DOCSLIB.ORG

Recommendations for the Use of Acetylcholinesterase Inhibitors For

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Recommendations for the Use of Acetylcholinesterase Inhibitors For Guidelines on the use of Antidementia Drugs in People Living with Dementia GUIDELINE VERSION 6 RATIFYING COMMITTEE Drugs and Therapeutics Group DATE FIRST RATIFIED April 26th, 2011. Reviewed & updated: September 2012 February 2013 June 2016 July 2019 NEXT REVIEW DATE July 2022, or earlier if there is new national guidance GUIDELINE SPONSOR Chief Medical Officer ORIGINAL GUIDELINE Jed Hewitt – Chief Pharmacist, AUTHOR Governance & Professional Practice THIS VERSION REVIEWED BY Grant Salvage – Lead Pharmacist Mental Health (Chichester Locality) If you require this document in an alternative format, ie easy read, large text, audio, Braille or a community language please contact the Pharmacy Team on 01243 623349 (Text Relay calls welcome) Guidelines on the use of Antidementia Drugs in People Living with Dementia 1. Pharmacological Management of Dementia The following medications for dementia are available to prescribe on the Trust formulary: o The acetylcholinesterase inhibitors (AChEIs); donepezil, rivastigmine and galantamine. o The NMDA receptor antagonist; memantine. Patients with mild to moderate Alzheimer’s disease should initially be offered treatment with an acetylcholinesterase inhibitor. The initial acetylcholinesterase inhibitor offered should usually be donepezil tablets as these have the lowest ongoing cost, however it may be appropriate on an individual basis to offer an alternative choice after taking into account the adverse effect profile of the medications, concurrent medications and possible interactions, expected patient adherence and medication dosing regimens. Patients with moderate Alzheimer’s disease who are intolerant or have contraindications to treatment with acetylcholinesterase inhibitors should be offered treatment with memantine. Patients with severe Alzheimer’s disease should be offered treatment with the NMDA receptor antagonist memantine. The decision to offer initial treatment of Alzheimer’s disease with either an acetylcholinesterase inhibitor or memantine should only be undertaken on the advice of a secondary care specialist (consultant, associated specialist, geriatrician, neurologist) or other healthcare professional who has expertise in diagnosing and treating Alzheimer’s Disease (GP, nurse consultant, advanced nurse practitioner). Once a decision has been made to start an acetylcholinesterase inhibitor or memantine, the first prescription may be provided by primary care, but if a specialist is seeing the patient they should initiate treatment to avoid delay. Patients with moderate Alzheimer’s disease who are already taking an acetylcholinesterase inhibitor should be considered for treatment with memantine in addition to their other treatment. Patients with severe Alzheimer’s disease who are already taking an acetylcholinesterase inhibitor should be offered treatment with memantine in addition to their other treatment. Where patients have an established diagnosis of Alzheimer’s disease and are already taking an acetylcholinesterase inhibitor, primary care prescribers may start treatment with memantine in addition to their other treatment without taking specialist advice. The pharmacological treatment of Alzheimer’s disease should not be stopped on the basis of disease progression or disease severity only. Patients with non-Alzheimer’s dementia should be offered the following treatments: o Patients with mild to moderate dementia with Lewy bodies should be offered treatment with donepezil or rivastigmine, o Patients with severe dementia with Lewy bodies should be considered for treatment with donepezil or rivastigmine o Galantamine should only be offered in the treatment of dementia with Lewy Bodies if donepezil or rivastigmine are not