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1
Giles, Kurt. "Post-translational modifications of acetylcholinesterase." Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.260127.
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Yau, Kenneth Kwok-Chi. "Assessing and predicting treatment responses to cholinesterase inhibitor pharmacotherapy in Alzheimer's disease." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0015/MQ54172.pdf.
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Connelly, Stephen. "Studies on pyroglutamyl carboxyl peptidase enzymes and cholinesterase inhibitors : implications for Alzheimer's disease." Thesis, University of Exeter, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.430098.
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Spowart-Manning, Laura. "The evaluation of behavioural tasks and animal models of Alzheimer's disease for assessing putative cognition enhancers, using a cholinesterase inhibitor as reference compound." Thesis, University of Bristol, 2001. http://hdl.handle.net/1983/09e768fe-f64c-47c0-b4d4-d0a19b8ff23d.
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Foka, Germaine Boulenoue. "Synthesis and evaluation of novel coumarin-donepezil derivatives as dual acting monoamine oxidase B and cholinesterase in Alzheimer's disease." University of the Western Cape, 2016. http://hdl.handle.net/11394/5549.
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Magister Pharmaceuticae - MPharm<br>Alzheimer's disease is a progressive neurodegenerative disease characterised by low acetylcholine (ACh) levels in the hippocampus and cortex of the brain, causing symptoms like progressive memory loss, decline in language skills and other cognitive impairments to occur. The hallmarks of AD include the presence of extracellular insoluble amyloid beta plaques, intracellular neurofibrillary tangles, and the decrease in ACh concentration. The pathophysiology of AD is not well understood, however, acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and monoamine oxidases (MAO) are conspicuous role players in AD pathogenesis. Based on the cholinergic hypothesis, the AChE inhibitor donepezil was developed and has been used effectively clinically in the management of AD, with minimal side effects. Studies regarding the binding interactions of donepezil with AChE has shown that the benzyl-piperidine moiety of this compound shows substantial binding interactions at the CAS site of AChE where it blocks AChE activity. Coumarin is a compound of natural source that has shown some MAO inhibitory activity. Further studies done to clarify the potential of coumarin as a drug against AD has shown that coumarin has the capacity to bind at the PAS site of AChE, thus giving it the potential to prevent AChE induced amyloid plaque formation. Due to the multifactorial nature of AD, the drugs in the market show limited therapeutic benefits and are mainly for symptomatic relief. In order to address this limitation in AD treatment, researchers are exploring the possibility of designing a multi-target-directed-ligand (MTDL). The aim of this study was to synthesise a series of compounds out of pharmacophoric groups of donepezil and coumarin that will be able to inhibit both cholinesterases and MAO B. Four series of 5 compounds per series were synthesised. The first series of compounds consisted of the coumarin moiety to which a 1,4-dibromo benzene moiety was attached. The second series represented the coumarin moiety to which a piperidine (donepezil moiety shown to confer cholinesterase inhibitory property) was attached. The third series represented the coumarin moiety to which bromobenzyl-piperazine was attached and in the last series were compounds similar in structure to series 1 with an unsubstituted benzyl moiety as opposed to the dibromobenzyl moiety. Prior to the synthesis, molecular modelling was conducted in order to have an idea of the binding capacity of the compounds to MAO A and B and cholinesterases. In vitro biological evaluation of the compounds was done and used to determine the IC₅₀ values of the compounds. Nineteen compounds were synthesised and purified successfully as shown by their NMR, MS and IR spectra. The compounds to which dual inhibitory activity was conferred were those in series 2 and 3, of which series 2 showed the best overall inhibitory activity with IC₅₀ values within the low μM range. The compound with the best overall activity was Cp 9. Molecular modelling of Cp 9 showed that the coumarin core was located in the PAS region of AChE while the benzyl-piperidine moiety was situated in the CAS region of the enzyme. This compound orientation demonstrates the potential of Cp 9 to inhibit AChE induced amyloid beta plaque formation. Cp 9 showed no inhibitory activity towards MAO A, but showed good inhibitory activity towards MAO B with an IC₅₀ value of 0.30 μM. Its inhibitory activity towards cholinesterases also fell within the low μM range (AChE IC50 = 9.1 μM and BuChE IC₅₀ = 5.9 μM). From the results, it can be concluded that Cp 9 was able to inhibit both cholinesterase and MAO B catalytic activities at low μM concentrations. This thus means that our novel compound will not only increase ACh levels in the brain thus improving cognitive activity, but it will also have neuroprotective effect from its MAO B inhibitory property and also potentially slow down amyloid plaque formation due to AChE activity.<br>National Research Foundation (NRF)
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Svensson, Anne-Lie. "Cholinesterase inhibitors in Alzheimer's disease : an experimental study on mechanisms of interaction with muscarinic and nicotinic receptors and neuroprotection /." Stockholm, 1997. http://diss.kib.ki.se/1997/91-628-2733-2.
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Anderholm, Louise. "Behandling av beteendemässiga ochpsykiska symtom med fokus påagitation hos äldre med Alzheimerssjukdom. : En jämförelse mellan neuroleptika ochacetylkolinesterashämmare." Thesis, Umeå universitet, Farmakologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-119733.
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Inledning: År 2030 uppskattas det vara ungefär 230 000 stycken människor i Sverige somhar drabbats av någon typ av demenssjukdom. Sjukdomens stadier delas in i begynnande,mild, måttlig och svår demens. Där första symtomen i den begynnande fasen brukar vara attden drabbade inte kommer ihåg vart den lagt sina saker. I den svåra fasen av sjukdomen ärpatienten förmodligen beroende av dygnet runt vård, patienten brukar även ha svårt attprata, enstaka ord eller meningar brukar upprepas. Beteendemässiga och psykiska symtom(BPSD) hos demenssjuka är symtom som kan orsaka lidande hos patienten och dessanhöriga. Symtomen delas in i fyra undergrupper affektiva, psykossymtom, hyperaktivitetoch apati. Riskfaktorn med högst evidens är Apolipoprotein E (ApoE), ApoEε4-allelen.Riskfaktorer med lägre evidensgrad är t.ex. låg utbildning och släktskap. Sjukdomen orsakas av att nervcellerna i hjärnan dör, framförallt i delen av hjärnan därminnet sitter. En röntgen av hjärnan visar onormala proteininlagringar, amyloida plack.Amyloidhypotesen påstår att det blir en överproduktion av amyloid-beta proteinet vilken trosvara den patologiska händelsen vid Alzheimers sjukdom. Tauproteinet hyperfosfyleras till enisoform som är tre gånger större än i en frisk hjärna, om överproduktion av tau på specifikaställen eller hela hjärnan orsakar sjukdomen har forskarna inte kommit fram till ännu. Mildtill måttlig Alzheimers sjukdom behandlas med acetylkolinesterashämmarna donepezil,rivastagmin och galantamin. Svår Alzheimers sjukdom behandlas med en NMDAreceptoragonist,memantin. Syfte: Att undersöka om acetylkolinesterashämmare eller neuroleptika fungerar bäst vidsymtom som uppkommer vid BPSD, samt undersöka vilka biverkningar som är vanligast. Metod: PubMed har använts för att hitta studier som stämmer in på inklusionskriterierna.Studier som exkluderas är de som undersökt fel substans, fel indikation eller fel preparat t.ex.omega-3. Resultat: De vanligaste biverkningarna som rapporterats hos acetylkolinesterashämmarnaär bland annat illamående och kräkningar. Av neuroleptika preparaten verkar det varasömnighet som är den mest rapporterade biverkningen. Studierna som undersökteneuroleptika kom fram till ungefär samma sak, att preparaten kan förbättra symtomen. Av destudier som undersökte acetylkolinesterashämmarna var det tre studier som drog slutsatsenatt de kan ha effekt. En studie säger att det inte sågs någon skillnad mellan donepezil ochplacebo vid dessa typer av symtom. Diskussion: Då de olika studierna som använts i arbetet har undersökt olika effektmått hardet varit svårt att göra en rättvis bedömning om läkemedlen fungerar eller ej. Då i de flestafall bara gått och jämföra ett effektmått från studierna. Hade jag bestämt vilka effektmåttsom fick finnas i varje studie redan från början och sedan gjort en exkludering utifrån det,hade det varit enklare att jämföra studierna och därefter kommit fram till en bra slutsats. Viden jämförelse mellan de olika substanserna ur neuroleptikagruppen, är sömnighet denvanligaste biverkningen i tre av fyra grupper. Viktökning är också en av de vanligastebiverkningarna i två av grupperna där ungefär 32% drabbades av just denna biverkning.Varför patienterna ökat i vikt framgår inte i studierna. Slutsats: Acetylkolinesterashämmare och neuroleptika kan ha effekt vid symtom somuppkommer vid BPSD. Acetylkolinesterashämmarna bör provas i första hand om intebehandlingen redan är insatt.
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Forsström, Karin. "Longitudinal Changes in Astroglial and Inflammatory Markers in Patients with MCI and AD." Thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-192975.
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Since neuroinflammation is present in patients with mild cognitive impairment (MCI) andAlzheimer's disease (AD) and since cholinesterase inhibitors increases the level ofacetylcholine, the aim was to investigate whether inflammatory markers of cholinoceptive cellsare affected in these patients. Near a biological hallmark of AD, amyloid plaque, activatedastrocytes and microglia can be found and higher levels of proinflammatory cytokines, i.e. IL-1β. To study the inflammatory response, proteins GFAP and S100B are used as CSF glialmarkers. IL-1β can bind to the membrane-bound IL-1 receptor or soluble sIL-1β-RII. When IL-1β binds to the soluble receptor instead of the membrane-bound receptor, no intracellular signalpropagation occur, thereby sIL-1βRII exerts an antagonistic effect and diminishedinflammatory responses. Thus a reduction in ratio of IL-1β to sIL-1RII levels may be indicativeof anti-inflammatory response. Available data on CSF GFAP, S100B, IL-1β and sIL-1β-RIIlevels in AD patients and MCI patients was used. MCI group were longitudinally followedafter start of treatment with a cholinesterase inhibitor (ChEI). AD group had data from baselineand after short-term treatment with a ChEI. The statistics application StatView was used toanalyse data. The activity of the cholinesterase enzymes, BuChE and AChE showed significantinhibition in the CSF of the MCI patients compared to baseline CSF GFAP level wassignificantly lower in MCI than AD patients at baseline. The levels of both GFAP and S100Bwere increased with time in MCI patients to comparable levels in the AD patients, indicative ofastroglial activation in MCI patients. However, the ratio of IL-1β to sIL-1RII showed alongitudinal reduction in the MCI patients after the treatment with the ChEIso that this ratiowas significantly higher in AD than in MCI patients. Thus despite the activation of astroglialcells in the treated MCI patients the proinflammatory effect of IL-1β was prevented byinduction of sIL-1βRII levels indicative of an anti-inflammatory outcome of treatment. Thisstudy suggests that proper activation of astroglial cells may have beneficial effect on ADpathogenesis, and conversion of MCI to AD. It also suggests that cholinesterase inhibitors may have an anti-inflammatory effect.
