DOCSLIB.ORG

(12) United States Patent (10) Patent No.: US 6,369,052 B1 Kellar Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) United States Patent (10) Patent No.: US 6,369,052 B1 Kellar Et Al USOO6369052B1 (12) United States Patent (10) Patent No.: US 6,369,052 B1 Kellar et al. (45) Date of Patent: Apr. 9, 2002 (54) COMBINATION OF HUPERZINE AND Ayer et al., 1989," Alkaloids of Lycopodium selago. On the NCOTINC COMPOUNDS ASA identity of Selagine with huperzine A and the Structure of a NEUROPROTECTIVE AGENT related alkaloid”, Can. J. Chem. 67: 1538–1540. Bai et al., 1993, "Traditional Chinese medicines and New (75) Inventors: Kenneth J. Kellar, Bethesda, MD drug development', Pure and Appl. Chem. 65:1103-1112. (US); Alan P. Kozikowski, Princeton, Choi et al., 1989, “Aspartate Neurotoxicity on Cultured NJ (US) Cortical Neurons', J. of Neuroscience Res. 23:116-121. Choi et al., 1993, "Calcium and Excitotoxic Neuronal (73) Assignee: Georgetown University, Washington, Injury', annals NY Acdemy of Sciences 162-170. DC (US) Coyle et al., 1984,. “Alzheimers Disease: A disorder of cortical cholinergic innervation”, Science 219:1184-1190. (*) Notice: Subject to any disclaimer, the term of this Decker et al., 1994, “(S)-3-Methyl-5-(1-Methyl-2- Pyr patent is extended or adjusted under 35 rolidinyl) Isoxazole (ABT 418): A novel cholinergic ligand U.S.C. 154(b) by 0 days. with cognition enhancing and anxiolytic activities: II. In vivo characterization”, J. of Pharmacology and Exp. Ther (21) Appl. No.: 09/910,819 270:319-328. (22) Filed: Jul. 23, 2001 Decket et al., 1992, “Effects of nicotine on spatial memory deficits in rats with septal lesions”, Brain Res. 572:281-285. Gordon et al., 1997, "Huperzine-A(HUP-A) Interacts with Related U.S. Application Data the NMDA Receptor Ion Channel”, FASEB Journal, Core (60) Provisional application No. 60/223,605, filed on Aug. 7, Abstracts, 11(9):268. 2000, and provisional application No. 60/241,670, filed on Harsing et al., 1992, “Dopamine Efflux from Striatum After Oct. 18, 2000. Chronic Nicotine: Evidence for Autoreceptor Desensitiza tion”, J. of Neurochem. 59(1):48–54. (51) Int. Cl." ........................ A61K 31/55; A61K 31/44; Hartley et al., 1989, “Delayed Rescue of N-Methyl-D-AS A61K 31/665; A61K 31/435 partate Receptor Mediated Neuronal Injury in Cortical Cul ture”, J. of Pharmacology and Exp. Ther. 250:752–758. (52) U.S. Cl. ....................... 514/221; 514/286; 514/290; Kaneko et al., 1997, “Nicotine protects cultured cortical 514/295; 514/339; 514/343 neurons against glutamate induced cytotoxicity Via C-,neu ronal receptors and neuronal CNS receptors”, Brain Res. (58) Field of Search ................................. 514/221, 286, 765:135-140. 514/290, 295,339, 343 Kozikowski and Tuckmantel, 1999, “Chemistry, Pharmacol ogy, and Clinical Efficacy of the Chinese Nootropic Agent (56) References Cited Huperzine A', Acc. Chem. Res. 32:641-650. U.S. PATENT DOCUMENTS Ladner et al., 1998, “Pharmacological Drug Treatment of Alzheimer Diseasse: The Cholinergic Hypothesis Revis 4929,731 A 5/1990 Kozikowski et al. ited”, J. of Neuropathology and Exp. Neurology 5,104,880 A 4/1992 Kozikowski 5,106,979 A 4/1992 Kozikowski et al. 5798):719–731. 