tolerated. o If acetylcholinesterase inhibitors are not tolerated or are contraindicated, consider offering memantine in the treatment of dementia with Lewy bodies. o Patients with mild to moderate Parkinson’s disease dementia should be offered treatment with an acetylcholinesterase inhibitor. o Patients with severe Parkinson’s disease dementia should be considered for treatment with an acetylcholinesterase inhibitor. o If acetylcholinesterase inhibitors are not tolerated or are contraindicated, consider offering memantine in the treatment Parkinson’s disease dementia. o Patient with vascular dementia should only be offered treatment with acetylcholinesterase inhibitors or memantine if they have co-morbid Alzheimer’s disease, dementia with Lewy bodies or Parkinson’s disease dementia. Patients with frontotemporal dementia should not be offered treatment with acetylcholinesterase inhibitors or memantine. Patients with cognitive impairment caused by multiple sclerosis should not be offered treatment with acetylcholinesterase inhibitors or memantine. Patients with mild cognitive impairment should not be offered treatment with acetylcholinesterase inhibitors as current evidence suggests they do not reduce the risk of developing dementia, and that they are ineffective in the treatment of mild cognitive impairment whilst also increasing the risk to the patient from adverse effects. There are no studies to support the prescribing of memantine in mild cognitive impairment. 2. Contra-indications and Cautions Acetylcholinesterase inhibitors are contraindicated by the manufacturers where patients have a known hypersensitivity to the active pharmaceutical ingredient, piperidine derivatives, carbamate derivatives, or to any excipients present in the formulation. o Galantamine is additionally contraindicated in patients with severe renal and hepatic dysfunction o Rivastigmine is additionally contraindicated in patients with application site reactions suggestive of allergic contact dermatitis with rivastigmine patches, unless further allergy testing is negative. Patients who have become sensitised to rivastigmine may not be able to take rivastigmine in any form. Acetylcholinesterase inhibitors must be used with caution in conditions which may be exacerbated by the increase in systemic acetylcholine caused by the treatment, this includes: o Patients with on-going gastro-intestinal disorders such as nausea, vomiting, and diarrhoea. o Patients experiencing weight loss. o Patients who are at high risk of developing torsade de pointes, for example those with uncompensated heart failure, recent myocardial infarction, bradycardia, hypokaelaemia, hypomagnesaemia, and prolonged QTc interval or concomitant use of medications known to prolong QTc interval. o Patients with sick sinus syndrome or conduction deficits. o Patients with active gastric or duodenal ulcers or patients predisposed to these conditions. o Patients with a history of asthma or chronic obstructive pulmonary disease. o Patients predisposed to urinary obstructions and seizures. Memantine must be used with caution in the following situations: o Patients with epilepsy, history of convulsions, or patients with predisposing factors for epilepsy. o Concomitant use of NMDA receptor antagonists such as amantadine, ketamine or dextromethorphan, which may exacerbate incidence and severity of adverse effects. o Patients with raised urinary pH, as alkalinisation of urine may lead to the elimination of memantine being reduced by a factor of 7 to 9. o Patients with recent myocardial infarction, uncompensated heart failure, or uncontrolled hypertension. 