DOCSLIB.ORG

(12) Patent Application Publication (10) Pub. No.: US 2012/0157420 A1 Schneider (43) Pub

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) Patent Application Publication (10) Pub. No.: US 2012/0157420 A1 Schneider (43) Pub US 2012O157420A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0157420 A1 Schneider (43) Pub. Date: Jun. 21, 2012 (54) TREATMENT AND PREVENTION OF A 6LX 3L/505 (2006.01) SECONDARY INTURY AFTER TRAUMA OR A6IP 29/00 (2006.01) DAMAGE TO THE CENTRAL NERVOUS A6II 3/47 (2006.01) SYSTEM A6IP 25/00 (2006.01) A6IP3/06 (2006.01) (76) Inventor: Eric B Schneider, Glen Arm, MD A6IP 9/00 (2006.01) (US) A6IP 25/22 (2006.01) A6IP 25/24 (2006.01) (21) Appl. No.: 13/392,371 A63L/366 (2006.01) A6II 3/40 (2006.01) (22) PCT Filed: Aug. 31, 2010 (52) U.S. Cl. ......... 514/171; 514/460, 514/419:514/510; (86). PCT No.: PCT/US 10/472O6 514/277; 514/275: 514/423: 514/311 S371 (c)(1), (57) ABSTRACT (2), (4) Date: Feb. 24, 2012 A method of administering one or multiple medications to human patients with CNS injury through oral or parenteral Related U.S. Application Data (including transdermal, intravenous, Subcutaneous, intra (60) Provisional application No. 61/238,453, filed on Aug. muscular) routes. Inflammatory and immunological pro 31, 2009. cesses have been shown to cause secondary damage to CNS s tissues in individuals with acute CNS injury. The present O O invention administers one or more of the following medica Publication Classification tions, which have properties that mitigate the inflammatory (51) Int. Cl. and immunological processes that lead to secondary CNS A6 IK3I/56 (2006.01) damage, via trans-dermal absorption: a statin compound A6 IK 3/405 (2006.01) (e.g., a HMG-CoA reductase inhibitor), a progesterone com A6 IK 3L/25 (2006.01) pound, or a cholinesterase inhibiting compound, among oth A6 IK 3/448 (2006.01) ers, either alone or in combination with other compounds. Patent Application Publication Jun. 21, 2012 Sheet 1 of 8 US 2012/O15742.0 A1 Matrix systems - rig-irradhesive Matilayer Reserweis system Simple matrix system atix inpei vious layer ifug i? ailesive matrix Polynesis: matrix i Achesive Bayer Polymeric matrix 2 S. Rate-contfošing S Reservoir layer frters & FIG. 1. Patent Application Publication Jun. 21, 2012 Sheet 2 of 8 US 2012/O15742.0 A1 as is a writis trus Scietios Sai Solution ESS FRESSESSEE SEESSES FIG. 2. Patent Application Publication Jun. 21, 2012 Sheet 3 of 8 US 2012/O15742.0 A1 SSSSSS SS S s | ''''''''''''''''''''''''''''''| tsSS Sir S FIG. 3. Patent Application Publication Jun. 21, 2012 Sheet 4 of 8 US 2012/O15742.0 A1 itrasotis FIG. 4. Patent Application Publication Jun. 21, 2012 Sheet 5 of 8 US 2012/O15742.0 A1 FIG 5. Patent Application Publication Jun. 21, 2012 Sheet 6 of 8 US 2012/O15742.0 A1 - tri-sers FIG. 6. Patent Application Publication Jun. 21, 2012 Sheet 7 of 8 US 2012/O15742.0 A1 FIG. 7. Patent Application Publication Jun. 21, 2012 Sheet 8 of 8 US 2012/O15742.0 A1 & s'ss is as 8.8s is is & 88ss S8. 888 & FIG. 8. US 2012/O157420 A1 Jun. 21, 2012 TREATMENT AND PREVENTION OF 0006 Inflammation in the central nervous system is not SECONDARY INTURY AFTER TRAUMA OR limited to acute conditions but is also present in chronic DAMAGE TO THE CENTRAL NERVOUS progressive conditions leading to dementia. From the time of SYSTEM Alois Alzheimer, neuro-inflammation has also been impli cated as a factor in dementia. At this point, population-based FIELD studies are equivocal as to a potential moderating role for statins in late life dementia. It seems likely that the long-term 0001. This application describes methods of treatment or inflammatory processes associated with many chronic neu prevention of secondary injury to the human central nervous rological and neuropsychiatric illnesses may either com system after trauma or damage (both internal and external in mence as a result of neuro-immuno-biochemical process origin) and pharmaceutical preparations for use in Such meth associated with acute CNS insult or that these long term ods, as well as methods of manufacture of such preparations. inflammatory processes may be abetted by acute insults and the body's reaction to them. BACKGROUND 0007. At present, there are limited pharmacological inter ventions available to reduce the impact or delay the onset of 0002 Brain injury and dementia are significant public dementing conditions in either acute or chronic settings. health issues at present and are likely to grow in importance as Available agents, including Aricept, Namenda and Meman the population ages. Nearly 1.5 million individuals suffer a