in methanol or propylene against growth phase Gram-negative bacteria including glycol.
    [Show full text]
  • CAS Number Index
    2334 CAS Number Index CAS # Page Name CAS # Page Name CAS # Page Name 50-00-0 905 Formaldehyde 56-81-5 967 Glycerol 61-90-5 1135 Leucine 50-02-2 596 Dexamethasone 56-85-9 963 Glutamine 62-44-2 1640 Phenacetin 50-06-6 1654 Phenobarbital 57-00-1 514 Creatine 62-46-4 1166 α-Lipoic acid 50-11-3 1288 Metharbital 57-22-7 2229 Vincristine 62-53-3 131 Aniline 50-12-4 1245 Mephenytoin 57-24-9 1950 Strychnine 62-73-7 626 Dichlorvos 50-23-7 1017 Hydrocortisone 57-27-2 1428 Morphine 63-05-8 127 Androstenedione 50-24-8 1739 Prednisolone 57-41-0 1672 Phenytoin 63-25-2 335 Carbaryl 50-29-3 569 DDT 57-42-1 1239 Meperidine 63-75-2 142 Arecoline 50-33-9 1666 Phenylbutazone 57-43-2 108 Amobarbital 64-04-0 1648 Phenethylamine 50-34-0 1770 Propantheline bromide 57-44-3 191 Barbital 64-13-1 1308 p-Methoxyamphetamine 50-35-1 2054 Thalidomide 57-47-6 1683 Physostigmine 64-17-5 784 Ethanol 50-36-2 497 Cocaine 57-53-4 1249 Meprobamate 64-18-6 909 Formic acid 50-37-3 1197 Lysergic acid diethylamide 57-55-6 1782 Propylene glycol 64-77-7 2104 Tolbutamide 50-44-2 1253 6-Mercaptopurine 57-66-9 1751 Probenecid 64-86-8 506 Colchicine 50-47-5 589 Desipramine 57-74-9 398 Chlordane 65-23-6 1802 Pyridoxine 50-48-6 103 Amitriptyline 57-92-1 1947 Streptomycin 65-29-2 931 Gallamine 50-49-7 1053 Imipramine 57-94-3 2179 Tubocurarine chloride 65-45-2 1888 Salicylamide 50-52-2 2071 Thioridazine 57-96-5 1966 Sulfinpyrazone 65-49-6 98 p-Aminosalicylic acid 50-53-3 426 Chlorpromazine 58-00-4 138 Apomorphine 66-76-2 632 Dicumarol 50-55-5 1841 Reserpine 58-05-9 1136 Leucovorin 66-79-5
    [Show full text]
  • The Impact of D-Cycloserine and Sarcosine on in Vivo Frontal Neural
    Yao et al. BMC Psychiatry (2019) 19:314 https://doi.org/10.1186/s12888-019-2306-1 RESEARCH ARTICLE Open Access The impact of D-cycloserine and sarcosine on in vivo frontal neural activity in a schizophrenia-like model Lulu Yao1, Zongliang Wang1, Di Deng1, Rongzhen Yan1, Jun Ju1 and Qiang Zhou1,2* Abstract Background: N-methyl-D-aspartate receptor (NMDAR) hypofunction has been proposed to underlie the pathogenesis of schizophrenia. Specifically, reduced function of NMDARs leads to altered balance between excitation and inhibition which further drives neural network malfunctions. Clinical studies suggested that NMDAR modulators (glycine, D-serine, D-cycloserine and glycine transporter inhibitors) may be beneficial in treating schizophrenia patients. Preclinical evidence also suggested that these NMDAR modulators may enhance synaptic NMDAR function and synaptic plasticity in brain slices. However, an important issue that has not been addressed is whether these NMDAR modulators modulate neural activity/spiking in vivo. Methods: By using in vivo calcium imaging and single unit recording, we tested the effect of D-cycloserine, sarcosine (glycine transporter 1 inhibitor) and glycine, on schizophrenia-like model mice. Results: In vivo neural activity is significantly higher in the schizophrenia-like model mice, compared to control mice. D-cycloserine and sarcosine showed no significant effect on neural activity in the schizophrenia-like model mice. Glycine induced a large reduction in movement in home cage and reduced in vivo brain activity in control mice which prevented further analysis of its effect in schizophrenia-like model mice. Conclusions: We conclude that there is no significant impact of the tested NMDAR modulators on neural spiking in the schizophrenia-like model mice.
