Analysis of Mecamylamine Stereoisomers on Human Nicotinic Receptor Subtypes
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The Pharmacology of Autonomic Failure: from Hypotension to Hypertension
1521-0081/69/1/53–62$25.00 http://dx.doi.org/10.1124/pr.115.012161 PHARMACOLOGICAL REVIEWS Pharmacol Rev 69:53–62, January 2017 Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics ASSOCIATE EDITOR: STEPHANIE W. WATTS The Pharmacology of Autonomic Failure: From Hypotension to Hypertension Italo Biaggioni Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, Tennessee Abstract .....................................................................................53 I. Introduction . ...............................................................................54 A. Overview of Normal Cardiovascular Autonomic Regulation ...............................54 B. The Baroreflex . .........................................................................54 C. Pathophysiology of Orthostatic Hypotension and Autonomic Failure. ....................54 D. Ganglionic Blockade as a Pharmacological Probe To Understand Autonomic Failure.......55 E. Autonomic Failure as a Model To Understand Pathophysiology . ..........................55 II. Targeting Venous Compliance in the Treatment of Orthostatic Hypotension...................55 III. Pharmacology of Volume Expansion. .......................................................56 Downloaded from A. Fludrocortisone . .........................................................................56 B. Erythropoietin . .........................................................................56 IV. Replacing Noradrenergic Stimulation -
Synthesis and Characterization of in Vitro and in Vivo Profiles of Hydroxybupropion Analogues: Aids to Smoking Cessation
Barrow Neurological Institute at St. Joseph's Hospital and Medical Center Barrow - St. Joseph's Scholarly Commons Neurobiology 6-24-2010 Synthesis And Characterization Of In Vitro And In Vivo Profiles Of Hydroxybupropion Analogues: Aids To Smoking Cessation Ronald J. Lukas Barrow Neurological Institute, [email protected] Ana Z. Muresan M. Imad Damaj Bruce E. Blough Xiaodong Huang See next page for additional authors Follow this and additional works at: https://scholar.barrowneuro.org/neurobiology Recommended Citation Lukas, Ronald J.; Muresan, Ana Z.; Damaj, M. Imad; Blough, Bruce E.; Huang, Xiaodong; Navarro, Hernan A.; Mascarella, S. Wayne; Eaton, J. Brek; Marxer-Miller, Syndia K.; and Carroll, F. Ivy, "Synthesis And Characterization Of In Vitro And In Vivo Profiles Of Hydroxybupropion Analogues: Aids To Smoking Cessation" (2010). Neurobiology. 280. https://scholar.barrowneuro.org/neurobiology/280 This Article is brought to you for free and open access by Barrow - St. Joseph's Scholarly Commons. It has been accepted for inclusion in Neurobiology by an authorized administrator of Barrow - St. Joseph's Scholarly Commons. For more information, please contact [email protected], [email protected]. Authors Ronald J. Lukas, Ana Z. Muresan, M. Imad Damaj, Bruce E. Blough, Xiaodong Huang, Hernan A. Navarro, S. Wayne Mascarella, J. Brek Eaton, Syndia K. Marxer-Miller, and F. Ivy Carroll This article is available at Barrow - St. Joseph's Scholarly Commons: https://scholar.barrowneuro.org/neurobiology/ 280 J. Med. Chem. 2010, 53, 4731–4748 4731 DOI: 10.1021/jm1003232 Synthesis and Characterization of in Vitro and in Vivo Profiles of Hydroxybupropion Analogues: Aids to Smoking Cessation Ronald J. -
In Silico Methods for Drug Repositioning and Drug-Drug Interaction Prediction
In silico Methods for Drug Repositioning and Drug-Drug Interaction Prediction Pathima Nusrath Hameed ORCID: 0000-0002-8118-9823 Submitted in total fulfilment of the requirements for the degree of Doctor of Philosophy Department of Mechanical Engineering THE UNIVERSITY OF MELBOURNE May 2018 Copyright © 2018 Pathima Nusrath Hameed All rights reserved. No part of the publication may be reproduced in any form by print, photoprint, microfilm or any other means without written permission from the author. Abstract Drug repositioning and drug-drug interaction (DDI) prediction are two fundamental ap- plications having a large impact on drug development and clinical care. Drug reposi- tioning aims to identify new uses for existing drugs. Moreover, understanding harmful DDIs is essential to enhance the effects of clinical care. Exploring both therapeutic uses and adverse