5,177,082 A 1/1993 Yu et al. Linville et al., 1993, “Nicotinic Agonists Modulate Basal 5,547,960 A 8/1996 Kozikowski et al. Forebrain Control of Cortical Cerebral Blood Flow in Anes 5,663,344 A 9/1997 Kozikowski et al. thetized Rats', J. of Pharmacology and Exp. Ther. 5,869.672 A 2/1999 Kozikowski et al. 267:441-447. 5,929,084 A 7/1999 Zhu et al. (List continued on next page.) OTHER PUBLICATIONS Primary Examiner Raymond Henley, III Akaike et al., 1994, “Nicotine induced protection of cultured cortical neurons against N-methyl-D-aspartate receptor (74) Attorney, Agent, or Firm-Pennie & Edmonds LLP mediated glutamate cytotoxicity', Brain Res. 644:181-187. (57) ABSTRACT Akaike et al., 1994, "Regulation by neuroprotective factors of NMDA receptor mediated nitric oxide synthesis in the The present invention provides compositions and methods brain and retina”, Prog Brain Res. 103:391-403. for treating, preventing, or reversing neuronal dysfunction Arneric et al., 1994, “Nicotinic agonists in Alzheimers including cognitive decline, Such as cognitive decline asso disease: does the molecular diversity of nicotine receptors ciated with aging and minimal cognitive impairment; Severe offer the opportunity for developing CNS-selective cholin neurodegenerative disorders, Such as Alzheimer's disease; ergic channel activators?”, Recent Advances in the Treat and neuronal dysfunction associated with loSS of motor ment of Neurodegenerative Disorders and Cognitive Dys skills, Such as Parkinson's disease and amyotrophic lateral function. Sclerosis. The compositions and methods of the invention Arneric et al., 1994, "(S)-3-Methyl-5-(1-Methyl-2- Pyr can also treat or prevent neuronal dysfunction resulting from rolidinyl) Isoxazole (ABT 418): A Novel Cholinergic CNS injury, Such as Stroke, Spinal-cord injury, and Ligand with Cogniton-Enhancing and Anxiolytic Activi peripheral-nerve injury. The compositions of the invention ties”, J. of Pharmacology and Exp. Ther. 270:310-318. comprises a huperzine compound and a nicotinic compound. Ayer et al., 1989, “Some new Lycopodium alkaloids”, Can. J. Chem. 67; 1077–1086. 58 Claims, 3 Drawing Sheets US 6,369,052 B1 Page 2 OTHER PUBLICATIONS Sanberg et al., 1993, “Nicotine Potentiation of Haloperidol Liu et al., 1986, “The Structures of Huperzine A and B two Induced Catalepsy: Striatal Mechanisms”, Pharmacology new alkaloids exhibiting marked anticholinesterase activ Biochem. And Behavior 46:303-307. ity”, Can. J. Chem. 6 4:837-839. Sjak-Shie et al., 1991, “Some Novel Actions of Nicotine in Marin et al., 1994, “Nicotine protects cultured striatal neu Nucleus Basalis Lesioned Rats and in Hippocampal Slices”, rones against N-methily-D-aspartate receptor-mediated Cholinergic Basis for Alzheimer Therapy 379-385. neurotoxicity”, NeuroReport 5:1977-1980. Mattson et al., 1988, “Neurotransmitters in the regulation of Sullivan et al., 1995, “Cholinergenic Channel Activators: neuronal cytoarchitecture', Brain Res. Reviews Novel Opportunities for the Treatment of CNS Disorders”, 