Wo 2009/132050 A2

Total Page:16

File Type:pdf, Size:1020Kb

Wo 2009/132050 A2 (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 29 October 2009 (29.10.2009) WO 2009/132050 A2 (51) International Patent Classification: 61/101,1 12 29 September 2008 (29.09.2008) US A61K 39/395 (2006.01) A61K 47/34 (2006.01) 61/140,033 22 December 2008 (22. 12.2008) US A61P 27/16 (2006.01) A61K 9/06 (2006.01) 61/160,233 13 March 2009 (13.03.2009) US (21) International Application Number: (71) Applicants (for all designated States except US): OTON- PCT/US2009/041320 OMY, INC. [US/US]; 5626 Oberlin Drive, Suite 100, San Diego, CA 92121 (US). THE REGENTS OF THE (22) International Filing Date: UNIVERSITY OF CALIFORNIA [US/US]; 1111 2 1 April 2009 (21 .04.2009) Franklin Street, 12th Floor, Oakland, CA 94607 (US). (25) Filing Language: English (72) Inventors; and (26) Publication Language: English (75) Inventors/Applicants (for US only): LICHTER, Jay [US/US]; P.O. Box 676244, Rancho Santa Fe, CA 92067 (30) Priority Data: (US). VOLLRATH, Benedikt [DE/US]; 4704 Niagara 61/046,543 2 1 April 2008 (21 .04.2008) US Avenue, San Diego, CA 92107 (US). TRAMMEL, An¬ 61/048,878 29 April 2008 (29.04.2008) US drew, M. [US/US]; 12485 South Alden Circle, Olathe, 61/127,7 13 14 May 2008 (14.05.2008) us KS 66062 (US). DURON, Sergio, G. [US/US]; 1605 61/055,625 23 May 2008 (23.05.2008) us Neale Street, San Diego, CA 92103 (US). PIU, Fabrice 61/060,425 10 June 2008 (10.06.2008) us [FR/US]; 11859 Stonedale Ct., San Diego, CA 92131 61/073,7 16 18 June 2008 (18.06.2008) us (US). DELLAMARY, Luis, A. [US/US]; 829 Quiet Hills 61/074,583 20 June 2008 (20.06.2008) us Dr, San Marcos, CA 92069 (US). YE, Qiang [US/US]; 61/076,576 27 June 2008 (27.06.2008) us 7395 Mannix Court, San Diego, CA 92129 (US). 61/076,567 27 June 2008 (27.06.2008) us LEBEL, Carl [US/US]; 23256 Mariposa De Oro St., 61/082,450 2 1 July 2008 (21 .07.2008) us Malibu, CA 90265 (US). SCAIFE, Michael, Christo¬ 61/083,871 25 July 2008 (25.07.2008) us pher [US/US]; 60 Marvin Avenue, Los Altos, CA 94022 61/083,830 25 July 2008 (25.07.2008) us 61/086,105 4 August 2008 (04.08.2008) us (US). HARRIS, Jeffrey, P. [US/US]; 7717 Sierra Mar 61/086,094 4 August 2008 (04.08.2008) us Drive, La Jolla, CA 92037 (US). 61/087,905 11 August 2008 ( 11.08.2008) us (74) Agents: AKHAVAN, Ramin et al; 650 Page Mill Road, 61/087,951 11 August 2008 ( 11.08.2008) us Palo Alto, CA 94304 (US). 61/088,275 12 August 2008 (12.08.2008) us 61/094,384 4 September 2008 (04.09.2008) us [Continued on nextpage] (54) Title: AURIS FORMULATIONS FOR TREATING OTIC DISEASES AND CONDITIONS (57) Abstract: Disclosed herein are compositions and methods for the treatment of otic disorders with immunomodulating agents and auris pressure modulators. In these methods, the auris compositions and formulations are administered locally to an individual afflicted with an otic disorder, through direct application of the immunomodulating and/or auris pressure modulating composi tions and formulations onto the auris media and/or auris interna target areas, or via perfusion into the auris media and/or auris in terna structures. (81) Designated States (unless otherwise indicated, for every GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, kind of national protection available): AE, AG, AL, AM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR), HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MR, NE, SN, TD, TG). MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, Published: NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, — without international search report and to be republished UG, US, UZ, VC, VN, ZA, ZM, ZW. upon receipt of that report (Rule 48.2(g)) (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, AURIS FORMULATIONS FOR TRE-VTING OTIC DISEASES AND CONDITIONS RELATED APPUCATIONS [0001] This patent application claims the benefit of U.S. Provisional Application Ser. Nos. 61/087,905, filed on August 11, 2008, 61/055,625 filed on May 23, 2008, 61/086,105 filed on August 04, 2008, 61/073,716 filed on June 18, 2008 61/140,033 filed on December 22, 2008, 61/127,713 filed on May 14, 2008, 61/101,1 12 filed on September 29, 2008, 61/094,384 filed on September 04, 2008, 61/074,583 filed on June 20, 2008, 61/060,425 filed on June 10, 2008, 61/048,878 filed on April 29 2008, 61/046,543 filed on April 2 1, 2008, 61/076,567 filed on June 27, 2008, 61/076,576 filed on June 27, 2008, 61/160,233 filed on March 13, 2009, 61/086,094 filed on August 04, 2008, 61/083,830 filed on July 25, 2008. 