effects of drugs or a pair of drugs have significant benefits in pharmacology. The use of computational methods to support drug repositioning and DDI prediction en- able improvements in the speed of drug development compared to in vivo and in vitro methods. This thesis investigates the consequences of employing a representative training sam- ple in achieving better performance for DDI classification. The Positive-Unlabeled Learn- ing method introduced in this thesis aims to employ representative positives as well as reliable negatives to train the binary classifier for inferring potential DDIs. Moreover, it explores the importance of a finer-grained similarity metric to represent the pairwise drug similarities. Drug repositioning can be approached by new indication detection. In this study, Anatomical Therapeutic Chemical (ATC) classification is used as the primary source to determine the indications/therapeutic uses of drugs for drug repositioning. -
Cognitive, Behavioral, and Physiologic Responses John T
Combined Nicotinic and Muscarinic Blockade in Elderly Normal Volunteers: Cognitive, Behavioral, and Physiologic Responses John T. Little, M.D., Douglas N. Johnson, Ph.D., Marcia Minichiello, M.A., Herb Weingartner, Ph.D., and Trey Sunderland, M.D. Establishing a pharmacologic model of the memory deficits scopolamine alone. Increased impairment was also seen for of Alzheimer’s disease could be an important tool in the mecamylamine 1 scopolamine condition as compared to understanding how memory fails. We examined the scopolamine alone in selected behavioral ratings. Pupil size combined effects of the muscarinic antagonist scopolamine increased when mecamylamine was added to scopolamine, and the nicotinic antagonist mecamylamine in eight normal while systolic blood pressure and pulse changed in elderly volunteers (age 61.9 6 8.3 yrs, SD). Each received concordance with ganglionic blockade. These data together four separate drug challenges (scopolamine (0.4 mg IV), with previous brain-imaging results suggest that this mecamylamine (0.2 mg/kg up to 15 mg PO), muscarinic–nicotinic drug combination may better model mecamylamine 1 scopolamine, and placebo). There was a Alzheimer’s disease than either drug alone. trend toward increased impairment in explicit memory for [Neuropsychopharmacology 19:60–69, 1998] the mecamylamine 1 scopolamine condition as compared to Published by Elsevier Science Inc. KEY WORDS: Scopolamine; Mecamylamine; Cognitive; al. 1985; Shimohama et al. 1986; Whitehouse and Au Geriatrics; Muscarinic antagonist; Nicotinic antagonist 1986; D’Amato et al. 1987; Zubenko et al. 1988), many cognitive dysfunction modeling studies have focused Given the limited animal models of Alzheimer’s disease on this system (Beatty et al. -
Lubeluzole/Mecamylamine Hydrochloride 1331 Precautions Ing Treated
Lubeluzole/Mecamylamine Hydrochloride 1331 Precautions ing treated. Mannitol infusion has also been used to de Manzanas; Pol.: Purisole SM; Port.: Purisole; Xarope de Macas Reinetas; Rus.: Rheogluman (Реоглюман); Spain: Salcemetic†; Salmagne; Switz.: Mannitol is contra-indicated in patients with pulmo- prevent acute renal failure during cardiovascular and Cital†. nary congestion or pulmonary oedema, intracranial other types of surgery, or after trauma. bleeding (except during craniotomy), heart failure (in To reduce raised intracranial or intra-ocular pres- patients with diminished cardiac reserve, expansion of sure mannitol may be given by intravenous infusion as Mebutamate (BAN, USAN, rINN) the extracellular fluid may lead to fulminating heart a 15 to 25% solution in a dose of 0.25 to 2 g/kg over 30 Mébutamate; Mebutamato; Mebutamatum; W-583. 2-sec-Butyl- failure), and in patients with renal failure unless a test to 60 minutes. Rebound increases in intracranial or 2-methyltrimethylene dicarbamate. dose has produced a diuretic response (if urine flow is intra-ocular pressure may occur but are less frequent Мебутамат inadequate, expansion of the extracellular fluid may than with urea. C10H20N2O4 = 232.3. lead to acute water intoxication). During transurethral prostatic resection a 2.5 to 5% CAS — 64-55-1. Mannitol should not be given with whole blood. ATC — N05BC04. solution of mannitol has been used for irrigating the ATC Vet — QN05BC04. All patients given mannitol should be carefully ob- bladder. served for signs of fluid and electrolyte imbalance and Ciguatera poisoning. Ciguatera poisoning occurs throughout O O renal function should be monitored. the Caribbean and Indopacific as a result of the consumption of certain fish contaminated with ciguatoxin; it is increasingly seen Pharmacokinetics in Europe, in travellers returning from these areas, or as a result H2NO O NH2 Only small amounts of mannitol are absorbed from the of eating imported fish. -