3. Dosing Recommendations: All acetylcholinesterase inhibitors and memantine must be prescribed by generic name. Donepezil o 5mg once daily for 4 weeks, increasing to 10mg once daily if necessary. Galantamine o Immediate release - 4mg twice daily for 4 weeks, increasing to 8mg twice daily for at least 4 weeks, the usual maintenance dose is 8 to 12 mg twice daily. o Modified release capsules – 8mg once daily for 4 weeks, increasing to 16mg once daily for at least 4 weeks. Usual maintenance dose is 16 to 24mg daily. Rivastigmine o Capsules – 1.5mg twice daily for 2 weeks, increasing in steps of 1.5mg twice daily at intervals of at least 2 weeks according to tolerance. Usual maintenance dose is 3 to 6mg twice daily. o Transdermal patches – One 4.6mg/24 hour patch daily for at least 4 weeks, increased if tolerated to one 9.5mg/24 hour patch daily for a further 6 months, then increased if necessary to one 13.3mg/24 hour patch daily if well tolerated. Memantine o 5mg once daily for 1 week, increasing in 5mg steps every week. Usual maintenance dose 20mg daily. Doses may need to be adjusted according to renal and hepatic function, refer to product literature. If patients suffer from intolerable adverse effects during treatment with acetylcholinesterase inhibitors, treatment should be discontinued and adverse effects allowed the time to resolve completely. Treatment can then either be restarted and titrated at a slower rate, or an alternative medication tried instead. Where patents have been non-adherent with their medication, treatment may require re-titration to avoid dose related adverse effects such as those caused by systemic increases in acetylcholine with acetylcholinesterase inhibitors, as per when they were first initiated: o This is most evident with rivastigmine, whereby if 3 days of treatment is missed in a row it must be restarted from 1.5mg twice daily for the capsules or one 4.6mg/24 hours patch daily for the transdermal patches. 4. Monitoring and Review GPs should be asked to review patients after a maintenance dose has been achieved and if treatment is well tolerated and there are no complications; continue the treatment long-term. When reviewing
Load more

Recommended publications
  • Nerve Agent - Lntellipedia Page 1 Of9 Doc ID : 6637155 (U) Nerve Agent
    This document is made available through the declassification efforts and research of John Greenewald, Jr., creator of: The Black Vault The Black Vault is the largest online Freedom of Information Act (FOIA) document clearinghouse in the world. The research efforts here are responsible for the declassification of MILLIONS of pages released by the U.S. Government & Military. Discover the Truth at: http://www.theblackvault.com Nerve Agent - lntellipedia Page 1 of9 Doc ID : 6637155 (U) Nerve Agent UNCLASSIFIED From lntellipedia Nerve Agents (also known as nerve gases, though these chemicals are liquid at room temperature) are a class of phosphorus-containing organic chemicals (organophosphates) that disrupt the mechanism by which nerves transfer messages to organs. The disruption is caused by blocking acetylcholinesterase, an enzyme that normally relaxes the activity of acetylcholine, a neurotransmitter. ...--------- --- -·---- - --- -·-- --- --- Contents • 1 Overview • 2 Biological Effects • 2.1 Mechanism of Action • 2.2 Antidotes • 3 Classes • 3.1 G-Series • 3.2 V-Series • 3.3 Novichok Agents • 3.4 Insecticides • 4 History • 4.1 The Discovery ofNerve Agents • 4.2 The Nazi Mass Production ofTabun • 4.3 Nerve Agents in Nazi Germany • 4.4 The Secret Gets Out • 4.5 Since World War II • 4.6 Ocean Disposal of Chemical Weapons • 5 Popular Culture • 6 References and External Links --------------- ----·-- - Overview As chemical weapons, they are classified as weapons of mass destruction by the United Nations according to UN Resolution 687, and their production and stockpiling was outlawed by the Chemical Weapons Convention of 1993; the Chemical Weapons Convention officially took effect on April 291997. Poisoning by a nerve agent leads to contraction of pupils, profuse salivation, convulsions, involuntary urination and defecation, and eventual death by asphyxiation as control is lost over respiratory muscles.