61/083,871 filed on July 25, 2008, 61/087,951 filed on August 11, 2008, 61/088,275 filed on August 12, 2008, the disclosures of all of which are herein incorporated by reference in their entirety. BACKGROUND OF THE INVENTION [0002] Described herein are formulations for enhanced drug delivery into the external, middle and/or inner ear, including the cochlea and vestibular labyrinth; preferably with little or no systemic release of the drug. SUMMARY OF THE INVENTION 10003} The auris formulations and therapeutic methods described herein have numerous advantages that overcome the previously-unrecognized limitations of formulations and therapeutic methods described io prior art. Sterility [0004] The environment of the inner ear is an isolated environment. The endolymph and the perilymph are static fluids and are not in contiguous contact with the circulatory system. The blood - labyrinth - barrier (BLB), which includes a blood-endolymph barrier and a blood-perilymph barrier, consists of tight junctions between specialized epithelial cells i the labyrinth spaces (i.e., the vestibular and cochlear spaces). The presence of the BLB limits delivery of active agents (e.g., imraunomodulators, aural pressure modulators, antimicrobials) to the isolated microenvironment of the inner ear. Aaris hair cells are bathed in endolymphatic or perilymphatic fluids and cochlear recycling of potassium ions is important for hair cell function. When the inner ear is infected, there is n influx of leukocytes and/or immunoglobins (e.g. in response to a microbial infection) into the endolymph and/or the perilymph and the delicate ionic composition of inner ear fluids is upset by the influx of leukocytes and/or immunoglobins. In certain instances, a change in the ionic composition of inner ear fluids results in hearing loss, loss of balance and/or ossification of auditory structures. In certain instances, even trace amounts of pyrogens and/or microbes can trigger infections and related physiological changes in the isolated microenvironment of the inner ear. [0005] Due to the susceptibilty of the inner ear to infections, auris formulations require a level of sterility that has not been recognized hitherto in prior art. Provided herein are auris formulations that are sterilized with stringent sterilty requiremenls and are suitable for administration to the middle and/or inner ear. In some embodiments, the auris compatible compositions described herein are substantially free of pyrogens and/or microbes. Compatibility with Inner Ear Environment [00061 Described herein are otic formulations with an ionic balance that is compatible with the perilymph and/or the endolymph and does not cause any change in cochlear potential . In specific embodiments, osmolarity/osraolality of the present formulations is adjusted, for example, by the use of appropriate salt concentrations (eg,, concentration of sodium salts) or the use of tonicity agents which renders, the formulations endolyrαph-compatibie and/or perilymph-compatible (i.e. isotonic with the endolymph and/or perilymph). In some instances, the endolymph-compatible and/or perilymph-compatible formulations described herein cause minimal disturbance to the environment of the inner ear and cause minimum discomfort (e.g, vertigo) to a mammal (e.g., a human) upon adminstration. Further, the formulations comprise polymers that are biodegradable and/or dispersable, and/or otherwise non-toxic to the inner ear environment. In some embodiments, the formulations described herein are free of preservatives and cause minimal disturbance (e.g., change in pH or osmolality, irritation) in auditory structures, In some embodiments, the formulations described herein comprise antioxidants that are non-irritating and/or non-toxic to otic structures. Dosing Frequency [0007] The current standard of care for auris formulations requires multiple administrations of drops or injections (e.g. intratympauie injections) over several days (e.g., up to two weeks), including schedules of receiving multiple injections per day.