III IIHIIII US005574052A United States Patent (19) 11 Patent Number: 5,574,052 Rose Et Al
III IIHIIII US005574052A United States Patent (19) 11 Patent Number: 5,574,052 Rose et al. 45) Date of Patent: *Nov. 12, 1996 54) AGONIST-ANTAGONIST COMBINATION TO Nicotine Self-Administration..., H. M. Hanson, et al., Ch. REDUCE THE USE OF NICOTINE AND 7 Norman A. Krasnegor, NIDA Research Monograph 23, OTHER DRUGS Jan. 1979. Influencing Cigarette Smoking ..., I. P. Stolerman, et. al., (75 Inventors: Jed E. Rose, Venice; Edward D. Psychopharmacologia (Berl.) 28–247-249 (1973). Levin, Los Angeles, both of Calif. Effects of Mecamylamine On Human Cigarette Smoking . , Nemeth-Coslett, et al., Pharmacology (1986) (73) Assignee: Robert J. Schaap, Los Angeles, Calif.; 88:420-425. a part interest Rapid Phsiologic Effects of Nicotine ..., J. Henningfield, et al., U.S. Dept. of Health and Human Services, 259-265. * Notice: The term of this patent shall not extend Could Nicotine Antagonists Be Used..., by I. P. Stolerman, beyond the expiration date of Pat. No. Br, Jr. of Addiction (1986) 81, 47-53. 5,316,759. Mecamylamine Pretreatment . , C. S. Pomerleau, et. al., Pharmacology (1987) 91:391-393. (21) Appl. No.: 235,454 Clinical Evaluation of Mecamylamine..., F. S. Tennant, Jr., et al., NIDA Research Monograph, Feb. 9 (1984). 239–246. (22 Filed: Apr. 29, 1994 Withdrawl From Nicotine Dependence ..., F. S. Tennant, Jr., et al., NIDA Research Monograph, 55 (1985). Related U.S. Application Data Double-Blind Comparison . , F. S. Tennant, Jr., UCLA, Los Angeles, California. 63) Continuation of Ser. No. 54,144, Apr. 30, 1993, which is a Involvement of Cholinergic Nicotine-like Receptors . continuation of Ser. No. 855,868, Mar. -
MECAMYLAMINE Hydrochloride Tablets, USP, 2.5 Mg
MECAMYLAMINE HYDROCHLORIDE- mecamylamine hydrochloride tablet Nexgen Pharma, Inc. ---------- MECAMYLAMINE Hydrochloride Tablets, USP, 2.5 mg DESCRIPTION Mecamylamine HCl is a potent, oral antihypertension agent and ganglion blocker, and is a secondary amine. It is N,2,3,3-tetramethyl-bicyclo [2.2.1] heptan- 2 -amine hydrochloride. Its empirical formula is C11H21N • HCl and its structural formula is: It is a white, odorless, or practically odorless, crystalline powder, is highly stable, soluble in water and has a molecular weight of 203.75. Mecamylamine HCl is supplied as tablets for oral use, each containing 2.5 mg mecamylamine HCl. Inactive ingredients are calcium phosphate, D&C Yellow 10, FD&C Yellow 6, lactose, magnesium stearate, cornstarch, and talc. CLINICAL PHARMACOLOGY Mecamylamine HCl reduces blood pressure in both normotensive and hypertensive individuals. It has a gradual onset of action (1/2 to 2 hours) and a long-lasting effect (usually 6 to 12 hours or more). A small oral dosage often produces a smooth and predictable reduction of blood pressure. Although this antihypertensive effect is predominantly orthostatic, the supine blood pressure is also significantly reduced. Pharmacokinetics and Metabolism Mecamylamine HCl is almost completely absorbed from the gastrointestinal tract, resulting in consistent lowering of blood pressure in most patients with hypertensive cardiovascular disease. Mecamylamine HCl is excreted slowly in the urine in the unchanged form. The rate of its renal elimination is influenced markedly by urinary pH. Alkalinization of the urine reduces, and acidification promotes, renal excretion of mecamylamine. Mecamylamine HCl crosses the blood-brain and placental barriers. INDICATIONS AND USAGE For the management of moderately severe to severe essential hypertension and in uncomplicated cases of malignant hypertension. -
Nicotinic Mechanisms Modulate Ethanol Withdrawal and Modify Time Course and Symptoms Severity of Simultaneous Withdrawal from Alcohol and Nicotine