13:179-212. Proc. West. Pharmacol. Soc. 38:127-130. Meldrum and Garthwaite, 1990, “Excitatory amino acid neurotoxicity and neurodegenerative disease”, TIPS Ved et al., 1997, "Huperzine A, a potential therapeutic agent 11:379-387. for dementia, reduces neuronal cell death caused by Sahaklan et al., 154, “The Effects of Nicotine on Attention, glutamate”, Medicinal Chem. 8(43):963–968. Information Processing, and Short Term Memory in Patients Wesnes et al., 1984, “Effects of Scopolamine and nicotine on with Demential of the Alzheimer Type”, British J. of Psy human rapid information processing perfromance', Psy chiatry 154:797–800. chopharmacology 82:147-150. U.S. Patent Apr. 9, 2002 Sheet 1 of 3 US 6,369,052 B1 3 4. S. t C2 ces ce -S. S. U v. 2 C N ver 1. -- v. CD- L CS S LL 2 E. N 1. l Ol O C S : O O O O O O O Se do d r N JOXO WOWN O % O 9 S is < Y - 5a CD - 2, l U 4. 5 C2 2. C O O O O O O S2 OO O tr OXO WONN O % U.S. Patent Apr. 9, 2002 Sheet 2 of 3 US 6,369,052 B1 O O d se Z R O C2 s O 2 Le S. on 2 CN S. 2 Se S C D l O LL t N n 1 1 Ll 55 C C C O O O Co O O O O C O on O CO CO sh- N ALIOIXOL 3Olddd OIOIAWV-8 40% O O S. s. g Cn s s 3 CD g A. Ll R O C 2. O O O O O O O O O CN O O d s on ALIOXO1 3OLld3d OIOJWV-8 40% U.S. Patent Apr. 9, 2002 Sheet 3 of 3 US 6,369,052 B1 O O C U s 2 s O O Se O is s S. 9. O S2O is4 no 5 tL Us 95 asCD 55N - E. Ll 1 1 U Ol Cl O O C O O O O O O O O 3 o O r on OXO WOWN O % US 6,369,052 B1 1 2 COMBINATION OF HUPERZINE AND binding to N-methyl-D-aspartate (“NMDA') receptors, NCOTINC COMPOUNDS ASA which play a crucial role in glutamate-induced neurodegen NEUROPROTECTIVE AGENT eration (Mattson, 1988, Brain Res. 13:174; Choi et al., 1989, J. Neurosci. Res. 23:116; Hartley & Choi, 1989, J. Phar 5 macol. Exp. Ther. 250:752; Meldrum & Garthwaire, 1990, This application claims the benefit of U.S. Provisional Trends Pharmacol. Sci. 11:379). For example, symptoms of Application No. 60/223,605, filed Aug. 7, 2000, hereby neuronal damage caused by organophosphate (“OP”) toxic incorporated herein by reference in its entirety and U.S. ity (i.e. tremors, seizures or convulsions) have been partially Provisional Application No. 60/241,670, filed Oct. 18, 2000, attributed to the release of large quantities of glutamate hereby incorporated herein by reference in its entirety. during OP intoxication. The released glutamate causes acti This invention was made in part under Department of vation of NMDA receptors and increases Ca' influx that in Army Grant No. DAMD 17-99-2-9907. turn causes persistent elevation in Ca" concentrations, 1. FIELD OF THE INVENTION eventually resulting in neuronal death (Ved et al., 1997, The present invention relates to compositions comprising Neuroreport 8:963; Choi, 1994, Ann. NY Acad. Sci. huperzine compounds and nicotinic compounds and to 15 747:162). Nicotine protects cultured cortical neurons against methods of using huperzine compounds and nicotinic com NMDA receptor-mediated, glutamate-induced cell death pounds in combination to provide a neuroprotective effect. (Marin et al., 1994, Neuropharmacology and Neurotoxicol ogy 5:1977; Kaneko et al., 1997, Brain Research 765:135.