tine, may delay disability or slow deterioration to a small traumatic brain injury (TBI) each year and 5.3 million indi extent, but these agents do not preventor reverse the course of viduals are living with disabilities that were acquired through dementia. It is important to note that many of the studies on TBI. Among those who suffer brain trauma in the United the cost effectiveness of these medications were sponsored by States every year, more that 50,000 die as a result of their the pharmaceutical industry (see: Loveman, et al. 2006). injury. Further, 235,000 individuals with brain injury require Appropriately applied, the therapeutic interventions for acute hospitalization and approximately 1.1 million are treated in CNS injury described herein may play a role in reducing the emergency medical facilities and released. (Brain Injury long-term risk of chronic CNS illness and in lowering the Association B.I.A., 2006) burdens associated with these devastating diseases. WO 0003 Acute incidents that damage the central nervous 2006/002127, WO 2006/119598, WO 2009/080301, WO system (CNS) including the brain, such as but not limited to 2007/106862, WO 2003/086379 are all incorporated herein TBI, have been implicated as possible contributors to by reference in their entirety. increased risk of developing chronic neurological and neu ropsychiatric illness, including dementia and parkinsonism SUMMARY among others, across the lifespan. Looking at Alzheimer's 0008. The present invention provides methods for the disease (AD), which is just one of many chronic neuropsy treatment and prevention of acute CNS injury whereby sec chiatric illnesses, it is projected that there will be approxi ondary damage to the CNS is mitigated or eliminated. The mately 8,640,000 individuals in the U.S. alone living with a new methods described herein are especially useful in treat diagnosis of AD by the middle of this century. The economic, ing patients who are unconscious, intubated or who otherwise Social and family burdens associated with caring for this cannot accept medications via oral administration. The number of individuals are daunting. present invention provides a method of treating or preventing 0004 To date, no pharmacological therapy has been avail secondary injury in a patient with a brain injury where a statin able to treat acute trauma to the central nervous system (in is administered to a patient. It also provides a method of cluding the brain and spinal cord) at or very near the time of treating or preventing secondary injury in a patient currently injury with the aim of preventing secondary damage related to on lipid-lowering therapy by administering a statin to a naturally occurring internal inflammatory and immunologi patient. The invention provides a method of treating or pre cal responses in the CNS. Acute traumas to the CNS include venting secondary injury in a patient at risk for a brain injury traumatic brain injury, traumatic spinal cord injury, ischemic by prophylactically administering a statin to a patient. and hemorrhagic events (e.g., stroke), transient ischemic 0009. In one aspect, the present invention includes a attack, encephalopathies (including but not limited to viral method of administering one or multiple medications to encephalitis and acute disseminated encephalomyelitis), human patients with CNS injury through oral or parenteral cerebral anoxia, and any other event where the CNS is acutely (including transdermal, intravenous, Subcutaneous, intra damaged Such that inflammatory and immunological pro muscular) routes. Inflammatory and immunological pro cesses are activated. A continuing and unmet need exists for cesses have been shown to cause secondary damage to CNS new and innovative medical treatments for the prevention and tissues in individuals with acute CNS injury. It is another treatment of post-traumatic secondary injury to the CNS. aspect of the present invention to administer one or more of 0005 Statin use has been associated with reduced mortal statin-like medications, which have properties that mitigate ity and reduced damage to brain tissue in controlled trials of the inflammatory and immunological processes that lead to animals Subjected to traumatic brain injury or induced secondary CNS damage, via trans-dermal absorption: a statin ischemic stroke (Elkind, et al., 2005). While the underlying compound (e.g., a HMG-CoA reductase inhibitor), a proges mechanisms are not clearly understood, it is Suspected that terone compound, or a cholinesterase inhibiting compound, statins may function as “potent vascular anti-inflammatory