    [Show full text]
  • CYCLOSERINE Proposal for Revision of the International Pharmacopoeia (August 2012)
    Working document QAS/12.463 August 2012 RESTRICTED CYCLOSERINE Proposal for revision of The International Pharmacopoeia (August 2012) Draft for comment This document was provided by a quality control expert. Should you have any comments thereon, please send these to Dr Herbert Schmidt, Medicines Quality Assurance Programme, Quality Assurance and Safety: Medicines, World Health Organization, 1211 Geneva 27, Switzerland; fax: (+41 22) 791 4730 or e-mail: [email protected] with a copy to [email protected] by 17 September 2012. In order to speed up the process for receiving draft monographs and for sending comments, please let us have your e-mail address (to [email protected] ) and we will add it to our electronic mailing list. Please specify if you wish to receive monographs. © World Health Organization 2012 All rights reserved. This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means outside these individuals and organizations (including the organizations' concerned staff and member organizations) without the permission of the World Health Organization. The draft should not be displayed on any web site. Please send any request for permission to: Dr Sabine Kopp, Medicines Quality Assurance Programme, Quality Assurance and Safety: Medicines, Department of Essential Medicines and Health Products , World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730; e-mail: [email protected] . The designations employed and the presentation of the material in this draft do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.
    [Show full text]
  • Estonian Statistics on Medicines 2016 1/41
    Estonian Statistics on Medicines 2016 ATC code ATC group / Active substance (rout of admin.) Quantity sold Unit DDD Unit DDD/1000/ day A ALIMENTARY TRACT AND METABOLISM 167,8985 A01 STOMATOLOGICAL PREPARATIONS 0,0738 A01A STOMATOLOGICAL PREPARATIONS 0,0738 A01AB Antiinfectives and antiseptics for local oral treatment 0,0738 A01AB09 Miconazole (O) 7088 g 0,2 g 0,0738 A01AB12 Hexetidine (O) 1951200 ml A01AB81 Neomycin+ Benzocaine (dental) 30200 pieces A01AB82 Demeclocycline+ Triamcinolone (dental) 680 g A01AC Corticosteroids for local oral treatment A01AC81 Dexamethasone+ Thymol (dental) 3094 ml A01AD Other agents for local oral treatment A01AD80 Lidocaine+ Cetylpyridinium chloride (gingival) 227150 g A01AD81 Lidocaine+ Cetrimide (O) 30900 g A01AD82 Choline salicylate (O) 864720 pieces A01AD83 Lidocaine+ Chamomille extract (O) 370080 g A01AD90 Lidocaine+ Paraformaldehyde (dental) 405 g A02 DRUGS FOR ACID RELATED DISORDERS 47,1312 A02A ANTACIDS 1,0133 Combinations and complexes of aluminium, calcium and A02AD 1,0133 magnesium compounds A02AD81 Aluminium hydroxide+ Magnesium hydroxide (O) 811120 pieces 10 pieces 0,1689 A02AD81 Aluminium hydroxide+ Magnesium hydroxide (O) 3101974 ml 50 ml 0,1292 A02AD83 Calcium carbonate+ Magnesium carbonate (O) 3434232 pieces 10 pieces 0,7152 DRUGS FOR PEPTIC ULCER AND GASTRO- A02B 46,1179 OESOPHAGEAL REFLUX DISEASE (GORD) A02BA H2-receptor antagonists 2,3855 A02BA02 Ranitidine (O) 340327,5 g 0,3 g 2,3624 A02BA02 Ranitidine (P) 3318,25 g 0,3 g 0,0230 A02BC Proton pump inhibitors 43,7324 A02BC01 Omeprazole
    [Show full text]