Load more

Recommended publications
  • Roger Lee Papke Box 100267 JHM Health Science Center Gainesville, Florida 32610
    CURRICULUM VITAE Roger Lee Papke DEPARTMENT OF PHARMACOLOGY AND THERAPEUTICS UNIVERSITY OF FLORIDA SCHOOL OF MEDICINE Box 100267 J.H.M. Health Science Center Gainesville, Florida 32610 (352) 392-4712, FAX (352) 392-9696 [email protected] BIOGRAPHICAL DATA: Born: October 12, 1953, Kenmore, New York Married: December 24, 1980 to Clare Stokes Citizenship: U. S. A. EDUCATION: Starpoint Central School Pendleton, N. Y. Primary and Secondary N.Y.S. Regents Diploma 1971 New York University Washington Square College of Arts and Sciences 1971 - 1975 Majors in Biology and Classical Civilization Bachelor of Arts awarded May 1975 New York University Graduate school of Arts and Sciences 1975 - 1976 Thesis advisor: Dr. Fleur L. Strand Thesis title: An Alpha Adrenergic Response of Cardiac Muscle at an Alkaline pH Master of Science awarded May 1976 Cornell University Graduate School of Arts and Science 1976-1979: Section of Physiology Graduate Research Assistant in Reproductive Physiology Advisor: Dr. William Hansel Research topic: The endocrine control of delayed implantation in mink Cornell University Graduate School of Arts and Science 1979-1986: Section of Neurobiology and Behavior Thesis Advisor: Dr. Robert Oswald Primary research topic: Pharmacology of nicotinic acetylcholine receptors Thesis Title: The Gating of Single Channel Currents Through the Nicotinic Acetylcholine Receptors of BC3H-1 Cells: Effects of Agonists and Allosteric Ligands Ph.D. conferred January 1987 ACADEMIC APPOINTMENTS: 1987 Postdoctoral Research Associate: Department of Pharmacology,
    [Show full text]
  • Differential Effects of Alkaloids on Memory in Rodents
    www.nature.com/scientificreports OPEN Diferential efects of alkaloids on memory in rodents Patrick M. Callahan1,2, Alvin V. Terry Jr.1,2, Manuel C. Peitsch3, Julia Hoeng3* & Kyoko Koshibu3* Nicotinic acetylcholine receptors (nAChRs) play a critical role in the neuropharmacology of learning and memory. As such, naturally occurring alkaloids that regulate nAChR activity have gained interest for understanding and potentially improving memory function. In this study, we tested the acute efects of three known nicotinic alkaloids, nicotine, cotinine, and anatabine, in suppressing scopolamine-induced memory defcit in rodents by using two classic memory paradigms, Y-maze and novel object recognition (NOR) in mice and rats, respectively. We found that all compounds were able to suppress scopolamine-induced spatial memory defcit in the Y-maze spontaneous alternation paradigm. However, only nicotine was able to suppress the short-term object memory defcit in NOR, despite the higher doses of cotinine and anatabine used to account for their potential diferences in nAChR activity. These results indicate that cotinine and anatabine can uniquely regulate short-term spatial memory, while nicotine seems to have more robust and general role in memory regulation in rodents. Thus, nAChR-activating alkaloids may possess distinct procognitive properties in rodents, depending on the memory types examined. Te cholinergic system of the brain is a critical regulator of attention, memory, and higher-order cognitive processing, and its defcits are central to the etiology of dementia1. As such, nicotinic acetylcholine receptors (nAChRs) have gained much interest as a target of drug development 2. Neuronal nAChRs are pentameric pro- teins composed of various combinations of α (α2–α9) and β (β2–β4) nAChR subunits, diferentially expressed throughout the nervous system.