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Navaratnam, Dasakumar Selveraj. "Cholinesterases in Alzheimer's disease." Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.306734.
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Blanco, Silvente Lídia. "La relación beneficio-riesgo del tratamiento farmacológico para la enfermedad de Alzheimer." Doctoral thesis, Universitat de Girona, 2019. http://hdl.handle.net/10803/667938.
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The evidence available in the medical literature is conclusive that the risk-benefit relationship of the current medications for Alzheimer's disease is not favourable. This risk-benefit relationship is not significantly modified by any factor related to the design of the clinical trials, neither with the intervention nor with patient’s characteristics. It is also important to highlight that redundant studies that do not provide new evidence have been identified, so the realization of new clinical trials to evaluate the efficacy and safety of current medications for Alzheimer's disease would be questionable. The findings of this thesis show the need to take positions by the responsible regarding the use of cholinesterase inhibitors and memantine in patients with Alzheimer's disease.<br>Les evidències disponibles en la literatura mèdica són concloents que la relació benefici-risc dels medicaments actualment indicats per la malaltia d'Alzheimer no és favorable. Aquesta relació benefici-risc no es troba modificada de manera rellevant per cap factor relacionat ni amb el disseny dels assaigs clínics, ni amb la intervenció ni amb les característiques dels pacients. És important destacar també que s’ha identificat estudis redundants que no aporten noves evidències, de tal manera que la realització de nous assajos clínics per avaluar la eficàcia i la seguretat dels actuals medicaments per la malaltia d'Alzheimer seria qüestionable. Les troballes d’aquesta tesi posen de manifest la necessitat de prendre posició per part dels organismes responsables en quant a l’ús dels inhibidors de la colinesterasa i de la memantina en pacients amb malaltia d'Alzheimer.
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Benchekroun, Mohamed. "Synthèse multicomposants et évaluation pharmacologique de nouveaux adduits de Ugi et de Passerini pour le traitement de la maladie d'Alzheimer." Thesis, Besançon, 2014. http://www.theses.fr/2014BESA3007/document.
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La maladie d'Alzheimer est la pathologie neurodégénérative la plus courante affectant les personnes âgées. Cette neuropathologie se caractérise par une étiologie complexe dont le déficit en acétylcholine, les plaques amyloïdes, les dégénérescences neurofibrillaires ou le stress oxydant en sont les principaux acteurs.Au cours de cette thèse, nous nous sommes intéressés à l'application des réactions multicomposants de Ugi et de Passerini, pour la synthèse de nouveaux adduits multi-cibles basées sur différents motifs antioxydants et anticholinestérasiques. Ces réactions permettent d'accéder à une vaste diversité chimique en une étape, ce qui les rend adaptées pour la synthèse rapide de molécules ayant plusieurs pharmacophores d'intérêt et ciblant ainsi différentes cause étiologiques de la maladie d'Alzheimer.Au total, 56 composés finaux, répartis dans cinq séries, ont été synthétisés :les alpha-acylaminocarboxamides prototypes (série A)les hybrides tacrine-acide férulique (série B)les hétérotrimères tacrine-mélatonine-acides antioxydant (série C)> les hybrides donépézil-acide férulique (série D)^ les dérivés chromone (série E)Toutes les séries ont été évaluées pour leur capacité à inhiber les enzymes cholinestérases et leur pouvoir antioxydant. L'hépatotoxicité des séries B et C. portant un motif tacrine, a été évaluée sur les cellules HepG2. Par ailleurs, l'étude de la série B a été complétée par d'autres tests pharmacologiques, physico-chimiques et toxicologiques.Ces différents travaux démontrent et valident l'utilisation des réactions de Ugi et de Passerini dans le développement de molécules multi-cibles pour le traitement potentiel de la maladie d'Alzheimer<br>Alzheimer's disease (AD) is thé most common type of dementia affecting elderly people. This neuropathology is characterized by a highiy complex and intricated etiology including cholinergic déficit, amyloid deposits, neurofibrillary tangles and oxidative stress.During this thesis, we sought to apply Ugi and Passerini multicomponent reactions for thé synthesis of new multi-target adducts based on différent antioxidant and anticholinergic scaffolds.Thèse réactions provides access to a broad range of chemical diversity in a one-pot fashion, which makes them suitable for thé expeditious synthesis of molécules having several pharmacophores of interest and hitting différent targets related to thé multifaceted etiology of Alzheimer's disease.A total of 56 final compounds, spread over 5 séries, hâve been synthesized:alpha-acylaminocarboxamides prototypes (A séries)tacrine-ferulic acid hybrids (B séries)tacrine-melatonin-antioxydant acids heterotrimers (C séries)donepezil-ferulic acid hybrids (D séries)Chromone derivatives (E séries)Ail thé séries were tested for their ability to inhibit thé cholinesterases enzymes and for their antioxidant power. Hepatotoxicity of thé B and C séries, bearing a tacrine fragment, was evaluated on HepG2 cells. Moreover, thé study of thé B séries was supplemented by further pharmacological, physicochemical and toxicological tests (NMR conformational study, neuroprotection on SH-SY5Y cells. self-induced Abetai.42 peptide aggregation inhibition, docking ADMET).Such work demonstrated and validated thé use of Ugi and Passerini reactions for thé development of new multi-target directed molécules for thé potential treatment of AD
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Torres, Juliana Mariano. "Estudo cin?tico da atividade anticolinester?sica de derivados ?- Carbol?nicos do produto natural harmana." Universidade Federal Rural do Rio de Janeiro, 2011. https://tede.ufrrj.br/jspui/handle/jspui/1144.
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Previous issue date: 2011-07-22<br>Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico, CNPq.<br>The increase in life expectancy is a worldwide occurrence that shows the relative
success of public health politics, and Brazil is among the countries where people are
living longer and in better physical health. But the increase in life expectancy has a
negative effect: the appearance of degenerative diseases typical of old age, including
several forms of dementia, like Alzheimer?s Disease (AD) that is certainly the most
important. It is an irreversible and progressive disease characterized by neuronal
deterioration that results in loss of cognitive functions such as memory, communication
skills, judgment and reasoning. Donepezil, rivastigmine and galantamine are medicines
used for the treatment of AD and act reversibly inhibiting the acetylcholinesterase
(AChE). Evidences suggest that the enzyme butyrylcholinesterase (BChE), closely
related to AChE, plays a significant role in AD because it is involved in neural
functions such as cholinergic co-regulation and non-cholinergic neurotransmission. The
aim of this research is to provide new substances with anticholinesterase action by using
?-carboline derivatives from the natural product harmane and carry out a kinetic study
to determine the inhibition profile of the enzymes AChE e BChE, which could help in
the discovery of new compounds which could be useful in the treatment of AD. Firstly,
a screening was carried out with seven ?-carboline derivatives. In a second stage, a
kinetic investigation, employing Ellman?s method, was run with these compounds and
all of them presented high anticholinesterase action for both AChE and BChE. All
seven derivatives presented a non-competitive reversible inhibition.<br>Torres, Juliana Mariano. ESTUDO CIN?TICO DA ATIVIDADE
ANTICOLINESTER?SICA DE DERIVADOS -CARBOL?NICOS DO
PRODUTO NATURAL HARMANA. 2011. Disserta??o (mestrado em Qu?mica
Org?nica). Instituto de Ci?ncias Exatas, Departamento de Qu?mica, Universidade
Federal Rural do Rio de Janeiro, Serop?dica, RJ, 2011.
O aumento da expectativa de vida ? um fen?meno mundial que mostra o relativo
sucesso de pol?ticas de sa?de p?blica, e o Brasil se inclui entre os pa?ses em que as
pessoas est?o vivendo por mais tempo e em condi??es melhores de sa?de. No entanto, o
aumento da expectativa de vida tem como efeito negativo o aparecimento de doen?as
degenerativas, t?picas de idades mais avan?adas, incluindo-se as v?rias formas de
dem?ncia e entre estas, a mais importante ?, sem d?vida, a Doen?a de Alzheimer (DA),
patologia irrevers?vel e progressiva caracterizada pela deteriora??o neuronal que resulta
em perda de fun??es cognitivas, tais como mem?ria, capacidade de comunica??o,
julgamento e racioc?nio. Para o tratamento da DA s?o utilizados f?rmacos como o
donepezil, galantamina e rivastigmina, os quais agem inibindo revers?velmente a
acetilcolinesterase (AChE). Evid?ncias sugerem que a enzima butirilcolinesterase
(BChE), intimamente relacionada com a AChE, tem um papel significante na DA, uma
vez que est? envolvida em fun??es neurais tais como a corregula??o da
neurotransmiss?o colin?rgica e n?o-colin?rgica. Esta pesquisa pretendeu estudar novas
subst?ncias com a??o anticolinester?sica utilizando derivados -carbol?nicos do produto
natural harmana, bem como fazer um estudo cin?tico a fim de descobrir qual o perfil de
inibi??o das enzimas AChE e BChE, a fim de buscar novos compostos que poderiam ser
?teis no tratamento dos sintomas da DA. Desta forma, foi efetuada preliminarmente
uma triagem com 7 derivados -carbol?nicos e posteriormente foi realizada uma
investiga??o cin?tica com estes compostos, uma vez que, todos apresentaram alta a??o
anticolinester?sica tanto para AChE quanto para BChE. A cin?tica enzim?tica foi
estudada segundo o m?todo de Ellman. Contudo, observou-se que todos os 7 derivados
apresentaram uma inibi??o revers?vel n?o competitiva.
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Daltin, Jussemi Biazon [UNESP]. "Uso de medicamentos em pacientes idosos portadores de doença de Alzheimer." Universidade Estadual Paulista (UNESP), 2016. http://hdl.handle.net/11449/145031.