    [Show full text]
  • A Screening Tool for Acetylcholinesterase Inhibitors
    RESEARCH ARTICLE Comparative biophysical characterization: A screening tool for acetylcholinesterase inhibitors 1 1 2 1 Devashree N. Patil , Sushama A. Patil , Srinivas SistlaID , Jyoti P. JadhavID * 1 Department of Biotechnology, Shivaji University, Kolhapur, MS, India, 2 Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, Virginia, United States * [email protected] a1111111111 a1111111111 a1111111111 a1111111111 Abstract a1111111111 Among neurodegenerative diseases, Alzheimer's disease (AD) is one of the most grievous disease. The oldest cholinergic hypothesis is used to elevate the level of cognitive impairment and acetylcholinesterase (AChE) comprises the major targeted enzyme in AD. Thus, acetylcholinesterase inhibitors (AChEI) constitutes the essential remedy for the treat- OPEN ACCESS ment of AD. The study aims to evaluate the interactions between natural molecules and Citation: Patil DN, Patil SA, Sistla S, Jadhav JP AChE by Surface Plasmon Resonance (SPR). The molecules like alkaloids, polyphenols (2019) Comparative biophysical characterization: A screening tool for acetylcholinesterase inhibitors. and substrates of AChE have been considered for the study with a major emphasis on affin- PLoS ONE 14(5): e0215291. https://doi.org/ ity and kinetics. To better understand the activity of small molecules, the investigation is sup- 10.1371/journal.pone.0215291 ported by both experimental and theoretical approach such as fluorescence, Circular Editor: David A. Lightfoot, College of Agricultural Dichroism (CD) and molecular docking studies. Amongst the screened ones tannic acid Sciences, UNITED STATES showed promising results compared with others. The methodology followed here have Received: September 26, 2018 highlighted many molecules with a higher affinity towards AChE and these findings may Accepted: March 30, 2019 take lead molecules generated in preclinical studies to treat neurodegenerative diseases.
    [Show full text]
  • Acetylcholinesterase — New Roles for Gate a Relatively Long Distance to Reach the Active Site, Ache Is One of the Fastest an Old Actor Enzymes14
    PERSPECTIVES be answered regarding AChE catalysis; for OPINION example, the mechanism behind the extremely fast turnover rate of the enzyme. Despite the fact that the substrate has to navi- Acetylcholinesterase — new roles for gate a relatively long distance to reach the active site, AChE is one of the fastest an old actor enzymes14. One theory to explain this phe- nomenon has to do with the unusually strong electric field of AChE. It has been argued that Hermona Soreq and Shlomo Seidman this field assists catalysis by attracting the cationic substrate and expelling the anionic The discovery of the first neurotransmitter — understanding of AChE functions beyond the acetate product15. Site-directed mutagenesis, acetylcholine — was soon followed by the classical view and suggest the molecular basis however, has indicated that reducing the elec- discovery of its hydrolysing enzyme, for its functional heterogeneity. tric field has no effect on catalysis16.However, acetylcholinesterase. The role of the same approach has indicated an effect on acetylcholinesterase in terminating From early to recent discoveries the rate of association of fasciculin, a peptide acetylcholine-mediated neurotransmission The unique biochemical properties and phys- that can inhibit AChE17. made it the focus of intense research for iological significance of AChE make it an much of the past century. But the complexity interesting target for detailed structure–func- of acetylcholinesterase gene regulation and tion analysis. AChE-coding sequences have recent evidence for some of the long- been cloned so far from a range of evolution- a Peripheral Choline binding site suspected ‘non-classical’ actions of this arily diverse vertebrate and invertebrate binding enzyme have more recently driven a species that include insects, nematodes, fish, site profound revolution in acetylcholinesterase reptiles, birds and several mammals, among Active site research.
    [Show full text]
  • Skeletal Muscles in Chick Embryo (Cholinergic Receptor/Choline Acetyltransferase/Acetylcholinesterase/ Embryonic Development of Neuromuscular Junction) G
    Proc. Nat. Acad. Sci. USA Vol. 70, No. 6, pp. 1708-1712, June 1973 Effects of a Snake a-Neurotoxin on the Development of Innervated Skeletal Muscles in Chick Embryo (cholinergic receptor/choline acetyltransferase/acetylcholinesterase/ embryonic development of neuromuscular junction) G. GIACOBINI, G. FILOGAMO, M. WEBER, P. BOQUET, AND J. P. CHANGEUX Department of Human Anatomy, University of Turin, Turin, Italy; and Department of Molecular Biology, Institut Pasteur, Paris, France Communicated by Frankois Jacob, March 15, 1973 ABSTRACT The evolution of the cholinergic (nicotinic) The embryos were treated with a-toxin by three successive receptor in chick muscles is monitored during embryonic injections (the 3rd, 8th, and 12th day of incubation) in the yolk development with a tritiated a-neurotoxin from Naja nigri- collis and compared with the appearance of acetylcholines- sac with a Hamilton syringe, through a small window in the terase. The specific activity of these two proteins reaches a shell. Each time, 20-100 Al of a 1 mg/ml solution in sterile maximum around the 12th day of incubation. By contrast, Ringer's solution was injected. Embryos were examined the choline acetyltransferase reaches an early maximum of 16th day of incubation. About 30% of the injected embryos specific activity around the 7th day of development, and later continuously increases until hatching. Injection of died during development. a-toxin in the yolk sac at early stages ofdevelopment causes Homogenization. The tissue was added to ice-cold Ringer's an atrophy of skeletal and extrinsic ocular-muscles solution (for [3H ]a-toxin binding), to 0.5%O Triton X-100 in and of their innervation.