among others, either alone or in combination with other com agents' (Laio, 2004). Better functional outcomes, as mea pounds. Sured using spatial learning tasks, have been reported in sta 0010. In humans, statin use is associated with decreased tin-treated rats subjected to brain infarction/brain trauma than rates of severe inflammatory reactions, such as sepsis, in in similarly injured rats not treated with Statins (Lu, et al., individuals with bacterial infections (Almog, et al. 2004). The 2004). systemic inflammatory cascade seen in sepsis bears some US 2012/O157420 A1 Jun. 21, 2012 resemblance to the inflammatory processes seen in patients said patient. The invention can be used with a patient that has with traumatic injuries. Statins may have significant anti a history or cardiovascular disease, where the patient could be inflammatory effects in humans beyond their antihyperlipi an athlete, military personnel, an emergency responder, or a demic qualities (see: Liappis, et al., 2001).
Load more

Recommended publications
  • Novel Neuroprotective Compunds for Use in Parkinson's Disease
    Novel neuroprotective compounds for use in Parkinson’s disease A thesis submitted to Kent State University in partial Fulfillment of the requirements for the Degree of Master of Science By Ahmed Shubbar December, 2013 Thesis written by Ahmed Shubbar B.S., University of Kufa, 2009 M.S., Kent State University, 2013 Approved by ______________________Werner Geldenhuys ____, Chair, Master’s Thesis Committee __________________________,Altaf Darvesh Member, Master’s Thesis Committee __________________________,Richard Carroll Member, Master’s Thesis Committee ___Eric_______________________ Mintz , Director, School of Biomedical Sciences ___Janis_______________________ Crowther , Dean, College of Arts and Sciences ii Table of Contents List of figures…………………………………………………………………………………..v List of tables……………………………………………………………………………………vi Acknowledgments.…………………………………………………………………………….vii Chapter 1: Introduction ..................................................................................... 1 1.1 Parkinson’s disease .............................................................................................. 1 1.2 Monoamine Oxidases ........................................................................................... 3 1.3 Monoamine Oxidase-B structure ........................................................................... 8 1.4 Structural differences between MAO-B and MAO-A .............................................13 1.5 Mechanism of oxidative deamination catalyzed by Monoamine Oxidases ............15 1 .6 Neuroprotective effects
    [Show full text]
  • Bifeprunox: a Novel Antipsychotic Agent with Partial Agonist Properties at Dopamine D2 and Serotonin 5-HT1A Receptors
    DRUG EVALUATION Bifeprunox: a novel antipsychotic agent with partial agonist properties at dopamine D2 and serotonin 5-HT1A receptors Marie-Louise G Most second-generation, atypical, dopamine (DA) D2/5-HT2 blocking antipsychotics still Wadenberg induce extrapyramidal side effects (EPS) in higher doses. Weight gain and metabolic University of Kalmar, disturbances are also a problem, and negative and cognitive symptoms have not been Department of Natural Sciences, Norra Vagen 49, sufficiently addressed. The current brain DA mesolimbic hyperactive/mesocortical SE-391 82 Kalmar, Sweden hypoactive hypothesis of schizophrenia suggests that DA D2/5-HT1A receptor partial agonist Tel.: +46 480 446 277; properties may be more efficacious with less side effects. DA D2 receptor partial agonists Fax: +46 480 446 244; may stabilize a hyperactive/hypoactive DA condition. Additional 5-HT stimulation may marie-louise.wadenberg@ 1A hik.se enhance therapeutic efficacy and also improve EPS liability profile. In clinical trials in schizophrenic patients, the novel DA D2/5-HT1A partial agonist bifeprunox indeed demonstrates therapeutic efficacy, a safe EPS profile and appears beneficial regarding weight gain, prolactin, blood lipid and glucose levels and cardiac rhythm. The data on bifeprunox are promising and suggest that combined DA D2/5-HT1A partial agonism may well be important properties for future-generation antipsychotics. Bifeprunox, a novel antipsychotic agent with a (DA D1, D2, D4, 5-HT2A/C, 5-HT1A, hista- so-called third-generation atypical pharmacolog- mine H1, α1, α2, cholinergic muscarinic recep- ical profile, is currently in clinical trials and tor affinity) and comparatively lower affinity for expected to launch as a schizophrenia therapy in the DA D2 receptor than traditional APDs.