    [Show full text]
  • Chemicals in the Fourth Report and Updated Tables Pdf Icon[PDF
    Chemicals in the Fourth National Report on Human Exposure to Environmental Chemicals: Updated Tables, March 2021 CDC’s Fourth National Report on Human Exposure to Environmental Chemicals: Updated Tables, March 2021 provides exposure data on the following chemicals or classes of chemicals. The Updated Tables contain cumulative data from national samples collected beginning in 1999–2000 and as recently as 2015-2016. Not all chemicals were measured in each national sample. The data tables are available at https://www.cdc.gov/exposurereport. An asterisk (*) indicates the chemical has been added since publication of the Fourth National Report on Human Exposure to Environmental Chemicals in 2009. Adducts of Hemoglobin Acrylamide Formaldehyde* Glycidamide Tobacco Alkaloids and Metabolites Anabasine* Anatabine* Cotinine Cotinine-n-oxide* Hydroxycotinine* Trans-3’-hydroxycotinine* 1-(3-Pyridyl)-1-butanol-4-carboxylic acid* Nicotine* Nicotine-N’-oxide* Nornicotine* Tobacco-Specific Nitrosamines (TSNAs) N’-Nitrosoanabasine (NAB)* N’-Nitrosoanatabine (NAT)* N’-Nitrosonornicotine (NNN)* Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) (NNAL)* Volatile N-nitrosamines (VNAs) N-Nitrosodiethylamine (NDEA)* N-Nitrosoethylmethylamine (NMEA)* N-Nitrosomorpholine (NMOR)* N-Nitrosopiperidine (NPIP)* N-Nitrosopyrrolidine (NPYR)* Disinfection By-Products Bromodichloromethane Dibromochloromethane Tribromomethane (Bromoform) Trichloromethane (Chloroform) Personal Care and Consumer Product Chemicals and Metabolites Benzophenone-3 Bisphenol A Bisphenol F* Bisphenol
    [Show full text]
  • Federal Register/Vol. 82, No. 13/Monday, January 23, 2017/Proposed Rules
    8004 Federal Register / Vol. 82, No. 13 / Monday, January 23, 2017 / Proposed Rules DEPARTMENT OF HEALTH AND comment will be made public, you are www.regulations.gov. Submit both HUMAN SERVICES solely responsible for ensuring that your copies to the Division of Dockets comment does not include any Management. If you do not wish your Food and Drug Administration confidential information that you or a name and contact information to be third party may not wish to be posted, made publicly available, you can 21 CFR Part 1132 such as medical information, your or provide this information on the cover [Docket No. FDA–2016–N–2527] anyone else’s Social Security number, or sheet and not in the body of your confidential business information, such comments and you must identify this Tobacco Product Standard for N- as a manufacturing process. Please note information as ‘‘confidential.’’ Any Nitrosonornicotine Level in Finished that if you include your name, contact information marked as ‘‘confidential’’ Smokeless Tobacco Products information, or other information that will not be disclosed except in identifies you in the body of your accordance with 21 CFR 10.20 and other AGENCY: Food and Drug Administration, comments, that information will be applicable disclosure law. For more HHS. posted on http://www.regulations.gov. information about FDA’s posting of • ACTION: Proposed rule. If you want to submit a comment comments to public dockets, see 80 FR with confidential information that you 56469, September 18, 2015, or access SUMMARY: The Food and Drug do not wish to be made available to the the information at: http://www.fda.gov/ Administration (FDA) is proposing a public, submit the comment as a regulatoryinformation/dockets/ tobacco product standard that would written/paper submission and in the default.htm.
    [Show full text]
  • Molecular Mechanisms Associated with Nicotine Pharmacology and Dependence
    Molecular Mechanisms Associated with Nicotine Pharmacology and Dependence Christie D. Fowler, Jill R. Turner, and M. Imad Damaj Contents 1 Introduction 2 Basic Neurocircuitry of Nicotine Addiction 3 Role of Nicotinic Receptors in Nicotine Dependence and Brain Function 4 Modulatory Factors That Influence nAChR Expression and Signaling 5 Genomics and Genetics of Nicotine Dependence 5.1 Overview 5.2 Human and Animal Genetic Studies 5.3 Transcriptionally Adaptive Changes 6 Other Constituents in Nicotine and Tobacco Products Mediating Dependence 7 Therapeutic Approaches for Tobacco and Nicotine Dependence 7.1 Nicotine Replacement Therapies 7.2 Varenicline and Bupropion 7.3 Novel Approaches 8 Conclusion References Abstract Tobacco dependence is a leading cause of preventable disease and death world- wide. Nicotine, the main psychoactive component in tobacco cigarettes, has also C. D. Fowler Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA J. R. Turner Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA M. Imad Damaj (*) Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA Translational Research Initiative for Pain and Neuropathy at VCU, Richmond, VA, USA e-mail: [email protected] # Springer Nature Switzerland AG 2019 Handbook of Experimental Pharmacology, https://doi.org/10.1007/164_2019_252 C. D. Fowler et al. been garnering increased popularity in its vaporized form, as derived from e-cigarette devices. Thus, an understanding of the molecular mechanisms under- lying nicotine pharmacology and dependence is required to ascertain novel approaches to treat drug dependence. In this chapter, we review the field’s current understanding of nicotine’s actions in the brain, the neurocircuitry underlying drug dependence, factors that modulate the function of nicotinic acetylcholine receptors, and the role of specific genes in mitigating the vulnerability to develop nicotine dependence.