    [Show full text]
  • 388Fc33bdf5b91affd8650f371de
    molecules Article In Vitro and In Silico Acetylcholinesterase Inhibitory Activity of Thalictricavine and Canadine and Their Predicted Penetration across the Blood-Brain Barrier Jakub Chlebek 1,* , Jan Korábeˇcný 2,3 , Rafael Doležal 2,4,Šárka Štˇepánková 5, Daniel I. Pérez 6, Anna Hošt’álková 1 , Lubomír Opletal 1, Lucie Cahlíková 1, KateˇrinaMacáková 1, Tomáš Kuˇcera 3 , Martina Hrabinová 2,3 and Daniel Jun 2,3 1 ADINACO Research Group, Department of Pharmaceutical Botany, Faculty of Pharmacy, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic; [email protected] (A.H.); [email protected] (L.O.); [email protected] (L.C.); [email protected] (K.M.) 2 Biomedical Research Center, University Hospital Hradec Králové, Sokolská 581, 500 05 Hradec Králové, Czech Republic; [email protected] (J.K.); [email protected] (R.D.); [email protected] (M.H.); [email protected] (D.J.) 3 Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defense, Tˇrebešská 1575, 500 01 Hradec Králové, Czech Republic; [email protected] 4 Center for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Králové, Rokitanského 62, 50003 Hradec Králové, Czech Republic 5 Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentská 95, 532 10 Pardubice, Czech Republic; [email protected] 6 Centro de Investigaciones Biológicas, Avenida Ramiro de Maetzu 9, 280 40 Madrid, Spain; [email protected] * Correspondence: [email protected]; Tel.: +420-495067232; Fax: +420-495067162 Academic Editor: Derek J.
    [Show full text]
  • Acetylcholinesterase-Transgenic Mice Display Embryonic Modulations In
    Proc. Natl. Acad. Sci. USA Vol. 94, pp. 8173–8178, July 1997 Neurobiology Acetylcholinesterase-transgenic mice display embryonic modulations in spinal cord choline acetyltransferase and neurexin Ib gene expression followed by late-onset neuromotor deterioration (neuromuscular junctionymotoneurons) CHRISTIAN ANDRES*†‡,RACHEL BEERI*‡,ALON FRIEDMAN*, EFRAT LEV-LEHMAN*, SIVAN HENIS*, RINA TIMBERG*, MOSHE SHANI§, AND HERMONA SOREQ*¶ *Department of Biological Chemistry, The Hebrew University of Jerusalem, 91904 Israel; and §Department of Molecular Genetics, Agricultural Research Organization, The Volcani Center, Bet Dagan, 50250 Israel Communicated by Roger D. Kornberg, Stanford University School of Medicine, Stanford, CA, May 9, 1997 (received for review March 12, 1997) ABSTRACT To explore the possibility that overproduc- like domain of neurotactin was replaced with the homologous tion of neuronal acetylcholinesterase (AChE) confers changes domain from Torpedo AChE was reported to retain ligand- in both cholinergic and morphogenic intercellular interac- dependent cell-adhesive properties similar to the native mol- tions, we studied developmental responses to neuronal AChE ecule (10). This reinforced the notion that AChE may play a overexpression in motoneurons and neuromuscular junctions role in neuronal cell adhesion. of AChE-transgenic mice. Perikarya of spinal cord motoneu- In mammals, the AChE-homologous neuroligins were iden- rons were consistently enlarged from embryonic through tified as heterophilic ligands for a splice-site specific form of adult stages in AChE-transgenic mice. Atypical motoneuron the synapse-enriched neuronal cell surface protein neurexin Ib development was accompanied by premature enhancement in (11). Neurexins represent a family of three homologous genes the embryonic spinal cord expression of choline acetyltrans- (I, II, and III), giving rise to a and b forms that can undergo ferase mRNA, encoding the acetylcholine-synthesizing enzyme further alternative splicing to generate over 1,000 isoforms choline acetyltransferase.