    [Show full text]
  • HTR1A Polymorphisms and Clinical Efficacy Of
    International Journal of Neuropsychopharmacology, (2016) 19(5): 1–10 doi:10.1093/ijnp/pyv125 Advance Access publication November 14, 2015 Research Article research article HTR1A Polymorphisms and Clinical Efficacy of Antipsychotic Drug Treatment in Schizophrenia: A Meta-Analysis Yoshiteru Takekita, MD, PhD; Chiara Fabbri, MD; Masaki Kato, MD, PhD; Yosuke Koshikawa, MA; Aran Tajika, MD; Toshihiko Kinoshita, MD, PhD; Alessandro Serretti, MD, PhD Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy (Drs Takekita, Fabbri, and Serretti); Department of Neuropsychiatry, Kansai Medical University, Osaka, Japan (Drs Takekita, Kato, Koshikawa, and Kinoshita); Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health, Kyoto, Japan (Dr Tajika). Correspondence: Yoshiteru Takekita, MD, PhD, Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Viale Carlo Pepoli 5, Bologna, 40123, Italy ([email protected]). Abstract Background: This meta-analysis was conducted to evaluate whether HTR1A gene polymorphisms impact the efficacy of antipsychotic drugs in patients with schizophrenia. Methods: Candidate gene studies that were published in English up to August 6, 2015 were identified by a literature search of PubMed, Web of Science, and Google scholar. Data were pooled from individual clinical trials considering overall symptoms, positive symptoms and negative symptoms, and standard mean differences were calculated by applying a random-effects model. Results: The present meta-analysis included a total of 1281 patients from 10 studies. Three polymorphisms of HTR1A (rs6295, rs878567, and rs1423691) were selected for the analysis. In the pooled data from all studies, none of these HTR1A polymorphisms correlated significantly with either overall symptoms or positive symptoms.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2014/0371260 A1 Moebius (43) Pub
    US 20140371260A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0371260 A1 Moebius (43) Pub. Date: Dec. 18, 2014 (54) COMBINATION THERAPY USING (60) Provisional application No. 60/420,918, filed on Oct. 1-AMINOCYCLOHEXANEDERVATIVES 24, 2002. AND ACETYLCHOLINESTERASE INHIBITORS Publication Classification (71) Applicant: MERZ PHARMA GmbH & CO. (51) Int. Cl KGaA, Frankfurt Am Main (GE) A613 L/473 (2006.01) A613 L/445 (2006.01) (72)72). InventorI tor: talHans-J is: Moebius.Oebus, FraFrankfurt Am A63/325 (2006.01) A613 L/13 (2006.01) (73) Assignee: MERZPHARMA GmbH & CO. (52) U.S. Cl. KGaA, Frankfurt Am Main (GE) CPC ............... A61 K3I/473 (2013.01); A61K3I/13 (2013.01); A61 K3I/445 (2013.01); A61 K (21) Appl. No.: 14/280,405 31/325 (2013.01) USPC ............................ 514/297: 514/319; 514/479 (22) Filed: May 16, 2014 Related U.S. Application Data (57) ABSTRACT (60) Continuation of application No. 12/661,639, filed on The invention relates to a novel drug combination therapy Mar. 22, 2010, which is a continuation of application useful in the treatment of dementia comprising administering No. 12/072,539, filed on Feb. 27, 2008, now aban an 1-aminocyclohexane derivative such as memantine or ner doned, which is a division of application No. 10/691, amexane and an acetylcholinesterase inhibitor (AChEI) such 895, filed on Oct. 23, 2003, now abandoned. as galantamine, tacrine, donepezil, or rivastigmine. Patent Application Publication Dec. 18, 2014 Sheet 2 of 3 US 2014/0371260 A1 Patent Application Publication Dec. 18, 2014 Sheet 3 of 3 US 2014/0371260 A1 US 2014/0371260 A1 Dec.