Recommended publications
  • Compositions Comprising Drospirenone Molecularly
    (19) & (11) EP 1 748 756 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 9/00 (2006.01) A61K 9/107 (2006.01) 29.04.2009 Bulletin 2009/18 A61K 9/48 (2006.01) A61K 9/16 (2006.01) A61K 9/20 (2006.01) A61K 9/14 (2006.01) (2006.01) (2006.01) (21) Application number: 05708751.2 A61K 9/70 A61K 31/565 (22) Date of filing: 10.03.2005 (86) International application number: PCT/IB2005/000665 (87) International publication number: WO 2005/087194 (22.09.2005 Gazette 2005/38) (54) COMPOSITIONS COMPRISING DROSPIRENONE MOLECULARLY DISPERSED ZUSAMMENSETZUNGEN AUS DROSPIRENON IN MOLEKULARER DISPERSION DES COMPOSITIONS CONTENANT DROSPIRENONE A DISPERSION MOLECULAIRE (84) Designated Contracting States: (72) Inventors: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • FUNKE, Adrian HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR D-14055 Berlin (DE) Designated Extension States: • WAGNER, Torsten AL BA HR MK YU 13127 Berlin (DE) (30) Priority: 10.03.2004 EP 04075713 (74) Representative: Wagner, Kim 10.03.2004 US 551355 P Plougmann & Vingtoft a/s Sundkrogsgade 9 (43) Date of publication of application: P.O. Box 831 07.02.2007 Bulletin 2007/06 2100 Copenhagen Ø (DK) (60) Divisional application: (56) References cited: 08011577.7 / 1 980 242 EP-A- 1 260 225 EP-A- 1 380 301 WO-A-01/52857 WO-A-20/04022065 (73) Proprietor: Bayer Schering Pharma WO-A-20/04041289 US-A- 5 569 652 Aktiengesellschaft US-A- 5 656 622 US-A- 5 789 442 13353 Berlin (DE) 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]
  • Nitrate Prodrugs Able to Release Nitric Oxide in a Controlled and Selective
    Europäisches Patentamt *EP001336602A1* (19) European Patent Office Office européen des brevets (11) EP 1 336 602 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.7: C07C 205/00, A61K 31/00 20.08.2003 Bulletin 2003/34 (21) Application number: 02425075.5 (22) Date of filing: 13.02.2002 (84) Designated Contracting States: (71) Applicant: Scaramuzzino, Giovanni AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU 20052 Monza (Milano) (IT) MC NL PT SE TR Designated Extension States: (72) Inventor: Scaramuzzino, Giovanni AL LT LV MK RO SI 20052 Monza (Milano) (IT) (54) Nitrate prodrugs able to release nitric oxide in a controlled and selective way and their use for prevention and treatment of inflammatory, ischemic and proliferative diseases (57) New pharmaceutical compounds of general effects and for this reason they are useful for the prep- formula (I): F-(X)q where q is an integer from 1 to 5, pref- aration of medicines for prevention and treatment of in- erably 1; -F is chosen among drugs described in the text, flammatory, ischemic, degenerative and proliferative -X is chosen among 4 groups -M, -T, -V and -Y as de- diseases of musculoskeletal, tegumental, respiratory, scribed in the text. gastrointestinal, genito-urinary and central nervous sys- The compounds of general formula (I) are nitrate tems. prodrugs which can release nitric oxide in vivo in a con- trolled and selective way and without hypotensive side EP 1 336 602 A1 Printed by Jouve, 75001 PARIS (FR) EP 1 336 602 A1 Description [0001] The present invention relates to new nitrate prodrugs which can release nitric oxide in vivo in a controlled and selective way and without the side effects typical of nitrate vasodilators drugs.