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Previous issue date: 2016-11-08<br>Objetivos: Analisar o perfil da prescrição de inibidores da colinesterase e de outros medicamentos em pacientes idosos portadores de demência da doença de Alzheimer (ddA) atendidos em centro de atenção a idosos no município de Bauru/SP. Métodos: Estudo de delineamento transversal, descritivo e analítico, realizado com idosos portadores de demência da doença de Alzheimer (ddA), do Programa Municipal de Atenção ao Idoso (PROMAI), no período de abril de 2015 a agosto de 2015. Participantes: 81 idosos (66 mulheres e 15 homens) que faziam acompanhamento no Programa Municipal de Atenção ao Idoso (PROMAI). Resultados: Dos idosos, 81,5% pertencia ao sexo feminino, 92,6% tinham 75 anos ou mais de idade, 64,2% não eram casados, 58% tinham até 4 anos de escolaridade, 60,5% tinham renda de até um salário mínimo, 60,5% tinham como cuidador principal as filhas e 90,1% residiam com algum familiar. Dentre as comorbidades mais comuns associadas às demências encontramos hipertensão arterial (29,6%), diabetes melitus (13,4%), hipotireoidismo (8,4%) e dislipidemias (7,8%). A capacidade cognitiva expressa pelo MEEM foi em média 14,5 pontos. A polifarmácia esteve presente em 63% dos idosos e, dentre eles, 77,8% faziam uso de algum MPI. A frequência de prescrição dos ICH foi: 54,9% rivastigmina, 33,3% donepezila e 11,8% galantamina. A memantina teve uma prevalência de prescrição de 2,5%. Dos motivos do não uso de tratamento para a ddA, os efeitos colaterais indesejáveis representaram 28% dos casos. Dos idosos estudados, 91% tinha acesso ao tratamento com os ICH através do programa de medicamentos do CEAF. O CDR (Clinical Dementia Rating) não foi encontrado na totalidade dos prontuários analisados. Conclusão: A polifarmácia esteve presente em 63% dos idosos estudados e 77,8% faziam uso de algum MPI. A polifarmácia teve associação estatisticamente positiva com o número de comorbidades (p=0,0018), escolaridade (p=0,0017), hipertensão arterial (p=0,0013) e diabetes melittus (p<0,01) e o uso de MPI apresentou associação estatisticamente positiva com a polifarmácia (p<0,01). Dos medicamentos para tratar a ddA a rivastigmina aparece com a maior prevalência de uso, 34,6%, e 30,9% não faziam uso de nenhum tratamento para a ddA. Efeitos colaterais indesejáveis e doença em estado avançado, 28%, aparecem como os principais motivos de não uso de medicamentos.<br>Objectives: To analyze the profile of prescribing cholinesterase inhibitors and other medications in elderly patients with Dementia of Alzheimer's disease (DAD) met in Center of attention for the elderly in the city of Bauru/SP. Methods: Study of transverse, descriptive and analytical design, conducted with elderly patients with Dementia of Alzheimer's disease (DAD), in the Municipal Program of Attention to the older persons (PROMAI), from April to August 2015. Participants: 81 elderly (66 women and 15 men) who were monitoring the Municipal program of Attention to the Elderly (PROMAI). Results: Of the elderly 81.5% belonged to the female, 92.6% were 75 years or older, 64.2% were unmarried, 58% had up to 4 years of schooling, 60.5% had incomes up to 1 minimum salary, 60.5% had as main caregiver daughters and 90.1% lived with a family member. Among the most prevalent comorbid associated with dementias found Hypertension (29.6%), Diabetes mellitus (13.4%), Hypothyroidism (8.4%) and dyslipidemias (7.8%). Cognitive ability expressed by the MMSE was an average of 14.5 points. The polypharmacy was present in 63% of the elderly and among the elderly 77.8% made use of some MPI. The frequency of prescription of (the) ICH was: 54.9% rivastigmine, 33.3% Donepezil and 11.8% galantamina. Memantine had a prevalence of prescription of 2.5%. The reasons of the non-use of treatment for DAD, the undesirable side effects accounted for 28% of the cases. The elderly studied 91% had access to treatment with the ICH trough medication program CEAF. The CDR (Clinical Dementia Rating) was not found in all the analyzed records. Conclusion: Polypharmacy was present in 63% of the elderly studied and 77.8% made use of some MPI. The polypharmacy had statistically positive association with the number of comorbid (p<0.01), education (p < 0.01), hypertension (p<0.01) and melittus diabetes (p<0.01) and the use of MPI presented statistically positive association with polypharmacy (p < 0.01). Of the medications to treatment DAD the rivastigmine appears with the higher prevalence of use, 34.6% and 30.9% did not use any treatment for DAD. Undesirable side effects and advanced-stage disease, 28%, appear as the main reasons for non-use of medicines
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Darreh-Shori, Taher. "Molecular changes of acetylcholinesterase and butyrylcholinesterase in Alzheimer patients during the natural couse of the disease and treatment with cholinesterase inhibitors : insight into neurochemical mechanisms affecting the progression of the disease /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-547-X/.
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Bolea, Tomás Irene. "Study of new propargylamine and donepezil-derived compounds as multitarget agents for the treatment of alzheimer’s disease." Doctoral thesis, Universitat Autònoma de Barcelona, 2011. http://hdl.handle.net/10803/79083.
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El compuesto PF9601N es un derivado de propargilamina y un potente inhibidor irreversible de la enzima monoamino oxidasa B (IMAO-B) el cual fue identificado por nuestro grupo tras una extensiva búsqueda de potenciales IMAOs. Además de su potente capacidad inhibidora, el PF9601N posee varias propiedades neuroprotectoras demostradas en varios modelos animales y celulares de la enfermedad de Parkinson (EP). Estos efectos, los cuales han sido relacionados con la presencia de la propargilamina en su estructura, están mediados por acciones en vías involucradas en la neurodegeneración observada en otras enfermedades neurodegenerativas como la enfermedad de Alzheimer (EA). Así, para estudiar más en detalle las propiedades beneficiosas del PF9601N investigamos sus efectos en un modelo in vivo de excitotoxicidad, un mecanismo implicado en el daño neuronal observado en las enfermedades neurodegenerativas. El hallazgo de que el PF9601N era capaz de evitar el daño excitotóxico mediante la disminución de la liberación inducida de glutamato y aspartato, y el aumento de la liberación de taurina así como mediante la prevención de la activación glial y la apoptosis proporcionó un valor añadido a este compuesto para ser considerado en la terapia de estas enfermedades.
El tratamiento actual para la EA se basa principalmente en el uso de inhibidores de las enzimas colinesterasas (IChEs). Sin embargo, estos fármacos no son capaces de disminuir la progresión de la enfermedad y sólo producen una mejora temporal de los síntomas. Actualmente está ampliamente aceptado que la EA es una enfermedad multifactorial. En este contexto, la aproximación farmacológica más novedosa, conocida como aproximación de los MTDL (de las siglas en inglés “ligandos dirigidos hacia múltiples dianas”), propone el uso de compuestos multifuncionales capaces de abrazar varias propiedades biológicas. Esta tesis se centra en el estudio de la relación estructura-actividad (REA) así como la evaluación biológica de varios compuestos híbridos especialmente diseñados y sintetizados para actuar sobre múltiples factores involucrados en la EA. Los compuestos híbridos combinan la porción de bencilpiperidina de Donepecilo, un anticolinesterásico ampliamente utilizado en el tratamiento de la enfermedad, con el grupo propargilamina o indolil propargilamina presente en PF9601N, con el objetivo de obtener un compuesto capaz de retener la capacidad inhibidora de MAO así como las propiedades neuroprotectoras y antiapoptóticas de PF9601N. El trabajo presentado en esta tesis demuestra que algunos de los compuestos híbridos son potentes IMAOs (rango nM) y moderadamente potentes IChEs (rango subM). De entre todos los compuestos evaluados, ASS234 resultó ser un potente inhibidor de la agregación del péptido β−amiloide (A) y fue capaz de ejercer una acción protectora frente a la toxicidad inducida por Aβ y H2O2 en células neuronales.
En resumen, los datos presentados en esta tesis doctoral sugieren que el compuesto ASS234 es un compuesto multidiana muy prometedor que podría tener un papel modificador en la EA dada su demostrada capacidad de interactuar con varias dianas involucradas en la patogénesis de esta enfermedad.<br>PF9601N is a propargylamine-containing irreversible monoamine oxidase B inhibitor (MAOBI) previously identified by our group in an extensive screen of potential MAOIs. Besides its potent inhibitory capacity, it possesses several neuroprotective properties demonstrated in different animal and cellular models of Parkinson’s disease (PD). The beneficial effects of PF9601N, which have been related to the propargylamine group present in the molecule, are mediated through actions in pathways that are commonly involved in the neurodegeneration observed in other neurodegenerative disorders such as Alzheimer’s disease (AD), thus making this molecule a promising agent in the therapy of this disease as well. Thus, to study the beneficial properties of PF9601N in depth, we investigated its effects against an in vivo model of excitotoxicity, an important mechanism involved in the neuronal damage observed in neurodegenerative diseases. The finding that PF9601N was able to prevent the induced excitotoxic damage by decreasing the evoked release of excitatory neurotransmitters and decreasing the output of the inhibitory and neuroprotective taurine as well as preventing the induced glial activation and apoptosis gave more value to this compound to be considered in the therapy.
The current treatment for AD is the use of cholinesterase inhibitors (ChEIs) although there is also a NMDA receptor antagonist. However, far from stopping the disease’s progression, these drugs only produce a temporary symptomatic benefit, thus highlighting an urgent need to provide real disease-modifying drugs. At present, the most accepted notion is that AD is a multifactorial disease caused by many different factors and thus drug therapy with multifunctional compounds, the so-called multi-target-directed ligand (MTDL) approach, embracing diverse biological properties will have noticeable advantages over individual-target drugs or cocktails of drugs. In this context, this thesis focuses on the structure-activity relationship (SAR) study and the biological evaluation of different hybrid compounds specifically designed and synthesised to target multiple factors involved in AD. The hybrid molecules combine the benzyl piperidine moiety of Donepezil, a commonly used anticholinesterasic for the treatment of AD, with the propargylamine or the indolyl propargylamine substructure of PF9601N, with the aim of retaining the MAO inhibitory capacity as well as the neuroprotective and antiapoptotic properties observed for this compound. The work presented in this thesis demonstrates that some hybrid compounds are potent MAOIs (nM range) and moderately potent ChEIs (submicroM range). Among them, ASS234 has also been shown to reduce Αβ fibrillogenesis, and to protect neuronal cells from A and H2O2 toxicity. Thus, this compound has proved to be able to block the Aβ-induced cell death in two ways: by preventing caspase cleavage and activation and blocking LDH release.
Overall, the present data suggest ASS234 as a promising MTDL that may have a potential disease-modifying role in the treatment of AD since it is able to interact with diverse targets involved in the pathogenesis underlying AD.
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Teponnou, Gerard A. Kenfack. "Tacrine, trolox and tryptoline as lead compounds for the design and synthesis of multi-target drugs for Alzheimer's disease therapy." Thesis, University of the Western Cape, 2016. http://hdl.handle.net/11394/5344.