    [Show full text]
  • Human Erythrocyte Acetylcholinesterase
    Pediat. Res. 7: 204-214 (1973) A Review: Human Erythrocyte Acetylcholinesterase FRITZ HERZ[I241 AND EUGENE KAPLAN Departments of Pediatrics, Sinai Hospital, and the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Introduction that this enzyme was an esterase, hence the term "choline esterase" was coined [100]. Further studies In recent years the erythrocyte membrane has received established that more than one type of cholinesterase considerable attention by many investigators. Numer- occurs in the animal body, differing in substrate ous reviews on the composition [21, 111], immunologic specificity and in other properties. Alles and Hawes [85, 116] and rheologic [65] properties, permeability [1] compared the cholinesterase of human erythro- [73], active transport [99], and molecular organiza- cytes with that of human serum and found that, tion [109, 113, 117], attest to this interest. Although although both enzymes hydrolyzed acetyl-a-methyl- many studies relating to membrane enzymes have ap- choline, only the erythrocyte cholinesterase could peared, systematic reviews of this area are limited. hydrolyze acetyl-yg-methylcholine and the two dia- More than a dozen enzymes have been recognized in stereomeric acetyl-«: /3-dimethylcholines. These dif- the membrane of the human erythrocyte, although ferences have been used to delineate the two main changes in activity associated with pathologic condi- types of cholinesterase: (1) acetylcholinesterase, or true, tions are found regularly only with acetylcholinesterase specific, E-type cholinesterase (acetylcholine acetyl- (EC. 3.1.1.7). Although the physiologic functions of hydrolase, EC. 3.1.1.7) and (2) cholinesterase or erythrocyte acetylcholinesterase remain obscure, the pseudo, nonspecific, s-type cholinesterase (acylcholine location of this enzyme at or near the cell surface gives acylhydrolase, EC.