    [Show full text]
  • Specifications of Approved Drug Compound Library
    Annexure-I : Specifications of Approved drug compound library The compounds should be structurally diverse, medicinally active, and cell permeable Compounds should have rich documentation with structure, Target, Activity and IC50 should be known Compounds which are supplied should have been validated by NMR and HPLC to ensure high purity Each compound should be supplied as 10mM solution in DMSO and at least 100µl of each compound should be supplied. Compounds should be supplied in screw capped vial arranged as 96 well plate format.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2004/0224012 A1 Suvanprakorn Et Al
    US 2004O224012A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0224012 A1 Suvanprakorn et al. (43) Pub. Date: Nov. 11, 2004 (54) TOPICAL APPLICATION AND METHODS Related U.S. Application Data FOR ADMINISTRATION OF ACTIVE AGENTS USING LIPOSOME MACRO-BEADS (63) Continuation-in-part of application No. 10/264,205, filed on Oct. 3, 2002. (76) Inventors: Pichit Suvanprakorn, Bangkok (TH); (60) Provisional application No. 60/327,643, filed on Oct. Tanusin Ploysangam, Bangkok (TH); 5, 2001. Lerson Tanasugarn, Bangkok (TH); Suwalee Chandrkrachang, Bangkok Publication Classification (TH); Nardo Zaias, Miami Beach, FL (US) (51) Int. CI.7. A61K 9/127; A61K 9/14 (52) U.S. Cl. ............................................ 424/450; 424/489 Correspondence Address: (57) ABSTRACT Eric G. Masamori 6520 Ridgewood Drive A topical application and methods for administration of Castro Valley, CA 94.552 (US) active agents encapsulated within non-permeable macro beads to enable a wider range of delivery vehicles, to provide longer product shelf-life, to allow multiple active (21) Appl. No.: 10/864,149 agents within the composition, to allow the controlled use of the active agents, to provide protected and designable release features and to provide visual inspection for damage (22) Filed: Jun. 9, 2004 and inconsistency. US 2004/0224012 A1 Nov. 11, 2004 TOPCAL APPLICATION AND METHODS FOR 0006 Various limitations on the shelf-life and use of ADMINISTRATION OF ACTIVE AGENTS USING liposome compounds exist due to the relatively fragile LPOSOME MACRO-BEADS nature of liposomes. Major problems encountered during liposome drug Storage in vesicular Suspension are the chemi CROSS REFERENCE TO OTHER cal alterations of the lipoSome compounds, Such as phos APPLICATIONS pholipids, cholesterols, ceramides, leading to potentially toxic degradation of the products, leakage of the drug from 0001) This application claims the benefit of U.S.
    [Show full text]
  • The G Protein-Coupled Glutamate Receptors As Novel Molecular Targets in Schizophrenia Treatment— a Narrative Review
    Journal of Clinical Medicine Review The G Protein-Coupled Glutamate Receptors as Novel Molecular Targets in Schizophrenia Treatment— A Narrative Review Waldemar Kryszkowski 1 and Tomasz Boczek 2,* 1 General Psychiatric Ward, Babinski Memorial Hospital in Lodz, 91229 Lodz, Poland; [email protected] 2 Department of Molecular Neurochemistry, Medical University of Lodz, 92215 Lodz, Poland * Correspondence: [email protected] Abstract: Schizophrenia is a severe neuropsychiatric disease with an unknown etiology. The research into the neurobiology of this disease led to several models aimed at explaining the link between perturbations in brain function and the manifestation of psychotic symptoms. The glutamatergic hypothesis postulates that disrupted glutamate neurotransmission may mediate cognitive and psychosocial impairments by affecting the connections between the cortex and the thalamus. In this regard, the greatest attention has been given to ionotropic NMDA receptor hypofunction. However, converging data indicates metabotropic glutamate receptors as crucial for cognitive and psychomotor function. The distribution of these receptors in the brain regions related to schizophrenia and their regulatory role in glutamate release make them promising molecular targets for novel antipsychotics. This article reviews the progress in the research on the role of metabotropic glutamate receptors in schizophrenia etiopathology. Citation: Kryszkowski, W.; Boczek, T. The G Protein-Coupled Glutamate Keywords: schizophrenia; metabotropic glutamate receptors; positive allosteric modulators; negative Receptors as Novel Molecular Targets allosteric modulators; drug development; animal models of schizophrenia; clinical trials in Schizophrenia Treatment—A Narrative Review. J. Clin. Med. 2021, 10, 1475. https://doi.org/10.3390/ jcm10071475 1. Introduction Academic Editors: Andreas Reif, Schizophrenia is a common debilitating disease affecting about 0.3–1% of the human Blazej Misiak and Jerzy Samochowiec population worldwide [1].