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Magister Pharmaceuticae - MPharm<br>The cascade of neurotoxic events involved in the pathogenesis of Alzheimer's disease may explain the inefficacy of currently available treatment based on acetylcholinesterase inhibitors (AChEI - donepezil, galantamine, rivastigmine) and N-methyl-D-aspartate (NMDA) antagonists (memantine). These drugs were designed based on the "one-moleculeone- target" paradigm and only address a single target. Conversely, the multi-target drug design strategy increasingly gains recognition. Based on the versatile biological activities of tacrine, trolox and β-carboline derivatives, the attention they have received as lead structures for the design of multifunctional drugs for the treatment of Alzheimer's disease, and the topology of the active site of AChE, we have designed tacrine-trolox and tacrine-tryptoline hybrids with various linker chain lengths. The aim with these hybrids was to provide additive or synergistic therapeutic effects that might help overcome the limitation of current anti Alzheimer's disease drugs. All synthesized compounds were designed from lead structures (tacrine, tryptoline and trolox) to obtain cholinesterase (ChE) multisite binders and multifunctional AD agents. The study was rationalized by docking all structures in the active site of TcAChE using Molecular Operating Environment (MOE) software before proceeding with the synthesis. ChE inhibition was assessed in a UV enzyme inhibition assay using Ellman's method. Antioxidant activities were assessed using the 2, 2-diphenyl-1-picrylhydrazyl (DPPH.) absorbance assay. The hybrids containing the trolox moiety (compounds 8a-e) showed moderate to high AChE inhibitory activity in the nano to micro molar range (IC₅₀: 17.37 - 2200 nM), BuChE inhibition was observed in the same range (IC₅₀: 3.16 – 128.82 nM), and free radical scavenging activities in micro molar range (IC50: 11.48 – 49.23 µM). These are comparable or slightly higher than their reference compounds donepezil (AChE IC₅₀ = 220 nM), tacrine (BuChE IC₅₀: 14.12 nM), and trolox (DPPH IC₅₀: 17.57 µM). The hybrids with longer linker chain lengths, 6 and 8 carbons (8d and 8e), showed better ChE inhibitory activity than the shorter ones, 2, 3, and 4 carbons (8a-c respectively). This correlates well with literature. Free radical scavenging activities, however, seems not to be significantly affected by varying linker chain lengths. The hybrid compound (14) containing the tryptoline moiety linked with a 7 carbon spacer displayed the best AChE and BuChE inhibitory activity (IC₅₀ = 17.37 and 3.16 nM) but poor free radical scavenging activity. Novel anti-Alzheimer's disease drugs
with multi-target neuroprotective activities were thus obtained and hybrid molecules that exhibit good ChE inhibition (8d, 8e and 14) and anti-oxidant (8d and 8e) activity were identified as suitable candidates for further investigation.<br>National Research Foundation (NRF)
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Mzezewa, Sheunopa C. "Synthesis and evaluation of 7-substituted 3-propargylamine coumarin derivatives as multifunctional monoamine oxidase and cholinesterase inhibitors for Alzheimer’s Disease treatme." University of Western Cape, 2020. http://hdl.handle.net/11394/7399.
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>Magister Scientiae - MSc<br>Alzheimer’s Disease (AD) is a neurodegenerative disease which results from the irreversible loss of neurons in the brain. The disease is characterized by progressive cognitive impairment with recurrent short-term memory loss. AD is the leading cause of dementia and 4th leading cause of death in the elderly. Success in the treatment of AD has been limited, with drugs only treating it at a symptomatic level due to its pathology being complex and poorly understood. However, it is known that the cholinesterase and MAO-B enzymes play an important role in the disease through their association with production of amyloid plaques and oxidative stress respectively, two mechanisms associated with cell death and the symptoms seen in AD.
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Kadir, Ahmadul. "Functional brain activity in Alzheimer patients as studied by multi-tracer positron emission tomography : effects of treatment with cholinesterase inhibitors /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-357-3/.
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Toublet, Francois-Xavier. "Conception, synthèse et évaluation biologique de prodrogues pléiotropes d'intérêt dans la maladie d'Alzheimer." Thesis, Normandie, 2019. http://www.theses.fr/2019NORMC429.
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La maladie d’Alzheimer (MA) est une maladie neurodégénérative multifactorielle encore mal comprise. Les médicaments actuellement utilisés contre la MA, principalement des inhibiteurs de cholinestérases (IChE), sont considérés comme ayant un service médical rendu insuffisant et sont responsables d’effets secondaires délétères. Les ChE suscitent toutefois un regain d’intérêt grâce à la découverte du rôle de chaperon joué dans la pathogenèse de la MA. Ces enzymes pourraient également servir de protéine d'activation pour les promédicaments pléiotropes. En effet, l'inhibition des ChE centrales par des molécules possédant un groupement carbamate, conçus pour passer la barrière hématoencéphalique, et capables de se lier de manière covalente à l'enzyme permettrait de libérer des métabolites actifs dans le cerveau. Ceci pourrait constituer une approche plus efficace sur le plan clinique, qui en permettrait de diminuer les effets secondaires périphériques.Cette thèse a permis d’ouvrir de nouvelles voies de synthèse et a conduit à des études in vitro et in vivo de promédicaments pléiotropes ciblant à la fois l’AChE ou la BuChE et une autre cible thérapeutique telle que les récepteurs sérotoninergiques 5-HT4 et / ou 5-HT6, mais aussi l’étude de composés innovants : les ligands autoimmolables pléiotropes.Cette polyactivité pourrait apporter aux patients atteints de MA de réels bénéfices thérapeutiques à la fois symptomatiques et curatifs, ainsi qu’une relative innocuité<br>Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease which is still poorly understood. The drugs currently used against AD, mainly cholinesterase inhibitors (ChEI), are considered clinically insufficient and are responsible for deleterious side effects. ChE are, however, currently receiving renewed interest through the discovery of a chaperone role played in the pathogenesis of AD. But ChE could also serve as an activating protein for pleiotropic prodrugs. Indeed, inhibiting central ChE with brain-penetrating designed carbamates which are able to covalently bind to the enzyme and to concomitantly liberate active metabolites in the brain could constitute a clinically more efficient approach which, additionally, is less likely to cause peripheral side effects.This thesis has opened up new synthetic pathways, coupled with in vitro and in vivo studies of pleiotropic prodrugs targeting both AChE and BuChE with another therapeutic target such as 5-HT4 and / or 5-HT6 serotoninergic receptors. But also the study new compounds very interesting and never yet describes: pleiotropic self-immolative linkers.This plural activity could bring to AD patients effective, relatively safe, symptomatic and disease-modifying therapeutic benefits
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Bitencourt, Michelle 1985. "Modelagem MIA-QSAR de inibidores de acetilcolinesterase = MIA-QSAR modeling of inhibitors actylcholinesterase." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311808.
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Orientador: Roberto Rittner Neto<br>Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas<br>Made available in DSpace on 2018-08-21T10:40:13Z (GMT). No. of bitstreams: 1
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Previous issue date: 2012<br>Resumo: O presente trabalho trata de um estudo sobre compostos que se comportam como inibidores da acetilcolinesterase, uma importante enzima do processo de cognição. A acetilcolinesterase atua na hidrólise da acetilcolina, responsável pela comunicação entre os neurônios. Uma das modalidades para o design racional de fármacos é a estimativa de propriedades biológicas de novas moléculas utilizando métodos computacionais. Análise quantitativa entre estrutura química e atividade biológica (QSAR) é uma dessas técnicas. No presente trabalho, análise multivariada de imagens aplicada em QSAR (MIA-QSAR) foi utilizada para se construírem modelos QSAR preditivos para uma série congênere de carbamatos com atividade anticolinesterásica. Os bons resultados estatísticos da modelagem credenciaram o modelo MIA-QSAR construído a predizer a atividade biológica de alguns novos derivados, potencialmente úteis para o tratamento do Mal de Alzheimer<br>Abstract: The present work describes the study of some compounds which act as acetylcholinesterase inhibitors a very important enzyme in the cognitive process. zAcetylcholinesterase is responsible by the hydrolysis of acetylcholine, which accounts for the communication among the neurons. One of the approaches for the rational pharmaceuticals design is the estimation of the biological properties of new molecules using computational methods. The quantitative analysis between chemical structure and biological activity (QSAR) is one of these techniques. In the present work, the multivariate analysis of images applied in QSAR (MIA-QSAR) was employed for building predictable QSAR models for a congenial series of carbamates which exhibit anticholinesterase activity. The significant statistical results from this treatment enabled the MIA-QSAR model thus obtained to reliably predict the biological activity of some new derivatives, as potentially useful for the Alzheimer Disease treatment<br>Mestrado<br>Ciencias Biomedicas<br>Mestra em Ciências Médicas
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Talib, Leda Leme. "Biomarcadores na doença de Alzheimer: GSK3B e PLA2 na resposta aos inibidores de colinesterase." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/5/5142/tde-24062014-163102/.
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A Doença de Alzheimer (DA) é uma desordem neurodegenerativa progressiva que causa comprometimento cognitivo e demência. O diagnóstico é baseado em parâmetros clínicos, mas sua confirmação é post-mortem, após avaliação patológica durante a autópsia. Os tratamentos disponíveis para a DA são os inibidores da colinesterase (IChEs) e os antagonistas de receptores de N-metil-D-aspartato (NMDA), sendo que os IChEs compõe o principal grupo. Diversos estudos tem mostrado um efeito neuroprotetor dos IChEs, levando a alterações na patogênese da DA. Avaliar e mensurar essas alterações são papeis atribuídos aos biomarcadores. Neste sentido podemos destacar a fosfolipase A2 (PLA2), a principal responsável pelo metabolismo de fosfolípides de membrana, e que tem sido achada diminuída na DA, assim como a glicogênio sintase-quinase (GSK), responsável pela fosforilação da proteína Tau, que é um dos processos alterados na DA. O objetivo deste trabalho foi avaliar o efeito do tratamento com IChE sobre a atividade da PLA2 e expressão da GSK3B em plaquetas de 30 pacientes com DA após 3 e 6 meses de tratamento. Como grupo controle foram investigados 42 individuos idosos sem doença neurodegenerativa. Encontramos nos pacientes com DA antes do tratamento uma diminuição da atividade da iPLA2 quando comparada ao grupo controle. Após três e seis meses de tratamento a PLA2 aumentou, voltando ao nível dos controles. Os pacientes que apresentaram um aumento maior da iPLA2 apos 3 meses de tratamento apresentaram melhora cognitiva mais marcante após seis meses de tratamento, avaliado pelo CAMCOG. Apos 6 meses de tratamento encontramos um inativação da GSK3B, medida por um aumento em sua forma fosforilada. Nossos resultados sugerem que o donepezil apresenta propriedades modificadoras na doença de Alzheimer, e ainda que a medida da atividade da iPLA2 poderia ser usada como marcador de resposta terapêutica ao donepezil e, possivelmente, a outros IChEs, na doença de Alzheimer<br>Alzheimer\'s disease (AD) is a progressive neurodegenerative disorder that causes dementia and cognitive impairment. The Diagnosis is based on clinical parameters, but confirmation is post-mortem after pathologic evaluation during autopsy. The treatments available for AD are cholinesterase inhibitors (IChEs) and N-methyl-D-aspartate (NMDA) antagonists. The main group comprises the IChEs. Several studies have shown a neuroprotective effect of IChEs, leading to alterations in the pathogenesis of AD. Evaluate and measure these changes are assigned to biomarkers. In this regard we can highlight the phospholipase A2 (PLA2) the main enzyme in membrane phospholipids metabolism and that has been found decreased in AD as well as Glycogen Synthase kinase (GSK), a major responsible for tau phosphorylation which is one processes altered in AD. The objective of this study was to evaluate the effect of treatment with IChE on PLA2 activity and GSK3B expression in platelet of 30 AD patients after 3 and 6 months of treatment. The control group comprised 42 elderly individuals without neurodegenerative disease The results obtained were a decreased iPLA2 activity in patients with AD before treatment as compared to controls. After 3 and 6 months of treatment, we observed a significant increase in iPLA2 activity, restoring enzymatic activity similar to that observed among control. The patients who showed higher iPLA2 activity in the first three months were those showing cognitive improvement after six months of treatment, measured by CAMCOG. After 6 months of treatment a GSK3B inactivation were found, measured by an increase in its phosphorylated form. Our results suggest that donepezil present modifying properties in Alzheimer disease and that iPLA2 activity measurement could be used as a marker of therapeutic response to donepezil and possibly other IChEs in Alzheimer\'s disease
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Sarno, Tamires Alves. "Efeito de inibidor da acetilcolinesterase no metabolismo da proteína precursora do amiloide em plaquetas." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/5/5142/tde-18112016-112848/.