    [Show full text]
  • Acetylcholinesterase: the “Hub” for Neurodegenerative Diseases And
    Review biomolecules Acetylcholinesterase: The “Hub” for NeurodegenerativeReview Diseases and Chemical Weapons Acetylcholinesterase: The “Hub” for Convention Neurodegenerative Diseases and Chemical WeaponsSamir F. de A. Cavalcante Convention 1,2,3,*, Alessandro B. C. Simas 2,*, Marcos C. Barcellos 1, Victor G. M. de Oliveira 1, Roberto B. Sousa 1, Paulo A. de M. Cabral 1 and Kamil Kuča 3,*and Tanos C. C. França 3,4,* Samir F. de A. Cavalcante 1,2,3,* , Alessandro B. C. Simas 2,*, Marcos C. Barcellos 1, Victor1 Institute G. M. ofde Chemical, Oliveira Biological,1, Roberto Radiological B. Sousa and1, Paulo Nuclear A. Defense de M. Cabral (IDQBRN),1, Kamil Brazilian Kuˇca Army3,* and TanosTechnological C. C. França Center3,4,* (CTEx), Avenida das Américas 28705, Rio de Janeiro 23020-470, Brazil; [email protected] (M.C.B.); [email protected] (V.G.M.d.O.); [email protected] 1 Institute of Chemical, Biological, Radiological and Nuclear Defense (IDQBRN), Brazilian Army (R.B.S.); [email protected] (P.A.d.M.C.) Technological Center (CTEx), Avenida das Américas 28705, Rio de Janeiro 23020-470, Brazil; 2 [email protected] Mors Institute of Research (M.C.B.); on Natural [email protected] Products (IPPN), Federal (V.G.M.d.O.); University of Rio de Janeiro (UFRJ), CCS,[email protected] Bloco H, Rio de Janeiro (R.B.S.); 21941-902, [email protected] Brazil (P.A.d.M.C.) 32 DepartmentWalter Mors of Institute Chemistry, of Research Faculty of on Science, Natural Un Productsiversity (IPPN),
    [Show full text]
  • Exploring Structure-Activity Relationship in Tacrine-Squaramide Derivatives As Potent Cholinesterase Inhibitors
    biomolecules Article Exploring Structure-Activity Relationship in Tacrine-Squaramide Derivatives as Potent Cholinesterase Inhibitors 1,2, 1,2,3, 1,2 1,2 Barbora Svobodova y, Eva Mezeiova y, Vendula Hepnarova , Martina Hrabinova , Lubica Muckova 1,2 , Tereza Kobrlova 1 , Daniel Jun 1,2 , Ondrej Soukup 1,2, María Luisa Jimeno 4, José Marco-Contelles 3,* and Jan Korabecny 1,2,* 1 Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic 2 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic 3 Laboratory of Medicinal Chemistry, Institute of General Organic Chemistry, Juan de la Cierva 3, 28006-Madrid, Spain 4 Centro de Química Orgánica “Lora-Tamayo” (CSIC), C/Juan de la Cierva 3, 28006-Madrid, Spain * Correspondence: [email protected] (J.M.-C.); [email protected] (J.K.); Tel.: +34-91-2587554 (J.M.-C.); +420-495-833-447 (J.K.) These authors contributed equally to this paper. y Received: 2 August 2019; Accepted: 17 August 2019; Published: 19 August 2019 Abstract: Tacrine was the first drug to be approved for Alzheimer’s disease (AD) treatment, acting as a cholinesterase inhibitor. The neuropathological hallmarks of AD are amyloid-rich senile plaques, neurofibrillary tangles, and neuronal degeneration. The portfolio of currently approved drugs for AD includes acetylcholinesterase inhibitors (AChEIs) and N-methyl-d-aspartate (NMDA) receptor antagonist. Squaric acid is a versatile structural scaffold capable to be easily transformed into amide-bearing compounds that feature both hydrogen bond donor and acceptor groups with the possibility to create multiple interactions with complementary sites.
    [Show full text]
  • Biological Monitoring Ofexposure to Nerve Agents
    Br J Ind Med: first published as 10.1136/oem.49.9.648 on 1 September 1992. Downloaded from 648 British Journal of Industrial Medicine 1992;49:648-653 Biological monitoring of exposure to nerve agents J Bajgar Abstract occurred; at less than 30-55%, disturbed ven- Changes in acetylcholinesterase activity in tilation and fasciculations were seen, and at blood and some organs of rats after intoxica- 15-30%, convulsions occurred. Less than 10% tion with sarin, soman, VX, and 2-dimethy- was fatal. In experiments with narcotised dogs, laminoethyl-(dimethylamido)-phosphono- the blood acetylcholinesterase activity and the fluoridate (GV), in doses of roughly 2 x LD5. ability to reactivate it with trimedoxime were given intramuscularly, were obtained from determined after intoxication by intra- published data and by experiment. The time muscular administration of the four com- course of inhibition of acetylcholinesterase in pounds. It is concluded that acetylcholines- blood, regions ofbrain, and diaphragm and the terase activity in the blood corresponds to that occurrence of signs and symptoms of poison- in the target organs and can be considered as ing (none, salivation, disturbed ventilation and an appropriate parameter for biological fasciculations, convulsions, or death) were monitoring of exposure to nerve gases. More- summarised and compared. When blood over, determination of reactivation of blood enzyme activities were 70-100% normal, no acetylcholinesterase gives more information obvious signs were seen; at 60-70%, salivation than simple determination ofenzyme activity. Military Medical Academy, 502 60 Hradec Krilov6, Nerve agents are compounds ofhigh toxicity,' one of copyright. Czechoslovakia the many reasons for their possible use as chemical J Bajgar weapons.' Others from this class of chemicals Membrane Stressogenic r%tiRec spholipids.