    [Show full text]
  • Treatment Protocol Copyright © 2018 Kostoff Et Al
    Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al PREVENTION AND REVERSAL OF ALZHEIMER'S DISEASE: TREATMENT PROTOCOL by Ronald N. Kostoffa, Alan L. Porterb, Henry. A. Buchtelc (a) Research Affiliate, School of Public Policy, Georgia Institute of Technology, USA (b) Professor Emeritus, School of Public Policy, Georgia Institute of Technology, USA (c) Associate Professor, Department of Psychiatry, University of Michigan, USA KEYWORDS Alzheimer's Disease; Dementia; Text Mining; Literature-Based Discovery; Information Technology; Treatments Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al CITATION TO MONOGRAPH Kostoff RN, Porter AL, Buchtel HA. Prevention and reversal of Alzheimer's disease: treatment protocol. Georgia Institute of Technology. 2018. PDF. https://smartech.gatech.edu/handle/1853/59311 COPYRIGHT AND CREATIVE COMMONS LICENSE COPYRIGHT Copyright © 2018 by Ronald N. Kostoff, Alan L. Porter, Henry A. Buchtel Printed in the United States of America; First Printing, 2018 CREATIVE COMMONS LICENSE This work can be copied and redistributed in any medium or format provided that credit is given to the original author. For more details on the CC BY license, see: http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License<http://creativecommons.org/licenses/by/4.0/>. DISCLAIMERS The views in this monograph are solely those of the authors, and do not represent the views of the Georgia Institute of Technology or the University of Michigan. This monograph is not intended as a substitute for the medical advice of physicians. The reader should regularly consult a physician in matters relating to his/her health and particularly with respect to any symptoms that may require diagnosis or medical attention.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 9,314.465 B2 Brew Et Al
    US009314465B2 (12) United States Patent (10) Patent No.: US 9,314.465 B2 Brew et al. (45) Date of Patent: *Apr. 19, 2016 (54) DRUG COMBINATIONS AND USES IN 2008.0003280 A1 1/2008 Levine et al. ................. 424/456 TREATING A COUGHING CONDITION 2008/O176955 A1 7/2008 Hecket al. 2008, 0220078 A1 9, 2008 Morton et al. (71) Applicant: Infirst Healthcare Limited 2009, O136427 A1 5/2009 Croft et al. 2009, O220594 A1 9, 2009 Field (72) Inventors: John Brew, London (GB); Robin Mark 2012/O128738 A1 5, 2012 Brew et al. Bannister, London (GB) 2012fO252824 A1 10/2012 Brew et al. (73) Assignee: Infirst Healthcare Limited, London FOREIGN PATENT DOCUMENTS (GB) CN 1593451 3, 2005 CN 101024.014 A 8, 2007 (*) Notice: Subject to any disclaimer, the term of this CN 101112383 B 5, 2010 patent is extended or adjusted under 35 DE 4420708 A1 12, 1995 U.S.C. 154(b) by 0 days. EP 2050435 B1 4/2009 GB 2114001 A 8, 1983 This patent is Subject to a terminal dis GB 2284761 A 6, 1995 claimer. GB 2424.185 B 9, 2006 GB 2442828 A 4/2008 JP 62-249924 A 10, 1987 (21) Appl. No.: 14/287,014 JP H1O-316568 A 12/1998 JP 2001-518928 A 10, 2001 (22) Filed: May 24, 2014 JP 200219.3839. A T 2002 JP 2003-012514 A 1, 2003 (65) Prior Publication Data JP 20030552.58 A 2, 2003 JP 2003128549 A 5, 2003 US 2014/O256750 A1 Sep. 11, 2014 JP 2003-321357 A 11, 2003 JP 2005-516917 A 6, 2005 JP 2008O31146 A 2, 2008 Related U.S.