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A doença de Alzheimer (DA) é uma doença neurodegenerativa e a principal causa de demência em idosos. Os mecanismos fisiopatológicos mais envolvidos na DA são: o acúmulo do peptídeo beta amiloide (A?) em agregados extracelulares, e a formação dos emaranhados neurofibrilares (ENF). A Proteína Precursora do Amiloide (APP) é clivada pelas secretases alfa (ADAM10), beta (BACE1) e y (Presenilina 1 [PSEN1]). As plaquetas contêm 95% da APP circulante e possuem toda a maquinaria necessária para estudar perifericamente a APP e suas secretases. A pesquisa de biomarcadores na DA tem como objetivo identificar, em vida, os indicadores do processo patogênico em fluídos corporais e/ou por métodos de imagem cerebral. O objetivo do presente estudo foi investigar proteínas envolvidas no metabolismo da APP em plaquetas de pacientes com DA e o potencial de modificação destas vias pela ação do tratamento com cloridrato de donepezila. Para tanto foram analisadas amostras de 23 pacientes com DA leve ou moderada, avaliados antes e depois de 6 meses de tratamento e 38 indivíduos idosos cognitivamente saudáveis (controles). As variáveis de desfecho estudadas foram: (1) expressão protéica de ADAM10, BACE1 e PSEN1; (2) expressão protéica dos metabólitos secretados da APP de 110 e 130kDa, possibilitando o cálculo da razão de APP (rAPP); e (3) atividade enzimática das APP-secretases ADAM10 e BACE1. Foram utilizados os métodos de western blotting e o fluorimétrico. Encontramos, nos pacientes com DA pré-tratamento, uma diminuição da rAPP em relação aos controles; porém, não identificamos diferenças após seis meses de tratamento. Os níveis de ADAM10 mostraram-se menores em pacientes com DA na avaliação basal quando comparados aos controles, mas também sem modificação com o tratamento, o tratamento mostrou-se associado a uma redução da expressão de BACE1 em pacientes com DA, embora não tenhamos encontrado diferenças entre pacientes e controles na avaliação basal. A expressão de PSEN1 mostrou-se menor nos pacientes com DA pré-tratamento quando comparada aos controles, sem contudo haver alteração em resposta ao tratamento. Quanto à atividade enzimática de ADAM10 e BACE1, não observamos diferenças nos valores pré e pós-tratamento. Nossos achados reforçam a utilidade da utilização de plaquetas como matriz biológica para o estudo do metabolismo da APP em tecidos periféricos e para a investigação de efeitos modificadores da patogenia da DA a partir do tratamento com drogas antidemência<br>Alzheimer\'s disease (AD) is a neurodegenerative disease and the major cause of dementia in the elderly. The main mechanisms in AD are: extracellular aggregates of beta amyloid peptide (Abeta) and neurofibrillary tangles formation (NFT). Amyloid Precursor Protein (APP) is cleaved by the secretases alfa (ADAM10), beta (BACE1) and ? (Presenilin 1 [PSEN1]). Platelets containing 95% of the circulating APP and possess all the machinery necessary to study peripherically APP and its secretases. The search for biomarkers in AD aims to identify, in life, the pathogenic process indicators in body fluids and/or brain image methods. The aim of this study was to investigate proteins involved in APP metabolism in platelets of AD patients, and the potential modification of these pathways by treatment with Donepezil hydrochloride. Therefore, 23 patients with mild to moderate AD evaluated before and after 6 months treatment and 38 healthy elderly subjects (controls) were analyzed. Outcome variables were: (1) ADAM10, BACE1 and PSEN1 expression; (2) APP secreted metabolites expression (110 and 130kDa), allowing the APP ratio (rAPP) estimate; (3) APP-secretase ADAM10 and BACE1 enzymatic activity. Western blotting and fluorimetric methods were used. We found in AD patients pre-treatment, a decrease of rAPP compared to controls; however, we did not identify differences of this parameter after six months of treatment. The ADAM10 levels were lower in AD patients at baseline when compared to controls, however no differences were observed after treatment. Treatment was associated with a reduction of BACE1 expression in AD patients, although we have not found differences between patients and controls at baseline. PSEN1 expression was lower in pre-treatment AD patients compared to controls. No differences were observed after treatment. Concerning to BACE1 and ADAM10 enzymatic activity, we did not observe differences in pre and post-treatment. Our findings strengthen the use of platelets as a biological matrix for the APP metabolism as well as the modifying effects on AD pathogenicity of antidementia drugs
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Piovesana, Magda Cristina Flaitt Sanches. "Doença de Alzheimer: estudos sobre acurácia diagnóstica nos pacientes em uso de anticolinesterásicos e a percepção dos familiares quanto aos seus benefícios." Faculdade de Medicina de São José do Rio Preto, 2010. http://bdtd.famerp.br/handle/tede/93.
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Previous issue date: 2010-12-03<br>This study was realized in the Neurogeriatrics Clinic Base Hospital of Medicine Faculty in Sao Jose do Rio Preto. Objective: To study the diagnostic accuracy in Alzheimer's disease in patients treated with cholinesterase inhibitors available by Pharmacy of Exceptional Medicines and verify the impact of this therapy by the perception of families or caregivers. Methods: Cross-sectional study (prospective) the sample selection was random, in the period between May 2008 and February 2010. The certification of the diagnosis of Alzheimer's disease followed NINCDS-ADRDA, complemented by Scale Clinical Evaluation of Dementia (CDR), Scale for the Assessment of Disability in Dementia (DAD) and interviews with family and / or caregiver (structured questionnaire). Statistically used - to cross-frequency tables, chi-square test, Fisher exact test, Kruskal-Wallis test, t-test and principal component analysis, a significance level of 5%. Results: Participants 106 patients, categorized into Group MC, when met criteria for AD and the DNMC when not fulfilled. In the MC Group was observed, higher age (mean 78anos), 85% of patients with MMSE lower than expected, worse performance on the DAD (median 25), according to the severity 37% were in the mild stage, 48% at moderate and 15% at severe stage, the treatment time was larger and in full doses of anticholinesterase. In the DNMC Group ages were younger (mean 74anos), 50% of patients with MMSE lower than expected, better performance in the DAD (median 75) with less treatment time and at subtherapeutic doses. In EQ, in relation to the memory of the MC Group all patients showed a deficit, 18% improved and 54% worsened; 13% in the DNMC Group showed no deficit, 48% improved and 13%
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worsened. In the assessment of temporal orientation in the MC group, 8% of the patients had no disorientation, 8% improved and 62% worsened, since the DNMC Group, 37% had no disorientation, 30% improved and 16% worsened. In Topographical orientation, in the patients in MC Group, 77% did not go out alone and in the DNMC Group 54% had no difficulty in orienting themselves. In the MC Group, 14 of the 15 neuropsychiatric symptoms were more often, only depression was higher in the DNMC. In carrying out activities of daily living, patients of MC Group worsened in all the items in relation to the DNMC Group. Conclusions: It was observed that 51% of patients using anticholinesterases did not meet criteria for the diagnosis of AD likely, older age was associated with the MC Group, which had downgraded MMSE, worse performance in DAD and in the QE. In Structured Questionnaire the patients of DNMC Group showed a different behavior, perhaps by having other diagnoses, presented better performance.<br>Estudo realizado no Ambulatório de Neurogeriatria do Hospital de Base da Faculdade de Medicina de São José do Rio Preto. Objetivos: Estudar a acurácia diagnóstica na Doença de Alzheimer nos pacientes em tratamento com anticolinesterásicos disponibilizados pela Farmácia de Medicamentos Excepcionais e verificar o impacto desta terapêutica pela percepção dos familiares ou cuidadores. Métodos: Estudo transversal (prospectivo); a seleção da amostra ocorreu de forma aleatória, no período compreendido entre maio de 2008 e fevereiro de 2010. A certificação do diagnóstico da Doença de Alzheimer obedeceu critérios do NINCDS-ADRDA, complementada pela Escala de Avaliação Clínica da Demência (CDR), Escala para Avaliação de Incapacidades na Demência (DAD) e entrevista com familiar e ou cuidador (Questionário estruturado). Estatisticamente utilizaram-se tabelas de frequências cruzadas, teste Qui-Quadrado, teste exato de Fisher, teste de Kruskal-Wallis, teste t e análise de componentes principais, nível de significância 5%. Resultados: Participaram 106 pacientes, categorizados em Grupo PC, quando preenchiam os critérios para DA e Grupo ÑPC quando não preenchiam. O Grupo PC constituiu-se de 52 pacientes e o Grupo ÑPC de 54 pacientes. No Grupo PC observou-se idade elevada (média 78anos), 85% dos pacientes com MEEM abaixo do esperado, desempenho pior na DAD (mediana 25); de acordo com a gravidade 37% estavam na fase leve, 48% na fase moderada e 15% na fase grave, o tempo de tratamento era maior e com doses plenas de anticolinesterásicos. No Grupo ÑPC as idades eram menores (média de 74anos), 50% dos pacientes com MEEM abaixo do esperado, desempenho
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melhor na DAD (mediana 75), com menos tempo de tratamento e em doses subterapêuticas. No Questionário estruturado (QE), em relação à memória todos pacientes do Grupo PC apresentaram déficit, 18% melhoraram e 54% piorou e no Grupo ÑPC 13% não apresentaram déficit, 48% melhoraram e 13% piorou. Na avaliação da orientação temporal no Grupo PC, 8% dos pacientes não apresentaram desorientação, 8% melhoraram e 62% pioraram, já no Grupo ÑPC, 37% não apresentavam, 30% melhoraram e 16% pioraram. Na orientação topográfica, nos pacientes do Grupo PC, 77% não saíam sozinhos e no Grupo ÑPC 54% não apresentavam dificuldade em orientar-se. No Grupo PC, 14 dos 15 sintomas neuropsiquiátricos apresentavam maior freqüência; apenas depressão foi maior no Grupo ÑPC. No desempenho das Atividades de Vida Diária, os pacientes do Grupo PC pioraram em todos os itens em relação ao Grupo ÑPC. Conclusões: Foi observado que 51% dos pacientes que utilizavam anticolinesterásicos não preencheram os critérios para o diagnóstico de DA provável, idade elevada foi associada ao Grupo PC, que apresentou MEEM rebaixado, desempenho pior na DAD e no QE. No Questionário Estruturado os pacientes do Grupo ÑPC mostraram um comportamento diferente, talvez por ter outros diagnósticos, apresentaram desempenho melhor.