    [Show full text]
  • Evaluating the Real-World Effectiveness of Bupropion Versus Varenicline for Smoking Cessation: Exploring the Role of Nicotine Metabolism and Medication Adherence
    Evaluating the Real-World Effectiveness of Bupropion Versus Varenicline for Smoking Cessation: Exploring the Role of Nicotine Metabolism and Medication Adherence By Jiahui Zhang A thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Pharmacology and Toxicology University of Toronto © Copyright by Jiahui Zhang (2017) Evaluating the Real-World Effectiveness of Bupropion Versus Varenicline for Smoking Cessation: Exploring the Role of Nicotine Metabolism and Medication Adherence Jiahui Zhang Degree of Master of Science Graduate Department of Pharmacology and Toxicology University of Toronto ABSTRACT Bupropion and varenicline are effective, first-line prescription-only pharmacotherapies for smoking cessation; however, their real-world use is limited by affordability and accessibility. Using a novel internet-based randomized design, we evaluated the real-world effectiveness of mailed bupropion and varenicline, as well as the roles of nicotine metabolism (NMR) and medication adherence, in a sample of interested smokers using web-based recruitment and follow up. Quit rates at end of treatment (EOT) were significantly higher for varenicline (30.2%) compared to bupropion (19.6%). Quit rates at 6 months (14.0%) and 12 months (12.1%) were not significantly different between bupropion and varenicline. Increased medication compliance significantly improved cessation outcomes at EOT. NMR was associated with nicotine dependence. Varenicline benefited Slow Metabolizers of nicotine whilst bupropion benefited Normal Metabolizers. Even though real-world quit rates were comparable to clinical trials, improving medication compliance and implementing personalized pharmacological and behavioral interventions are promising approaches to increase efficacy of smoking cessation pharmacotherapies. ii ACKNOWLEDGEMENTS First and foremost, I would like to express my sincerest appreciation to my supervisor, Dr.
    [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]
  • NINDS Custom Collection II
    ACACETIN ACEBUTOLOL HYDROCHLORIDE ACECLIDINE HYDROCHLORIDE ACEMETACIN ACETAMINOPHEN ACETAMINOSALOL ACETANILIDE ACETARSOL ACETAZOLAMIDE ACETOHYDROXAMIC ACID ACETRIAZOIC ACID ACETYL TYROSINE ETHYL ESTER ACETYLCARNITINE ACETYLCHOLINE ACETYLCYSTEINE ACETYLGLUCOSAMINE ACETYLGLUTAMIC ACID ACETYL-L-LEUCINE ACETYLPHENYLALANINE ACETYLSEROTONIN ACETYLTRYPTOPHAN ACEXAMIC ACID ACIVICIN ACLACINOMYCIN A1 ACONITINE ACRIFLAVINIUM HYDROCHLORIDE ACRISORCIN ACTINONIN ACYCLOVIR ADENOSINE PHOSPHATE ADENOSINE ADRENALINE BITARTRATE AESCULIN AJMALINE AKLAVINE HYDROCHLORIDE ALANYL-dl-LEUCINE ALANYL-dl-PHENYLALANINE ALAPROCLATE ALBENDAZOLE ALBUTEROL ALEXIDINE HYDROCHLORIDE ALLANTOIN