    [Show full text]
  • WO 2016/001643 Al 7 January 2016 (07.01.2016) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/001643 Al 7 January 2016 (07.01.2016) P O P C T (51) International Patent Classification: (74) Agents: GILL JENNINGS & EVERY LLP et al; The A61P 25/28 (2006.01) A61K 31/194 (2006.01) Broadgate Tower, 20 Primrose Street, London EC2A 2ES A61P 25/16 (2006.01) A61K 31/205 (2006.01) (GB). A23L 1/30 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/GB20 15/05 1898 AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (22) International Filing Date: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 29 June 2015 (29.06.2015) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (25) Filing Language: English KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (26) Publication Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (30) Priority Data: SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 141 1570.3 30 June 2014 (30.06.2014) GB TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 1412414.3 11 July 2014 ( 11.07.2014) GB (84) Designated States (unless otherwise indicated, for every (71) Applicant: MITOCHONDRIAL SUBSTRATE INVEN¬ kind of regional protection available): ARIPO (BW, GH, TION LIMITED [GB/GB]; 39 Glasslyn Road, London GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, N8 8RJ (GB).
    [Show full text]
  • Global Current Trends in Drug Designing for Management of Type-2 Diabetes and Neurodegenerative Disorders
    Haque et al., Drug Des 2013, 2:2 Drug Designing: Open Access http://dx.doi.org/10.4172/2169-0138.1000e120 Editorial Open Access Global Current Trends in Drug Designing for Management of Type-2 Diabetes and Neurodegenerative Disorders Haque A, Alam Q, Alam MZ and Kamal MA* Fundamental and Applied Biology Group, King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia Abstract Neurodegenerative diseases (NDs) and Type 2 diabetes (T2D) are progressive disorder often advances with age. T2D is characterized by hyperglycaemia, insulin resistance or relative lack of insulin uptake whereas NDs are characterized by the decline in cognitive function, diffuse deposition of amyloid plaques and neurofibrillary tangles in AD and degeneration of dopaminergic neurons in substantia nigra, leading to a reduction of striatal dopamine (DA) levels in PD. Since conventional drugs fail to surpass the natural CNS protective barriers, therefore, in order to overcome these hurdles, targeted drug delivery is of foremost significance for the treatment of AD and PD. New generation of drugs has discovered through innovative nanotechnology approaches such as polymeric nanoparticles are promising candidates in the investigation of AD because nanoparticles are capable of opening the tight junctions, crossing the BBB. Thus, there is a need to adopt current trend and newer strategies such as nanotechnological, computational and gene therapy approaches for drug design and delivery. Keywords: Alzheimer disease; Type-2 diabetes; Insulin; Amyloid; function, diffuse deposition of amyloid plaques and neurofibrillary Nanotechnology; Nanodiagnostics; Nanomedicine; Neurodegenerative tangles. Various multi-disciplinary studies (epidemiologic and clinical) disorders; Drug design were carried out in an effort to identifying the etiology, pathogenesis and risk factors linked with AD.
    [Show full text]
  • The Role of Kinetic Context in Apparent Biased Agonism at Gpcrs
    ARTICLE Received 2 Jul 2015 | Accepted 27 Jan 2016 | Published 24 Feb 2016 DOI: 10.1038/ncomms10842 OPEN The role of kinetic context in apparent biased agonism at GPCRs Carmen Klein Herenbrink1, David A. Sykes2, Prashant Donthamsetti3,4, Meritxell Canals1, Thomas Coudrat1, Jeremy Shonberg5, Peter J. Scammells5, Ben Capuano5, Patrick M. Sexton1, Steven J. Charlton2, Jonathan A. Javitch3,4,6, Arthur Christopoulos1 & J Robert Lane1 Biased agonism describes the ability of ligands to stabilize different conformations of a GPCR linked to distinct functional outcomes and offers the prospect of designing pathway-specific drugs that avoid on-target side effects. This mechanism is usually inferred from pharmaco- logical data with the assumption that the confounding influences of observational (that is, assay dependent) and system (that is, cell background dependent) bias are excluded by experimental design and analysis. Here we reveal that ‘kinetic context’, as determined by ligand-binding kinetics and the temporal pattern of receptor-signalling processes, can have a profound influence on the apparent bias of a series of agonists for the dopamine D2 receptor and can even lead to reversals in the direction of bias. We propose that kinetic context must be acknowledged in the design and interpretation of studies of biased agonism. 1 Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia. 2 Cell Signalling Research Group, School of Life Sciences, University of Nottingham, Queen’s Medical Centre, Nottingham NG7 2UH, UK. 3 Departments of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. 4 Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
    [Show full text]
  • Predictive Value of Parkinsonian Primates in Pharmacological Studies, a Comparison Between the Macaque, Marmoset and Squirrel Monkey I
    Downloaded from jpet.aspetjournals.org at ASPET Journals on October 1, 2021 NV PH JPET #247171 i HA,PH 1 Adjia Hamadjida, Philippe Huot Adjia Philippe Hamadjida, , JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 JPET Fast Forward.