Neuropsychopharmacology (2015) 40, 2327–2336 © 2015 American College of Neuropsychopharmacology. All rights reserved 0893-133X/15 www.neuropsychopharmacology.org Nicotinic Mechanisms Modulate Ethanol Withdrawal and Modify Time Course and Symptoms Severity of Simultaneous Withdrawal from Alcohol and Nicotine 1,2 3 ,1,2,4 Erika Perez , Natalia Quijano-Cardé and Mariella De Biasi* 1 2 Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of 3 4 Neuroscience, Baylor College of Medicine, Houston, TX, USA; University of Puerto Rico at Mayagüez, Mayagüez, Puerto Rico; Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA Alcohol and nicotine are among the top causes of preventable death in the United States. Unfortunately, people who are dependent on alcohol are more likely to smoke than individuals in the general population. Similarly, smokers are more likely to abuse alcohol. Alcohol and nicotine codependence affects health in many ways and leads to poorer treatment outcomes in subjects who want to quit. This study examined the interaction of alcohol and nicotine during withdrawal and compared abstinence symptoms during withdrawal from one of the two drugs only vs both. Our results indicate that simultaneous withdrawal from alcohol and nicotine produces physical symptoms that are more severe and last longer than those experienced during withdrawal from one of the two drugs alone. In animals experiencing withdrawal after chronic ethanol treatment, acute nicotine exposure was sufficient to prevent abstinence symptoms. Similarly, symptoms were prevented when alcohol was injected acutely in mice undergoing nicotine withdrawal. These experiments provide evidence for the involvement of the nicotinic cholinergic system in alcohol withdrawal. -
Nicotinic Ach Receptors
Nicotinic ACh Receptors Susan Wonnacott and Jacques Barik Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK Susan Wonnacott is Professor of Neuroscience in the Department of Biology and Biochemistry at the University of Bath. Her research focuses on understanding the roles of nicotinic acetylcholine receptors in the mammalian brain and the molecular and cellular events initiated by acute and chronic nicotinic receptor stimulation. Jacques Barik was a PhD student in the Bath group and is continuing in addiction research at the Collège de France in Paris. Introduction and there followed detailed studies of the properties The nicotinic acetylcholine receptor (nAChR) is the of nAChRs mediating synaptic transmission at prototype of the cys-loop family of ligand-gated ion these sites. nAChRs at the muscle endplate and in sympathetic ganglia could be distinguished channels (LGIC) that also includes GABAA, GABAC, by their respective preferences for C10 and C6 glycine, 5-HT3 receptors, and invertebrate glutamate-, histamine-, and 5-HT-gated chloride channels.1,2 polymethylene bistrimethylammonium compounds, 7 nAChRs in skeletal muscle have been characterised notably decamethonium and hexamethonium. This DRIVING RESEARCH FURTHER in detail whereas mammalian neuronal nAChRs provided the first evidence that muscle and neuronal DRIVING RESEARCH FURTHER in the central nervous system have more recently nAChRs are structurally different. become the focus of intense research efforts. This In the 1970s, elucidation of the structure and function was fuelled by the realisation that nAChRs in the brain of the muscle nAChR, using biochemical approaches, and spinal cord are potential therapeutic targets for was facilitated by the abundance of nicotinic synapses a range of neurological and psychiatric conditions. -
(19) 11 Patent Number: 6165500
USOO6165500A United States Patent (19) 11 Patent Number: 6,165,500 Cevc (45) Date of Patent: *Dec. 26, 2000 54 PREPARATION FOR THE APPLICATION OF WO 88/07362 10/1988 WIPO. AGENTS IN MINI-DROPLETS OTHER PUBLICATIONS 75 Inventor: Gregor Cevc, Heimstetten, Germany V.M. Knepp et al., “Controlled Drug Release from a Novel Liposomal Delivery System. II. Transdermal Delivery Char 73 Assignee: Idea AG, Munich, Germany acteristics” on Journal of Controlled Release 12(1990) Mar., No. 1, Amsterdam, NL, pp. 25–30. (Exhibit A). * Notice: This patent issued on a continued pros- C.E. Price, “A Review of the Factors Influencing the Pen ecution application filed under 37 CFR etration of Pesticides Through Plant Leaves” on I.C.I. Ltd., 1.53(d), and is subject to the twenty year Plant Protection Division, Jealott's Hill Research Station, patent term provisions of 35 U.S.C. Bracknell, Berkshire RG12 6EY, U.K., pp. 237-252. 154(a)(2). (Exhibit B). K. Karzel and R.K. Liedtke, “Mechanismen Transkutaner This patent is Subject to a terminal dis- Resorption” on Grandlagen/Basics, pp. 1487–1491. (Exhibit claimer. C). Michael Mezei, “Liposomes as a Skin Drug Delivery Sys 21 Appl. No.: 07/844,664 tem” 1985 Elsevier Science Publishers B.V. (Biomedical Division), pp 345-358. (Exhibit E). 22 Filed: Apr. 8, 1992 Adrienn Gesztes and Michael Mazei, “Topical Anesthesia of 30 Foreign Application Priority Data the Skin by Liposome-Encapsulated Tetracaine” on Anesth Analg 1988; 67: pp 1079–81. (Exhibit F). Aug. 24, 1990 DE) Germany ............................... 40 26834 Harish M. Patel, "Liposomes as a Controlled-Release Sys Aug. -