    [Show full text]
  • Classification of Medicinal Drugs and Driving: Co-Ordination and Synthesis Report
    Project No. TREN-05-FP6TR-S07.61320-518404-DRUID DRUID Driving under the Influence of Drugs, Alcohol and Medicines Integrated Project 1.6. Sustainable Development, Global Change and Ecosystem 1.6.2: Sustainable Surface Transport 6th Framework Programme Deliverable 4.4.1 Classification of medicinal drugs and driving: Co-ordination and synthesis report. Due date of deliverable: 21.07.2011 Actual submission date: 21.07.2011 Revision date: 21.07.2011 Start date of project: 15.10.2006 Duration: 48 months Organisation name of lead contractor for this deliverable: UVA Revision 0.0 Project co-funded by the European Commission within the Sixth Framework Programme (2002-2006) Dissemination Level PU Public PP Restricted to other programme participants (including the Commission x Services) RE Restricted to a group specified by the consortium (including the Commission Services) CO Confidential, only for members of the consortium (including the Commission Services) DRUID 6th Framework Programme Deliverable D.4.4.1 Classification of medicinal drugs and driving: Co-ordination and synthesis report. Page 1 of 243 Classification of medicinal drugs and driving: Co-ordination and synthesis report. Authors Trinidad Gómez-Talegón, Inmaculada Fierro, M. Carmen Del Río, F. Javier Álvarez (UVa, University of Valladolid, Spain) Partners - Silvia Ravera, Susana Monteiro, Han de Gier (RUGPha, University of Groningen, the Netherlands) - Gertrude Van der Linden, Sara-Ann Legrand, Kristof Pil, Alain Verstraete (UGent, Ghent University, Belgium) - Michel Mallaret, Charles Mercier-Guyon, Isabelle Mercier-Guyon (UGren, University of Grenoble, Centre Regional de Pharmacovigilance, France) - Katerina Touliou (CERT-HIT, Centre for Research and Technology Hellas, Greece) - Michael Hei βing (BASt, Bundesanstalt für Straßenwesen, Germany).
    [Show full text]
  • Neuroprotection in Alzheimer's Disease
    Chapter 8 Neuroprotection in Alzheimer’s Disease Introduction Alzheimer’s disease (AD) is a progressive degenerative disorder of the brain that begins with memory impairment and eventually progresses to dementia, physical impairment, and death. Patients develop various psychiatric and neurological signs during the course of the disease. The prevalence rates of dementia vary significantly in different countries, but range from 2.1 to 10.5%. AD is the most common type of dementia, accounting for 50–60% of all cases, and is described in detail in a special report on AD (Jain 2010). Several other types of dementias are considered in the differential diagnosis of AD and sometimes all the dementias are lumped together if the type is not known. Other well-known types of dementias are vascular dementia, dementia of aging, and dementia associated with HIV infection. The focus of this section is on AD and some other dementias will be described in Chap. 11. Pathomechanism of Alzheimer’s Disease Several factors that play a role in the etiology and pathogenesis of AD include the following: • Aging • Genetic risk factors • Amyloid precursor protein (APP) and beta-amyloid (Ab) accumulation with neural and vascular sequelae • Tau hyperphosphorylation • Membrane disturbances, phospholipid metabolism, and disruption of signal transduction • Inflammatory reactions and immunological disturbances • Environmental toxins: trace metals • Neurotransmitter defects and imbalances K.K. Jain, The Handbook of Neuroprotection, DOI 10.1007/978-1-61779-049-2_8, 337 © Springer Science+Business Media, LLC 2011 338 8 Neuroprotection in Alzheimer’s Disease • Neuroendocrine disturbances • Oxidative injury and free radicals • Disturbances in regulation and receptors of neurotrophic factors (NTFs) Such a large number of factors in the etiology of AD are responsible for the plethora of theories of cause of AD.
    [Show full text]
  • Prevention Or Amelioration of Autism-Like Symptoms in Animal Models: Will It Bring Us Closer to Treating Human ASD?