    [Show full text]
  • Drug Treatments for Alzheimer's Disease
    Factsheet 407LP Drug treatments December 2014 for Alzheimer’s disease There are no drug treatments that can cure Alzheimer’s disease or any other common type of dementia. However, medicines have been developed for Alzheimer’s disease that can temporarily alleviate symptoms, or slow down their progression, in some people. This factsheet explains how the main drug treatments for Alzheimer’s disease work, how to access them, and when they can be prescribed and used effectively. For more information about Alzheimer’s disease see factsheet 401, What is Alzheimer’s disease? Contents n What are the main drugs used? n How do they work? n Are these drugs effective for everyone with Alzheimer’s disease? n Are there any side effects? n How are these drugs prescribed? n Are these drugs effective for other types of dementia? n Taking the drugs n Questions to ask the doctor when starting the drugs n Stopping treatment n NICE guidance: a summary n Research into new treatments n Other useful organisations. 2 Drug treatments for Alzheimer’s disease Drug treatments for Alzheimer’s disease Drug treatment for Alzheimer’s disease is important, but the benefits are small, and drugs should only be one part of a person’s overall care. Non- drug treatments, activities and support are just as important in helping someone to live well with Alzheimer’s disease. Many drugs have at least two names. The generic name identifies the substance. The brand name varies depending on the company that manufactures it. For example, a familiar painkiller has the generic name paracetamol and is manufactured under brand names such as Panadol and Calpol, among others.
    [Show full text]
  • What Killed Kim Jong-Nam? Was It the Agent Vx?
    Mil. Med. Sci. Lett. (Voj. Zdrav. Listy) 2017, vol. 86(2), p. 86-89 ISSN 0372-7025 DOI: 10.31482/mmsl.2017.013 LETTER TO THE EDITOR WHAT KILLED KIM JONG-NAM? WAS IT THE AGENT VX? INTRODUCTION Kim Jong-nam (10 May 1971 – 13 February 2017) was the eldest son of Kim Jong-il, leader of North Korea, and the estranged half-brother of North Korean dictator Kim Jong-un. From roughly 1994 to 2001, he was consid - ered the heir to his father [1]. Following a series of actions showing dissent to the North Korean regime, including a failed attempt to visit Tokyo Disneyland in May 2001 by entering Japan with a false passport, he was thought to have fallen out of favour with his father. On 13 February 2017, Kim was allegedly murdered by two women who fled after the crime [2]. The murder was commited in Malaysia during his return trip to Macau, at the low-cost carrier terminal of the Kuala Lumpur International Airport [3]. Initial reports suggest that Kim Jong-nam was mur - dered by VX, a type of agent used in chemical warfare [4]. Toxicological tests showed the presence of VX in Kim's eyes and face [5]. What is the agent VX and could this toxic substance cause the death of Kim? What is it VX? The VX is very toxic organophosphate (CAS Number 50782-69-9, O-ethyl-S-2-diisopropylaminoethyl methylphosphonothiolate) and extremely active cholinesterase inhibitor. At room temperature it is odorless, colorless to straw-colored liquid with m.p.
    [Show full text]