  • Ep 2932971 A1
    (19) TZZ ¥ __T (11) EP 2 932 971 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 21.10.2015 Bulletin 2015/43 A61K 31/54 (2006.01) A61K 31/445 (2006.01) A61K 9/08 (2006.01) A61K 9/51 (2006.01) (2006.01) (21) Application number: 15000954.6 A61L 31/00 (22) Date of filing: 06.03.2006 (84) Designated Contracting States: • MCCORMACK, Stephen, Joseph AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Claremont, CA 91711 (US) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI • SCHLOSS, John, Vinton SK TR Valencia, CA 91350 (US) • NAGY, Anna Imola (30) Priority: 04.03.2005 US 658207 P Saugus, CA 91350 (US) • PANANEN, Jacob, E. (62) Document number(s) of the earlier application(s) in 306 Los Angeles, CA 90042 (US) accordance with Art. 76 EPC: 06736872.0 / 1 861 104 (74) Representative: Ali, Suleman et al Avidity IP Limited (71) Applicant: Otonomy, Inc. Broers Building, Hauser Forum San Diego, CA 92121 (US) 21 JJ Thomson Avenue Cambridge CB3 0FA (GB) (72) Inventors: • LOBL, Thomas, Jay Remarks: Valencia, This application was filed on 09-04-2015 as a CA 91355-1995 (US) divisional application to the application mentioned under INID code 62. (54) KETAMINE FORMULATIONS (57) Formulations of ketamine for administration to the inner or middle ear. EP 2 932 971 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 932 971 A1 Description [0001] This application claims the benefit of Serial No. 60/658,207 filed March 4, 2005.
    [Show full text]
  • Effects of the Novel NMDA Receptor Antagonist Gacyclidine on Recovery from Medial Frontal Cortex Contusion Injury in Rats
    NEURAL PLASTICITY VOL. 7, NOS. 1-2, 2000 Effects of the Novel NMDA Receptor Antagonist Gacyclidine on Recovery from Medial Frontal Cortex Contusion Injury in Rats Jeffrey S. Smith:, Zoltan L. Fulop l, Steven A. Levinsohn, Richard S. Darrell l, and Donald G. Stein'2t Departments ofNeurology and Psychology, Emory University, Atlanta, GA 30322 ABSTRACT In fact, the ventricles of rats treated with 0.1 mg/kg of gacyclidine were larger than those of Gacyclidine, a novel, noncompetitive NMDA their vehicle treated counterparts, although receptor antagonist, was injected (i.v.) into we observed no behavioral impairment. rats at three different doses to determine if the drug could promote behavioral recovery and reduce the behavioral and anatomical KEYWORDS impairments that occur after bilateral con- tusions of the medial frontal cortex (MFC). In the Morris water maze, contused rats treated gacyclidine, contusion, medial frontal cortex, with gacyclidine at a dosage of 0.1 mg/kg trauma, Morris water maze, recovery of function, performed better than their vehicle-treated inflammation, NMDA-receptor antagonist conspecifics. Rats given gacyclidine at either 0.3 or 0.03 mg/kg performed better than brain-injured controls, but not as well as those INTRODUCTION treated with 0.1 mg/kg. Counts of surviving neurons in the nucleus basalis magnoceilularis Following traumatic brain injury, excitatory (NBM) and the medial dorsal nucleus (MDN) amino acids, such as glutamate, increase to toxic of the thalamus were used to determine levels and may cause further damage to whether gacyclidine treatment attenuated compromised neurons in the injury zone and to secondary cell death.
    [Show full text]