    International Journal of Molecular Sciences Review Prevention or Amelioration of Autism-Like Symptoms in Animal Models: Will it Bring Us Closer to Treating Human ASD? Asher Ornoy 1,* , Liza Weinstein-Fudim 1 and Zivanit Ergaz 1,2 1 Laboratory of Teratology, Department of Medical Neurobiology, Hebrew University Hadassah Medical School, Jerusalem 9112001, Israel; [email protected] 2 Neonatology Department, Hadassah Hebrew University Medical Center, Jerusalem 9112001, Israel; [email protected] * Correspondence: [email protected]; Tel.: +972-2-6758329 Received: 17 February 2019; Accepted: 23 February 2019; Published: 1 March 2019 Abstract: Since the first animal model of valproic acid (VPA) induced autistic-like behavior, many genetic and non-genetic experimental animal models for Autism Spectrum Disorder (ASD) have been described. The more common non-genetic animal models induce ASD in rats and mice by infection/inflammation or the prenatal or early postnatal administration of VPA. Through the establishment of these models, attempts have been made to ameliorate or even prevent ASD-like symptoms. Some of the genetic models have been successfully treated by genetic manipulations or the manipulation of neurotransmission. Different antioxidants have been used (i.e., astaxanthin, green tea, piperine) to reduce brain oxidative stress in VPA-induced ASD models. Agents affecting brain neurotransmitters (donepezil, agmatine, agomelatine, memantine, oxytocin) also successfully reduced ASD-like symptoms. However, complete prevention of the development of symptoms was achieved only rarely. In our recent study, we treated mouse offspring exposed on postnatal day four to VPA with S-adenosine methionine (SAM) for three days, and prevented ASD-like behavior, brain oxidative stress, and the changes in gene expression induced by VPA.
    [Show full text]
  • Dynamic L-Glutamate Signaling in the Prefrontal Cortex and the Effects of Methylphenidate Treatment
    University of Kentucky UKnowledge Theses and Dissertations--Neuroscience Neuroscience 2012 DYNAMIC L-GLUTAMATE SIGNALING IN THE PREFRONTAL CORTEX AND THE EFFECTS OF METHYLPHENIDATE TREATMENT Catherine Elizabeth Mattinson University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Mattinson, Catherine Elizabeth, "DYNAMIC L-GLUTAMATE SIGNALING IN THE PREFRONTAL CORTEX AND THE EFFECTS OF METHYLPHENIDATE TREATMENT" (2012). Theses and Dissertations--Neuroscience. 4. https://uknowledge.uky.edu/neurobio_etds/4 This Doctoral Dissertation is brought to you for free and open access by the Neuroscience at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Neuroscience by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained and attached hereto needed written permission statements(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine). I hereby grant to The University of Kentucky and its agents the non-exclusive license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. I agree that the document mentioned above may be made available immediately for worldwide access unless a preapproved embargo applies.
    [Show full text]
  • 8Th European Congress on Epileptology, Berlin, Germany, 21 – 25 September 2008
    Epilepsia, 50(Suppl. 4): 2–262, 2009 doi: 10.1111/j.1528-1167.2009.02063.x 8th ECE PROCEEDINGS 8th European Congress on Epileptology, Berlin, Germany, 21 – 25 September 2008 Sunday 21 September 2008 KV7 channels (KV7.1-5) are encoded by five genes (KCNQ1-5). They have been identified in the last 10–15 years by discovering the caus- 14:30 – 16:00 ative genes for three autosomal dominant diseases: cardiac arrhythmia Hall 1 (long QT syndrome, KCNQ1), congenital deafness (KCNQ1 and KCNQ4), benign familial neonatal seizures (BFNS, KCNQ2 and VALEANT PHARMACEUTICALS SATELLITE SYM- KCNQ3), and peripheral nerve hyperexcitability (PNH, KCNQ2). The fifth member of this gene family (KCNQ5) is not affected in a disease so POSIUM – NEURON-SPECIFIC M-CURRENT K+ CHAN- far. The phenotypic spectrum associated with KCNQ2 mutations is prob- NELS: A NEW TARGET IN MANAGING EPILEPSY ably broader than initially thought (i.e. not only BFNS), as patients with E. Perucca severe epilepsies and developmental delay, or with Rolando epilepsy University of Pavia, Italy have been described. With regard to the underlying molecular pathophys- iology, it has been shown that mutations in KCNQ2 and KCNQ3 Innovations in protein biology, coupled with genetic manipulations, have decrease the resulting K+ current thereby explaining the occurrence of defined the structure and function of many of the voltage- and ligand- epileptic seizures by membrane depolarization and increased neuronal gated ion channels, channel subunits, and receptors that are the underpin- firing. Very subtle changes restricted to subthreshold voltages are suffi- nings of neuronal hyperexcitability and epilepsy. Of the currently cient to cause BFNS which proves in a human disease model that this is available antiepileptic drugs (AEDs), no two act in the same way, but all the relevant voltage range for these channels to modulate the firing rate.