    [Show full text]
  • (12) United States Patent (10) Patent N0.: US 7,964,607 B2 Verhoest Et A1
    US007964607B2 (12) United States Patent (10) Patent N0.: US 7,964,607 B2 Verhoest et a1. (45) Date of Patent: Jun. 21, 2011 (54) PYRAZOLO[3,4-D]PYRIMIDINE FOREIGN PATENT DOCUMENTS COMPOUNDS EP 1460077 9/2004 WO 02085904 10/2002 (75) Inventors: Patrick Robert Verhoest, Old Lyme, CT WO 2004037176 5/2004 (US); Caroline ProulX-Lafrance, Ledyard, CT (US) OTHER PUBLICATIONS Wunder et a1, M01. PharmacoL, v01. 28, N0. 6, (2005), pp. 1776 (73) Assignee: P?zer Inc., New York, NY (U S) 1781. van der Staay et a1, Neuropharmacology, v01. 55 (2008), pp. 908 ( * ) Notice: Subject to any disclaimer, the term of this 918. patent is extended or adjusted under 35 USC 154(b) by 562 days. Primary Examiner * Susanna Moore (74) Attorney, Agent, or Firm * Jennifer A. Kispert; (21) Appl.No.: 12/118,062 Michael Herman (22) Filed: May 9, 2008 (57) ABSTRACT (65) Prior Publication Data The invention provides PDE9-inhibiting compounds of For US 2009/0030003 A1 Jan. 29, 2009 mula (I), Related US. Application Data (60) Provisional application No. 60/917,333, ?led on May 11, 2007. (51) Int. Cl. C07D 48 7/04 (2006.01) A61K 31/519 (2006.01) A61P 25/28 (2006.01) (52) US. Cl. ................................... .. 514/262.1; 544/262 (58) Field of Classi?cation Search ................ .. 544/262; 5 1 4/2 62 .1 See application ?le for complete search history. and pharmaceutically acceptable salts thereof, Wherein R, R1, (56) References Cited R2 and R3 are as de?ned herein. Pharmaceutical compositions containing the compounds of Formula I, and uses thereof in U.S.
    [Show full text]
  • Methods and Combination Therapies for Treating Alzheimer's Disease
    (19) & (11) EP 2 420 235 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 22.02.2012 Bulletin 2012/08 A61K 31/437 (2006.01) A61K 31/445 (2006.01) A61K 45/06 (2006.01) A61P 25/28 (2006.01) (21) Application number: 11181674.0 (22) Date of filing: 26.10.2007 (84) Designated Contracting States: • Protter, Andrew Asher AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Palo Alto, CA California CA 94301 (US) HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR (74) Representative: Sexton, Jane Helen J.A. Kemp & Co. (30) Priority: 27.10.2006 US 854866 P 14 South Square Gray’s Inn (62) Document number(s) of the earlier application(s) in London WC1R 5JJ (GB) accordance with Art. 76 EPC: 07867284.7 / 2 086 538 Remarks: This application was filed on 16-09-2011 as a (71) Applicant: Medivation Neurology, Inc. divisional application to the application mentioned San Francisco, CA 94105 (US) under INID code 62. (72) Inventors: • Hung, David T. Redwood City, CA California CA 94062 (US) (54) Methods and combination therapies for treating alzheimer’s disease (57) The invention provides methods and combina- bon) in conjunction with another compound, pharmaceu- tion therapies for treating and/or preventing and/or slow- tically acceptable salt thereof or therapy for Alzheimer’s ing the onset and/or development of Alzheimer’s disease disease. using a hydrogenated pyrido (4,3-b) indole (e.g., dime- EP 2 420 235 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 420 235 A1 Description CROSS-REFERENCE TO RELATED APPLICATIONS 5 [0001] This application claims priority to U.S.
    [Show full text]