ALLOPURINOL ALMOTRIPTAN ALOIN ALPRENOLOL ALTRETAMINE ALVERINE CITRATE AMANTADINE HYDROCHLORIDE AMBROXOL HYDROCHLORIDE AMCINONIDE AMIKACIN SULFATE AMILORIDE HYDROCHLORIDE 3-AMINOBENZAMIDE gamma-AMINOBUTYRIC ACID AMINOCAPROIC ACID N- (2-AMINOETHYL)-4-CHLOROBENZAMIDE (RO-16-6491) AMINOGLUTETHIMIDE AMINOHIPPURIC ACID AMINOHYDROXYBUTYRIC ACID AMINOLEVULINIC ACID HYDROCHLORIDE AMINOPHENAZONE 3-AMINOPROPANESULPHONIC ACID AMINOPYRIDINE 9-AMINO-1,2,3,4-TETRAHYDROACRIDINE HYDROCHLORIDE AMINOTHIAZOLE AMIODARONE HYDROCHLORIDE AMIPRILOSE AMITRIPTYLINE HYDROCHLORIDE AMLODIPINE BESYLATE AMODIAQUINE DIHYDROCHLORIDE AMOXEPINE AMOXICILLIN AMPICILLIN SODIUM AMPROLIUM AMRINONE AMYGDALIN ANABASAMINE HYDROCHLORIDE ANABASINE HYDROCHLORIDE ANCITABINE HYDROCHLORIDE ANDROSTERONE SODIUM SULFATE ANIRACETAM ANISINDIONE ANISODAMINE ANISOMYCIN ANTAZOLINE PHOSPHATE ANTHRALIN ANTIMYCIN A (A1 shown) ANTIPYRINE APHYLLIC
    [Show full text]
  • July 16, 2018 VIA ELECTRONIC SUBMISSION and HAND DELIVERY Division of Dockets Management Food and Drug Administration 5630 Fishe
    Jose Luis Murillo Vice President Regulatory Affairs July 16, 2018 VIA ELECTRONIC SUBMISSION AND HAND DELIVERY Division of Dockets Management Food and Drug Administration 5630 Fishers Lane, Rm. 1061 Rockville, MD 20852 Re: Docket No. FDA-2017-N-6189 (83 Fed. Reg. 11,818, March 16, 2018) Advance Notice of Proposed Rulemaking on Tobacco Product Standard for Nicotine Level of Certain Tobacco Products Altria Client Services (“ALCS”), on behalf of Philip Morris USA Inc. (“PM USA”), John Middleton Company (“JMC”), and Sherman Group Holdings LLC and its subsidiaries (“Nat Sherman”),1 submits these comments to the Food and Drug Administration’s (“FDA’s” or the “Agency’s”) Advance Notice of Proposed Rulemaking (“ANPRM”) on a Tobacco Product Standard for Nicotine Level of Certain Tobacco Products. The ANPRM comes within the context of an industry in the midst of transformative change. Cigarette smoking is at historically low levels and continues to decline. At the same time, a new market is emerging in innovative noncombustible tobacco products that are potentially less harmful than cigarettes. There is now a scientific consensus that noncombustible products, like e-vapor, are substantially less risky than conventional cigarettes. It is smoke, and not nicotine, that causes most tobacco- related harm. And adult smokers are increasingly expressing interest in switching from cigarettes to less risky alternatives. We agree that a nicotine product standard of some sort may make sense in a future regulatory system, but this requires the pre-existence of a marketplace with alternative, FDA-authorized, reduced risk products; more information about the relative risks of those products; and a regulatory system that respects the rights of adults to make decisions based on accurate information.