    [Show full text]
  • Etats Rapides
    List of European Pharmacopoeia Reference Standards Effective from 2015/12/24 Order Reference Standard Batch n° Quantity Sale Information Monograph Leaflet Storage Price Code per vial Unit Y0001756 Exemestane for system suitability 1 10 mg 1 2766 Yes +5°C ± 3°C 79 ! Y0001561 Abacavir sulfate 1 20 mg 1 2589 Yes +5°C ± 3°C 79 ! Y0001552 Abacavir for peak identification 1 10 mg 1 2589 Yes +5°C ± 3°C 79 ! Y0001551 Abacavir for system suitability 1 10 mg 1 2589 Yes +5°C ± 3°C 79 ! Y0000055 Acamprosate calcium - reference spectrum 1 n/a 1 1585 79 ! Y0000116 Acamprosate impurity A 1 50 mg 1 3-aminopropane-1-sulphonic acid 1585 Yes +5°C ± 3°C 79 ! Y0000500 Acarbose 3 100 mg 1 See leaflet ; Batch 2 is valid until 31 August 2015 2089 Yes +5°C ± 3°C 79 ! Y0000354 Acarbose for identification 1 10 mg 1 2089 Yes +5°C ± 3°C 79 ! Y0000427 Acarbose for peak identification 3 20 mg 1 Batch 2 is valid until 31 January 2015 2089 Yes +5°C ± 3°C 79 ! A0040000 Acebutolol hydrochloride 1 50 mg 1 0871 Yes +5°C ± 3°C 79 ! Y0000359 Acebutolol impurity B 2 10 mg 1 -[3-acetyl-4-[(2RS)-2-hydroxy-3-[(1-methylethyl)amino] propoxy]phenyl] 0871 Yes +5°C ± 3°C 79 ! acetamide (diacetolol) Y0000127 Acebutolol impurity C 1 20 mg 1 N-(3-acetyl-4-hydroxyphenyl)butanamide 0871 Yes +5°C ± 3°C 79 ! Y0000128 Acebutolol impurity I 2 0.004 mg 1 N-[3-acetyl-4-[(2RS)-3-(ethylamino)-2-hydroxypropoxy]phenyl] 0871 Yes +5°C ± 3°C 79 ! butanamide Y0000056 Aceclofenac - reference spectrum 1 n/a 1 1281 79 ! Y0000085 Aceclofenac impurity F 2 15 mg 1 benzyl[[[2-[(2,6-dichlorophenyl)amino]phenyl]acetyl]oxy]acetate
    [Show full text]
  • Convergent Pharmacological Mechanisms in Impulsivity And
    British Journal of DOI:10.1111/bph.12787 www.brjpharmacol.org BJP Pharmacology Themed Section: Animal Models in Psychiatry Research Correspondence Jeffrey W Dalley, Department of Psychology, University of REVIEW Cambridge, Downing St, Cambridge CB2 3EB, UK. E-mail: [email protected] Convergent ---------------------------------------------------------------- Received 20 February 2014 pharmacological Revised 2 May 2014 Accepted mechanisms in impulsivity 12 May 2014 and addiction: insights from rodent models B Jupp1,2 and J W Dalley1,3 1Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK, 2Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia, and 3Department of Psychiatry, University of Cambridge, Cambridge, UK Research over the last two decades has widely demonstrated that impulsivity, in its various forms, is antecedent to the development of drug addiction and an important behavioural trait underlying the inability of addicts to refrain from continued drug use. Impulsivity describes a variety of rapidly and prematurely expressed behaviours that span several domains from impaired response inhibition to an intolerance of delayed rewards, and is a core symptom of attention deficit hyperactivity disorder (ADHD) and other brain disorders. Various theories have been advanced to explain how impulsivity interacts with addiction both causally and as a consequence of chronic drug abuse; these acknowledge the strong overlaps in neural circuitry and mechanisms between impulsivity and addiction and the seemingly paradoxical treatment of ADHD with stimulant drugs with high abuse potential. Recent years have witnessed unprecedented progress in the elucidation of pharmacological mechanisms underpinning impulsivity. Collectively, this work has significantly improved the prospect for new therapies in ADHD as well as our understanding of the neural mechanisms underlying the shift from recreational drug use to addiction.
    [Show full text]