Discriminative Stimulus Effects of Mecamylamine and Nicotine In
Pharmacology, Biochemistry and Behavior 179 (2019) 27–33 Contents lists available at ScienceDirect Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh Discriminative stimulus effects of mecamylamine and nicotine in rhesus monkeys: Central and peripheral mechanisms T ⁎ Colin S. Cunningham, Megan J. Moerke, Lance R. McMahon Department of Pharmacodynamics, The University of Florida, Gainesville, FL, USA ABSTRACT Mecamylamine is a non-competitive nicotinic acetylcholine receptor (nAChR) antagonist that has been prescribed for hypertension and as an off-label smoking cessation aid. Here, we examined pharmacological mechanisms underlying the interoceptive effects (i.e., discriminative stimulus effects) of mecamylamine (5.6 mg/ kg s.c.) and compared the effects of nAChR antagonists in this discrimination assay to their capacity to block a nicotine discriminative stimulus (1.78 mg/kg s.c.) in rhesus monkeys. Central (pempidine) and peripherally restricted nAChR antagonists (pentolinium and chlorisondamine) dose-dependently substituted for the me- camylamine discriminative stimulus in the following rank order potency (pentolinium > pempidine > chlorisondamine > mecamylamine). In contrast, at equi- effective doses based on substitution for mecamylamine, only mecamylamine antagonized the discriminative stimulus effects of nicotine, i.e., pentolinium, chlor- isondamine, and pempidine did not. NMDA receptor antagonists produced dose-dependent substitution for mecamylamine with the following rank order potency (MK-801 > phencyclidine > ketamine). In contrast, behaviorally active doses of smoking cessation aids including nAChR agonists (nicotine, varenicline, and cytisine), the smoking cessation aid and antidepressant bupropion, and the benzodiazepine midazolam did not substitute for the discriminative stimulus effects of mecamylamine. These data suggest that peripheral nAChRs and NMDA receptors may contribute to the interoceptive stimulus effects produced by mecamylamine. -
Involvement of Nicotinic Receptor Subtypes in the Behavioral Effects of Nicotinic Drugs in Squirrel Monkeys
1521-0103/366/2/397–409$35.00 https://doi.org/10.1124/jpet.118.248070 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 366:397–409, August 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics Involvement of Nicotinic Receptor Subtypes in the Behavioral Effects of Nicotinic Drugs in Squirrel Monkeys Sarah L. Withey,1 Michelle R. Doyle,1,2 Jack Bergman, and Rajeev I. Desai Preclinical Pharmacology Laboratory, McLean Hospital/Harvard Medical School, Belmont, Massachusetts Received January 27, 2018; accepted May 17, 2018 ABSTRACT Evidence suggests that the a4b2, but not the a7, subtype of the except for lobeline, the nicotinic agonists produced either full nicotinic acetylcholine receptor (nAChR) plays a key role in [(1)-epibatidine, (2)-epibatidine, and nicotine] or partial (vare- Downloaded from mediating the behavioral effects of nicotine and related drugs. nicline, cytisine, anabaseine, and isoarecolone) substitution for However, the importance of other nAChR subtypes remains (1)-epibatidine. In interaction studies with antagonists differing unclear. The present studies were conducted to examine the in selectivity, (1)-epibatidine discrimination was substan- involvement of nAChR subtypes by determining the effects of tively antagonized by mecamylamine, slightly attenuated selected nicotinic agonists and antagonists in squirrel monkeys by hexamethonium (peripherally restricted) or dihydro- b a either 1) responding for food reinforcement or 2) discriminating the -erythroidine, and not altered by methyllycaconitine ( 7 jpet.aspetjournals.org nicotinic agonist (1)-epibatidine (0.001 mg/kg) from vehicle. In selective). Varenicline and cytisine enhanced (1)-epibati- food-reinforcement studies, nicotine, (1)-epibatidine, varenicline dine’s discriminative-stimulus effects.