    [Show full text]
  • Biomarkers of Exposure Among Adult Smokeless Tobacco Users in the Population Assessment of Tobacco and Health Study (Wave 1, 2013-14)
    Author Manuscript Published OnlineFirst on January 27, 2020; DOI: 10.1158/1055-9965.EPI-19-0766 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Biomarkers of Exposure among Adult Smokeless Tobacco Users in the Population Assessment of Tobacco and Health Study (Wave 1, 2013-14) Running Title: Biomarkers of Exposure in PATH Study Smokeless Tobacco Users Yu-Ching Cheng1, Carolyn M. Reyes-Guzman1,2, Carol H. Christensen1, Brian L. Rostron1, Kathryn C. Edwards3, Lanqing Wang4, Jun Feng4, Jeffery M. Jarrett4, Cynthia D. Ward 4, Baoyun Xia4, Heather L. Kimmel5, Kevin Conway5, Carmine Leggett1, Kristie Taylor3, Charlie Lawrence3, Ray Niaura6, Mark J. Travers7, Andrew Hyland7, Stephen S. Hecht8, Dorothy K. Hatsukami8, Maciej L. Goniewicz7, Nicolette Borek1, Benjamin C. Blount4, Dana M. van Bemmel1 1Center for Tobacco Products, Food and Drug Administration, MD, USA, 2National Cancer Institute, National Institutes of Health, MD, USA, 3Westat, MD, USA, 4US Centers for Disease Control and Prevention, USA, 5National Institute on Drug Abuse, National Institutes of Health, MD, USA, 6New York University College of Global Public Health, NY, USA, 7Roswell Park Cancer Institute, NY, USA, 8University of Minnesota, Masonic Cancer Center, USA. Key Words: biomarkers of exposure, smokeless tobacco Corresponding author: Yu-Ching Cheng, PhD 11785 Beltsville Drive, RM 8321 Beltsville, MD 20705 [email protected] 240-402-5957 1 Downloaded from cebp.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 27, 2020; DOI: 10.1158/1055-9965.EPI-19-0766 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
    [Show full text]
  • 7 Nicotinic Receptor Agonists
    CORE Metadata, citation and similar papers at core.ac.uk Provided by PubMed Central The Open Medicinal Chemistry Journal, 2010, 4, 37-56 37 Open Access 7 Nicotinic Receptor Agonists: Potential Therapeutic Drugs for Treatment of Cognitive Impairments in Schizophrenia and Alzheimer’s Disease Jun Toyohara, and Kenji Hashimoto* Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan Abstract: Accumulating evidence suggests that 7 nicotinic receptors (7 nAChRs), a subtype of nAChRs, play a role in the pathophysiology of neuropsychiatric diseases, including schizophrenia and Alzheimer’s disease (AD). A number of psychopharmacological and genetic studies shown that 7 nAChRs play an important role in the deficits of P50 auditory evoked potential in patients with schizophrenia, and that 7 nAChR agonists would be potential therapeutic drugs for cognitive impairments associated with P50 deficits in schizophrenia. Furthermore, some studies have demonstrated that 7 nAChRs might play a key role in the amyloid- (A)-mediated pathology of AD, and that 7 nAChR agonists would be potential therapeutic drugs for A deposition in the brains of patients with AD. Interestingly, the altered expression of 7 nAChRs in the postmortem brain tissues from patients with schizophrenia and AD has been reported. Based on all these findings, selective 7 nAChR agonists can be considered potential therapeutic drugs for cognitive impairments in both schizophrenia and AD. In this article, we review the recent research into the role of 7 nAChRs in the pathophysiology of these diseases and into the potential use of novel 7 nAChR agonists as therapeutic drugs. Keywords: 7 Nicotinic receptors, Cognition, Schizophrenia, Alzheimer’s disease.
    [Show full text]
  • Nicotinic Acetylcholine Receptor Signaling in Neuroprotection
    Akinori Akaike · Shun Shimohama Yoshimi Misu Editors Nicotinic Acetylcholine Receptor Signaling in Neuroprotection Nicotinic Acetylcholine Receptor Signaling in Neuroprotection Akinori Akaike • Shun Shimohama Yoshimi Misu Editors Nicotinic Acetylcholine Receptor Signaling in Neuroprotection Editors Akinori Akaike Shun Shimohama Department of Pharmacology, Graduate Department of Neurology, School of School of Pharmaceutical Sciences Medicine Kyoto University Sapporo Medical University Kyoto, Japan Sapporo, Hokkaido, Japan Wakayama Medical University Wakayama, Japan Yoshimi Misu Graduate School of Medicine Yokohama City University Yokohama, Kanagawa, Japan ISBN 978-981-10-8487-4 ISBN 978-981-10-8488-1 (eBook) https://doi.org/10.1007/978-981-10-8488-1 Library of Congress Control Number: 2018936753 © The Editor(s) (if applicable) and The Author(s) 2018. This book is an open access publication. Open Access This book is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The images or other third party material in this book are included in the book’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the book’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. The use of general descriptive names, registered names, trademarks, service marks, etc.
    [Show full text]