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Ávila, Renata. ""Reabilitação neuropsicológica dos processos de memória e das atividades da vida diária em pacientes com doença de Alzheimer leve e moderada"." Universidade de São Paulo, 2004. http://www.teses.usp.br/teses/disponiveis/5/5160/tde-24082005-150424/.
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O efeito da reabilitação neuropsicológica foi verificado em uma amostra de 16 pacientes com diagnóstico de doença de Alzheimer leve e moderado. Após ensaio clínico aberto com rivastigmina por 4 meses, os pacientes foram divididos em três grupos: sessões em grupo, individual e em casa com o cuidador. Os três grupos realizaram o mesmo protocolo de reabilitação, e antes e depois das 22 semanas de tratamento foram avaliados pelos mesmos instrumentos. Os resultados indicaram que as sessões em grupo são mais eficientes para sintomas psiquiátricos; individual para atividades da vida diária; e em casa, dependendo do perfil do paciente e do cuidador, pode ser uma alternativa de tratamento<br>The effect of a neuropsychological rehabilitation was tested in a sample of 16 patients with mild and moderate Alzheimer disease. After an open trial with rivastigmine for 4 months, they were divided in 3 groups: group sessions, individualized and at home with a caregiver. All 3 groups fulfilled the same rehabilitation protocol, and just before and after the 22 week period of treatment, all patients were evaluated using the same instruments. The results of the study indicated that group session are more effective for psychiatric symptoms, individualized sessions for activities of daily living training and at home training, depending on the patient's and caregiver's profiles, can be an option for treatment of these patients
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Lee, David. "Age-Related Differences in In-vitro Sensitivity to Inhibition of Human Red Blood Cell Acetylcholinesterase and Plasma Butyrylcholinesterase by the Cholinesterase Inhibitors Physostigmine (PHYS), Pyridostigmine (PYR), Donepezil (DON) and Galantamine (GAL)." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1937.
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Alzheimer’s disease (AD) is a chronic, progressive neurodegenerative disorder, characterized clinically by a progressive loss of memory, cognitive function, ability to care for oneself and psychiatric symptoms. First-line agents for the treatment of AD are ChE inhibitors (DON, GAL), whose modest clinical efficacy and the high incidence of dose-limiting toxicities limit their clinical utility. In addition to AD, ChE inhibitors (PYR) are used for other medical conditions, such as myasthenia gravis (MG). Furthermore, ChE inhibitors (PYR) are used by military personnel prophylactically if impending exposure to chemical warfare agents, e.g., soman, is suspected. The purpose of this research project was to understand the effect of age on the in-vitro sensitivity of ChE inhibitors in human RBCs and plasma. Understanding possible covariates, such as age and gender, may assist in optimizing dosing regimens of ChE inhibitors and/or developing newer ChE inhibitors with better adverse effect profiles. Plasma PHYS concentrations were measured by a validated HPLC-FD method. RBC AChE activity and plasma BuChE activity were measured by a modified Ellman’s colorimetric method using the model substrates, acetylthiocholine and butyrylthiocholine, respectively. The kinetics of RBC and plasma ChE activity followed Michaelis-Menten kinetics. Acetylthiocholine was found to be a nonselective substrate (RBC AChE Km = 73 μM; plasma BuChE Km = 117 μM); while butyrylthiocholine was a selective substrate for plasma BuChE (RBC AChE Km = 130,000 μM; plasma BuChE Km = 72 μM). For the following studies, RBC AChE activity was measured using acetylthiocholine as the substrate and plasma BuChE activity was measured using butyrylthiocholine as the substrate. This research project was performed in two parts: First, mechanistic studies of PHYS, PYR, DON and GAL, explored and determined the mechanism of in-vitro inhibition of RBC AChE and plasma BuChE inhibition, as well as the in-vitro degradation of PHYS in human whole blood, plasma and RBC. PHYS was rapidly degraded in human whole blood, RBC and plasma and followed Michaelis-Menten kinetics but its degradation clearance - scaled to whole blood clearance - was only predicted to account for 4-6% (i.e., 195-261 ml/min) of the reported total body clearance for PHYS (4500 ml/min). RBCs were responsible for 60% of the whole blood clearance while plasma accounted for 40% of the whole blood clearance. Inhibition results indicated that both PHYS and PYR were nonselective and rapid suicide ChE inactivators. PYR inactivated RBC AChE more rapidly at low concentrations and inactivated plasma BuChE more rapidly at high concentrations, but inactivated both more rapidly than PHYS. PHYS was a more potent inactivator than PYR with a Ki for RBC AChE of 0.011 μM and 0.063 μM, respectively, and 0.023 μM and 0.036 μM, respectively for plasma BuChE. DON was found to be a noncompetitive inhibitor for RBC AChE (Ki,noncomp = 114 μM), but a competitive inhibitor for plasma BuChE (Ki,comp = 213 μM). GAL was found to be a competitive inhibitor for both RBC AChE (Ki,comp = 66 μM) and plasma BuChE (Ki,comp = 358 μM). The second part involved a clinical study with ten young and nine elderly healthy subjects, balanced for gender, who donated blood for an in-vitro study in order to assess any age- and gender-related differences in in-vitro sensitivity to RBC AChE and plasma BuChE inhibition to all four ChE inhibitors. Elderly adults were found to be 2-3-fold less sensitive compared to the young adults for PHYS (BuChE Ki,pss; 0.010 and 0.015 μM, young and elderly, respectively) and PYR (AChE Ki,pss; 0.12 and 0.25 μM, young and elderly, respectively) only, while neither DON nor GAL showed any age-related differences in sensitivity. The observed differences for PHYS and PYR may be due to kinetic differences in ChE inactivation between young and aged adults, rather then a difference in binding affinities/potencies. These carbamate ChE inhibitors, presumably, have a slower decarbamoylation rate in younger adults than elderly adults, which leads to the observed difference in in-vitro sensitivity. The above in-vitro results were consistent with results of a meta-analysis: In a study by Knapp et al. (1991), young males (n=6), receiving 18 mg, 24 mg and 30 mg PHYS tablets, showed similar ex-vivo plasma BuChE sensitivity to (28 %/(ng/ml)) as the in-vitro sensitivity for young males in the current study (33 %/(ng/ml)). On the other hand, in the study by Men (2004), elderly males (n=8) and females (n=8), receiving 6.7 μg/kg PHYS as 30-minute infusion, showed similar ex-vivo RBC AChE sensitivity (12 %/(ng/ml)) as the in-vitro sensitivity for elderly subjects in the current study (9.7 %/(ng/ml)). This suggests that in-vitro measurement of ChE sensitivity is predictive of ex-vivo sensitivity in clinical studies. The study results suggest that elderly adults may require a 2-3-fold higher blood concentration than young adults to achieve the same ChE inhibition. This may explain why for epistigmine, an investigational carbamate ChE inhibitor for the treatment of AD, the maximum tolerated dose observed in young adults (40 mg single dose) was lower than for older adults (90 mg/day). Higher sensitivity in young adults prevented further dose escalation, while all elderly subjects tolerated higher doses. This research may have implications for other diseases and conditions, most notably MG and as a prophylaxis of nerve gases poisoning. As patients with MG age, they may become less sensitive to PYR, the most common symptomatic treatment for MG, and an increase in dose may be required. Further, older military personnel assigned to receive PYR, may require increased doses to achieve the targeted 10% RBC AChE inhibition, necessary to protect against nerve gas poisoning.
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Behl, Pearl. "Differential long-term cognitive, functional, and behavioral effects of cholinesterase inhibitors in Alzheimer's disease." 2006. http://link.library.utoronto.ca/eir/EIRdetail.cfm?Resources__ID=449939&T=F.
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Bailey, Jack. "An analysis of modifiable risk factors, genetic underpinnings, and current medications for Alzheimer's disease." Thesis, 2018. https://hdl.handle.net/2144/33007.
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Alzheimer’s disease (AD) is a widespread neurodegenerative disorder that affects tens of millions of patients worldwide. Throughout the last two decades an incredible amount of time and resources have been funneled into hopefully finding medications that would provide a cure. Unfortunately, no such compound has been identified and instead the only FDA approved medications for AD to date target symptomatic management and may not even be effective for longer than a couple of years. To this end, this paper sets out to identify modifiable risk factors for AD as well as provide recommendations for clinicians on how best to utilize the tools currently available to them to treat AD. Additionally this paper addresses common flaws in AD clinical trial study designs and provides future research directions to expand outside of the popular amyloid hypothesis and instead potentially focus on a multi-pathway mechanism of the disease. The following thesis will outline several potential mechanisms that can lead to the hallmark pathologies seen in AD, primarily amyloid deposition and neurofibrillary tangles as well as neuronal death. The majority of commercial and research interest into AD has been focused on the amyloid hypothesis and the notion that stopping the formation of amyloid plaques would stop the disease course. However, in recent years other mechanisms and neurotoxic pathways such as inhibition of tricarboxylic acid (TCA) cycle enzymes, neuroinflammation, and tauopathy have been shown to contribute both to the formation of amyloid plaques as well as contributing to AD pathology in their own right. The modifiable risk factors explored in this paper include the effects of triglycerides as well as intake of antioxidant vitamins and omega-3-fatty acids, both of which are beneficial for brain health. This paper will also highlight some of the extensive research on the Apolipoprotein E gene and the effects the various alleles have on AD risk. These being the putative protective effect of the APOE2 allele, “neutral” effect of the most commonly found APOE3 allele, and finally the deleterious effects of the APOE4 allele, believed to be the strongest genetic risk factor for late-onset AD.
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"High-level expression of recombinant acetylcholinesterase in silkworm larvae for screening of new inhibitors treating Alzheimer's disease." 2012. http://library.cuhk.edu.hk/record=b5549119.
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乙酰膽鹼酯酶主要存在於神經肌肉接頭處和中樞神經系統的膽鹼能突觸處，是神經遞質傳遞過程中極其重要的膽鹼水解酶。研究表明，阿茲海默病人的大腦通常呈現出乙酰膽鹼酯酶的異常表達和分佈，並伴隨著β澱粉樣蛋白的沉澱。目前，乙酰膽鹼酯酶抑製劑是治療阿茲海默症的主要臨床藥物。<br>在本研究中，我們利用Bac-to-Bac 桿狀病毒表達系統分別使人類和雞泡魚的重組乙酰膽鹼酯酶基因在家蠶幼蟲裡得到了高效的表達。我們將乙酰膽鹼酯酶的cDNA序列克隆到pFastBac{U+2122} Dual質粒的多角體蛋白啟動子下游。為了易於監控蛋白表達水平，橙色熒光蛋白的cDNA序列也被克隆到同一個質粒的p10啟動子下游。此外，我們將多聚組氨酸標籤加在了乙酰膽鹼酯酶基因的碳端，從而使蛋白的純化效率得到了顯著提高。我們通過皮下注射含有乙酰膽鹼酯酶的重組bacmid對五齡期的家蠶幼蟲進行了病毒轉染。感染後約4-7天，重組乙酰膽鹼酯酶在蠶蟲內成功得到了表達。酶促反應動力學研究表明，重組乙酰膽鹼酯酶的活性與來自相同物種的天然乙酰膽鹼酯酶基本相似。這種高效率、低成本、高產量的蛋白表達方法可以為我們提供大量的重組乙酰膽鹼酯酶，用於體外篩選治療阿茲海默症的乙酰膽鹼酯酶抑製劑。<br>隨著對阿茲海默症分子學水平上的進一步了解，研究提出乙酰膽鹼酯酶可能通過外周陰離子位點誘導β澱粉樣多肽聚集, 從而形成澱粉樣纖維。因此，理想的乙酰膽鹼酯酶抑製劑應該既有抑制乙酰膽鹼酯酶的活性，又可以對抗β澱粉樣蛋白沉澱的毒性, 從而達到神經保護的作用。因此，我們採用AutoDock Vina軟件對ZINC數據庫內的天然化合物進行了兩輪虛擬篩選，篩選出的化合物理論上是可以同時作用於催化位點和外周陰離子位點。接下來，我們將對候選化合物進行體外驗證。<br>Acetylcholinesterase (AChE: EC 3.1.1.7) is the acetylcholine-hydrolyzing enzyme that plays an essential role on cholinergic neurotransmission at the synapses of the brain and at the neuromuscular junctions. Abnormal expression and localization of AChE have been observed together with Aβ deposits in the brain of Alzheimer’s disease (AD) patient. Currently, AChE inhibitors are clinically used as drugs for AD treatment.<br>In this study, we demonstrated high-level expressions of functional recombinant human AChE and Tetraodon nigroviridis AChE using Bac-to-Bac baculovirus expression system in silkworm Bombyx mori larvae. The cDNA of AChE was cloned into the polyhedrin (PH) promoter of the plasmid pFastBac{U+2122} Dual. To monitor the level of expression, the cDNA coding for an orange fluorescent protein (OFP2) was cloned downstream to the p10 promoter of the same vector. We engineered a polyhistidine-tag (His-tag) tail to the C-terminal of each AChE gene to facilitate the purification. Transfection was carried out by subcutaneous injection of the recombinant bacmid DNA containing the AChE gene into the silkworm larvae of 5th instar. Approximately 4-7 days of post-infection, the recombinant AChE was expressed in the hemolymph of infected larvae. The kinetic studies showed that the biological activities of the recombinant AChEs were comparable to that of natural ones from other sources. This rapid, low-cost, and high yield production method could provide us sufficient amount of recombinant AChE for in vitro screening of AChE inhibitors for AD treatment.<br>Further advances in understanding the molecular basis of AD have proposed that AChE promote the assembly of Aβ peptide into amyloid fibrils through interaction at the peripheral anionic site of AChE. Consequently, new classes of AChE inhibitors are expected to be able to inhibit the active site of AChE and, at the same time, to protect neurons from Aβ toxicity. Therefore, we applied two rounds of virtual screening of ZINC database using AutoDock Vina to obtain new potential inhibitors which might be able to targeting both of the active and peripheral sites of AChE. The compounds with good performances in both of the two rounds of screening would be validated by the sequential in vitro tests.<br>Detailed summary in vernacular field only.<br>Detailed summary in vernacular field only.<br>Detailed summary in vernacular field only.<br>Li, Shuo.<br>Thesis (M.Phil.)--Chinese University of Hong Kong, 2012.<br>Includes bibliographical references (leaves 105-124).<br>Abstracts also in Chinese.<br>Acknowledgements --- p.I<br>Abstracts (English) --- p.II<br>Abstracts (Chinese) --- p.IV<br>Table of Contents --- p.VI<br>List of Abbreviations --- p.IX<br>List of Figures --- p.XII<br>List of Tables --- p.XIV<br>Chapter Chapter 1 Introduction --- p.1<br>Chapter 1.1 --- Acetylcholine mediated neutotransmission in nervous system --- p.1<br>Chapter 1.2 --- Acetylcholineterase --- p.2<br>Chapter 1.3 --- Comparison of AChE and BChE --- p.3<br>Chapter 1.4 --- Molecular sturcture of AChE --- p.5<br>Chapter 1.5 --- Molecular diversity of AChE --- p.7<br>Chapter 1.5.1 --- Regulation at transcriptional level --- p.8<br>Chapter 1.5.2 --- Regulation at post-transcriptional level --- p.11<br>Chapter 1.5.3 --- Regulation at post-translational level --- p.12<br>Chapter 1.6 --- Classic functions of AChE --- p.15<br>Chapter 1.7 --- Non-classic functions of AChE --- p.18<br>Chapter 1.8 --- Diseases associated with AChE --- p.19<br>Chapter 1.8.1 --- Myasthenia gravis --- p.19<br>Chapter 1.8.2 --- Alzheimer's disease --- p.20<br>Chapter 1.8.2.1 --- Pathogenesis of AD --- p.20<br>Chapter 1.8.2.2 --- Treatments for AD --- p.22<br>Chapter 1.9 --- Silkworm larvae as biofactory for protein expression --- p.24<br>Chapter 1.10 --- Traditional baculovirus expression system --- p.26<br>Chapter 1.11 --- Bac-to-Bac baculovirus expression system --- p.29<br>Chapter 1.12 --- Virtual screening with AutoDock Vina --- p.29<br>Chapter 1.13 --- Project overview and the aim of study --- p.31<br>Chapter Chapter 2 --- Materials and Methods --- p.33<br>Chapter 2.1 --- Materials --- p.33<br>Chapter 2.1.1 --- Chemicals and Reagents --- p.33<br>Chapter 2.1.2 --- Primers --- p.35<br>Chapter 2.1.3 --- Antibodies --- p.35<br>Chapter 2.1.4 --- Silkworms --- p.35<br>Chapter 2.2 --- Methods --- p.36<br>Chapter 2.2.1 --- Construction of the expression cassette --- p.36<br>Chapter 2.2.1.1 --- Preparation of E.coli competent cells --- p.36<br>Chapter 2.2.1.2 --- Transformation --- p.36<br>Chapter 2.2.1.3 --- Agarose gel electrophoresis --- p.37<br>Chapter 2.2.1.4 --- Gene clean --- p.37<br>Chapter 2.2.1.5 --- Subcloning of target genes --- p.38<br>Chapter 2.2.1.6 --- Plasmid DNA extraction --- p.40<br>Chapter 2.2.1.7 --- Quantification of plasmid DNA by spectrophotometer --- p.41<br>Chapter 2.2.1.8 --- Plasmid DNA sequencing --- p.41<br>Chapter 2.2.2 --- Generation of recombinant bacmid DNA --- p.42<br>Chapter 2.2.2.1 --- Transposition --- p.42<br>Chapter 2.2.2.2 --- White/Blue screening --- p.42<br>Chapter 2.2.2.3 --- Extraction of recombinant bacmid DNA --- p.42<br>Chapter 2.2.2.4 --- Analysis of recombinant bacmid DNA by PCR --- p.44<br>Chapter 2.2.3 --- Transfection of silkworm larvae --- p.45<br>Chapter 2.2.3.1 --- Raising silkworm larvae --- p.45<br>Chapter 2.2.3.2 --- Preparation of transfecting solution --- p.45<br>Chapter 2.2.3.3 --- Transfection of silkworm larvae --- p.45<br>Chapter 2.2.3.4 --- Collection of hemolymph after protein expression --- p.46<br>Chapter 2.2.3.5 --- Oral infection of sikworm larvae --- p.46<br>Chapter 2.2.4 --- Purification of AChE --- p.47<br>Chapter 2.2.4.1 --- Nickel-chelating afinity chromatography --- p. 47<br>Chapter 2.2.4.2 --- Determination of protein concenttration by BCA assay --- p.47<br>Chapter 2.2.4.3 --- Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) --- p.48<br>Chapter 2.2.4.4 --- Western blot --- p.49<br>Chapter 2.2.5 --- Kinetic analysis of AChE --- p.50<br>Chapter 2.2.5.1 --- Ellman assay --- p.50<br>Chapter 2.2.5.2 --- Curve fitting --- p.51<br>Chapter 2.2.6 --- Virtual screening --- p.51<br>Chapter Chapter 3 --- Expression of recombinant AChEs in silkworm larvae --- p.55<br>Chapter 3.1 --- Construction of the expression cassette --- p.55<br>Chapter 3.1.1 --- Human AChE and Tetraodon nigroviridis AChE --- p.55<br>Chapter 3.1.2 --- Amplification of target genes from the parent vectors --- p.56<br>Chapter 3.1.3 --- Insertion of target genes into pFastBac Dual --- p.58<br>Chapter 3.2 --- Generation of recombinant bacmid DNA --- p.60<br>Chapter 3.2.1 --- Phenotype verification --- p.60<br>Chapter 3.2.2 --- PCR analysis of the recoombinant bacmid DNA --- p.64<br>Chapter 3.3 --- Expression of AChE in silkworm larvae --- p.66<br>Chapter 3.3.1 --- Raising silkworms --- p.66<br>Chapter 3.3.2 --- High-level expression of AChE in silkworm larvae --- p.68<br>Chapter 3.4 --- Oral infeciton --- p.72<br>Chapter Chapter 4 --- Analysis of the recombinant AChEs --- p.73<br>Chapter 4.1 --- Purification of recombinant AChEs by nickel-chelating affinity chromatography --- p.73<br>Chapter 4.2 --- SDS-PAGE and western blot analysis of the recombinant AChEs --- p.76<br>Chapter 4.3 --- Kinetic studies of recombinant AChEs --- p.79<br>Chapter 4.4 --- Virtual screening --- p.84<br>Chapter Chapter 5 --- Discussion and conclusion --- p.95<br>Chapter 5.1 --- Demonstration of high-level expression of recombinant AChEs by Bac-to-Bac baculovirus expression system --- p.95<br>Chapter 5.2 --- Oral infection of silkworm larvae --- p.98<br>Chapter 5.3 --- Characterization of recombinant AChEs --- p.98<br>Chapter 5.4 --- Discovery of new AChE inhibitors by virtual screening --- p.100<br>Chapter 5.5 --- Future works --- p.101<br>Chapter 5.6 --- Other applications --- p.102<br>Chapter 5.7 --- Conclusion --- p.102<br>References --- p.104<br>Appendix I --- p.125<br>Appendix II --- p.127<br>Appendix III --- p.129
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"CNS target delivery of acetylcholine esterase inhibitors via intranasal administration: pilot studies with tacrine and Its dimers." 2013. http://library.cuhk.edu.hk/record=b5884375.
Full textAbstract:
Qian, Shuai.<br>Thesis (Ph.D.)--Chinese University of Hong Kong, 2013.<br>Includes bibliographical references (leaves 265-294).<br>Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.<br>Abstract also in Chinese.
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Jantzi, Micaela. "Use of Medications for Management of Alzheimer’s Disease in Ontario’s Home Care Population." Thesis, 2010. http://hdl.handle.net/10012/5056.
Full textAbstract:
Abstract
Background: Home care is an important care setting for those with Alzheimer’s disease (AD). It provides support that allows individuals with AD to remain at home and may delay the transition to long-term care homes. Many clients with AD receive medications that are used for managing the symptoms of AD: cholinesterase inhibitors (ChEIs) and memantine. Ontario’s provincial drug benefit plan (ODB) provides subsidies for some of these medications based on specific clinical criteria. These AD medications are costly and can have significant side effects, so it is important to understand how they are being used in practice.
Objectives: The objectives of this study were to report the proportion taking AD medications and which types were taken, show the change in receipt of AD medications over time, and show the covariates that were independently associated with receiving AD medications.
Methods: Analysis of secondary data was performed on the provincial home care dataset. All home care clients receiving long-term home care services were assessed using the RAI-Home Care (RAI-HC), which is a comprehensive and standardized assessment. One assessment from each individual over the age of 65 who was assessed between January 2004 and September 2008 was used, for a final sample size of 321,013.
Results: Overall, 65% of clients with a diagnosis of AD were receiving an AD medication. Logistic regression analysis among those diagnosed with AD showed that increased physical impairment and clinical complexity were associated with decreased odds of receiving AD medication. Contraindicating diagnoses such as congestive heart failure, lack of medical oversight and needing to make economic tradeoffs were also associated with decreased odds of receiving AD medication.
Conclusions: The multivariate model showed trends of rational prescribing, such as clients with contraindicating diagnoses or very high clinical complexity having decreased odds of receiving AD medications. At the same time, evidence of structural barriers to receiving the medications was shown. There is debate about the cost-effectiveness of these medications. The provincial government could consider expanding ODB guidelines to include all AD medications for those with all levels of cognitive impairment, but further analyses involving longitudinal outcomes available in this dataset should be performed to ensure it would be in the public interest.
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Mohamed, Tarek. "Design, Synthesis and Biological Evaluation of 2,4-Disubstituted Pyrimidine Derivatives: Multifunctional Candidates as Potential Treatment Options for Alzheimer’s Disease." Thesis, 2011. http://hdl.handle.net/10012/6183.
Full textAbstract:
Alzheimer’s disease (AD) is a highly complex and rapidly progressive neurodegenerative disorder characterized by the systemic collapse of cognitive function and formation of dense amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). AD pathology is derived from the cholinergic, amyloid and tau hypotheses, respectively. Current pharmacotherapy with known anti-cholinesterases, such as Aricept ® and Exelon ®, only offer symptomatic relief without any disease-modifying effects (DMEs). It is now clear that in order to prevent the rapid progression of AD, new therapeutic treatments should target multiple AD pathways as opposed to the traditional “one drug, one target” approach. This research project employed medicinal chemistry tools to develop multifunctional small organic molecules against three key targets of AD pathology – the cholinesterases (AChE and BuChE), AChE-induced and self-induced Aβ1-40 aggregation and generation (β-secretase). A chemical library composed of 112 derivatives was generated to gather structure-activity relationship (SAR) data. The derivatives were based on a novel, non-fused, 2,4-disubstituted pyrimidine ring (2,4-DPR) template with substituents at the C-2 and C-4 position varying in size, steric and electronic properties. Molecular modeling was utilized to investigate their binding modes within the target enzymes and along with the acquired SAR, the chemical library was screened to identify lead multifunctional candidates.
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Charbonneau, Claudie. "A retrospective study of cholinesterase inhibitors for Alzheimer's disease : the effect of cerebrovascular disease on patient outcomes and the impact of biases on the results." Thèse, 2010. http://hdl.handle.net/1866/4883.
Full textAbstract:
Introduction: La démence peut être causée par la maladie d’Alzheimer (MA), la
maladie cérébrovasculaire (MCEREV), ou une combinaison des deux. Lorsque la
maladie cérébrovasculaire est associée à la démence, les chances de survie sont
considérées réduites. Il reste à démontrer si le traitement avec des inhibiteurs de la
cholinestérase (ChEIs), qui améliore les symptômes cognitifs et la fonction
globale chez les patients atteints de la MA, agit aussi sur les formes vasculaires de
démence.
Objectifs: La présente étude a été conçue pour déterminer si la coexistence d’une
MCEREV était associée avec les chances de survie ou la durée de la période
jusqu’au placement en hebergement chez les patients atteints de la MA et traités
avec des ChEIs. Des études montrant de moins bons résultats chez les patients
souffrant de MCEREV que chez ceux n’en souffrant pas pourrait militer contre
l’utilisation des ChEIs chez les patients atteints à la fois de la MA et la MCEREV.
L'objectif d'une seconde analyse était d'évaluer pour la première fois chez les
patients atteints de la MA l'impact potentiel du biais de « temps-immortel » (et de
suivi) sur ces résultats (mort ou placement en hebergement).
Méthodes: Une étude de cohorte rétrospective a été conduite en utilisant les bases
de données de la Régie de l’Assurance Maladie du Québec (RAMQ) pour
examiner la durée de la période jusqu’au placement en hebergement ou jusqu’au
v
décès des patients atteints de la MA, âgés de 66 ans et plus, avec ou sans
MCEREV, et traités avec des ChEIs entre le 1er Juillet 2000 et le 30 Juin 2003.
Puisque les ChEIs sont uniquement indiquées pour la MA au Canada, chaque
prescription de ChEIs a été considérée comme un diagnostic de la MA. La
MCEREV concomitante a été identifié sur la base d'un diagnostic à vie d’un
accident vasculaire cérébral (AVC) ou d’une endartériectomie, ou d’un diagnostic
d'un accident ischémique transitoire au cours des six mois précédant la date
d’entrée. Des analyses séparées ont été conduites pour les patients utilisant les
ChEIs de façon persistante et pour ceux ayant interrompu la thérapie. Sept
modèles de régression à risque proportionnel de Cox qui ont varié par rapport à la
définition de la date d’entrée (début du suivi) et à la durée du suivi ont été utilisés
pour évaluer l'impact du biais de temps-immortel.
Résultats: 4,428 patients ont répondu aux critères d’inclusion pour la MA avec
MCEREV; le groupe de patients souffrant seulement de la MA comptait 13,512
individus. Pour le critère d’évaluation composite considérant la durée de la
période jusqu’au placement en hebergement ou jusqu’au décès, les taux de survie
à 1,000 jours étaient plus faibles parmi les patients atteints de la MA avec
MCEREV que parmi ceux atteints seulement de la MA (p<0.01), mais les
différences absolues étaient très faibles (84% vs. 86% pour l’utilisation continue
de ChEIs ; 77% vs. 78% pour la thérapie avec ChEIs interrompue). Pour les
critères d’évaluation secondaires, la période jusqu’au décès était plus courte chez
les patients avec la MCEREV que sans la MCEREV, mais la période jusqu’au
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placement en hebergement n’était pas différente entre les deux groupes. Dans
l'analyse primaire (non-biaisée), aucune association a été trouvée entre le type de
ChEI et la mort ou le placement en maison d'hébergement. Cependant, après
l'introduction du biais de temps-immortel, on a observé un fort effet différentiel.
Limitations: Les résultats peuvent avoir été affectés par le biais de sélection
(classification impropre), par les différences entre les groupes en termes de
consommation de tabac et d’indice de masse corporelle (ces informations
n’étaient pas disponibles dans les bases de données de la RAMQ) et de durée de
la thérapie avec les ChEIs.
Conclusions: Les associations entre la coexistence d’une MCEREV et la durée de
la période jusqu’au placement en hebergement ou au décès apparaissent peu
pertinentes cliniquement parmi les patients atteints de la MA traités avec des
ChEIs. L’absence de différence entre les patients atteints de la MA souffrant ou
non de la MCEREV suggère que la coexistence d’une MCEREV ne devrait pas
être une raison de refuser aux patients atteints de la MA l’accès au traitement avec
des ChEIs. Le calcul des « personne-temps » non exposés dans l'analyse élimine
les estimations biaisées de l'efficacité des médicaments.<br>Introduction: Dementia may be caused by Alzheimer’s disease (AD),
cerebrovascular disease (CVD), or a combination of both. When CVD is
associated with dementia, survival is thought to be reduced. It is unclear whether
treatment with cholinesterase inhibitors (ChEIs), which has been found to
improve cognitive symptoms and global function in AD patients, has similar
benefits in vascular forms of dementia.
Objectives: The present study was designed to determine whether co-existing
CVD is associated with survival or time to nursing home placement (NHP) among
AD patients treated with ChEIs. Findings of poorer outcomes in patients with
versus without CVD might argue against the use of ChEIs for AD patients in
whom CVD co-exists. The objective of a second analysis was to assess for the
first time in patients with AD the potential impact of immortal time (and followup)
bias on risk for these outcomes.
Methods: A retrospective cohort study was undertaken using the Régie de
l’Assurance Maladie du Québec (RAMQ) databases to examine the time to NHP
or death for AD patients aged 66+, with or without CVD, treated with ChEIs
between July 1, 2000, and June 30, 2003. Because ChEIs are approved only for
AD in Canada, a ChEI prescription was used as a surrogate for an AD diagnosis.
Concomitant CVD was identified on the basis of a lifetime diagnosis of stroke or
ii
endarterectomy, or a diagnosis of transient ischemic attack within the six months
prior to the index date. Separate analyses were performed for patients with
persistent ChEI use and those who discontinued ChEI therapy. Seven Cox
proportional hazard regression models which varied in the definition of the index
date (start of follow-up) and the duration of follow-up were used to evaluate the
impact of immortal time bias.
Results: 4,428 patients met inclusion criteria for AD with CVD; 13,512 were
classified as having AD alone. For the composite endpoint of NHP or death,
1,000-day survival rates were lower among AD patients with versus without CVD
(p<0.01), but absolute differences were very small (84% vs. 86% with continuous
ChEI use; 77% vs. 78% with discontinuous ChEI therapy). Of the secondary
endpoints, time to death was shorter for patients with versus without CVD, but
time to NHP did not differ between groups. In the primary, unbiased analysis, no
association was found between ChEI treatment type and death or NHP. However,
after introduction of immortal time bias, a strong differential effect was observed.
Limitations: Results may have been affected by selection (misclassification) bias,
between-group differences in smoking and body mass index (information on
which was not available in the RAMQ databases), and duration of ChEI therapy.
Conclusions: Associations between co-existing CVD and time to NHP or death
appeared to be of little clinical relevance among AD patients treated with ChEIs.
iii
The lack of difference between AD patients with and without CVD suggests that
CVD should not be used as a reason to deny AD patients access to ChEI
treatment. Properly accounting for unexposed person-time in the analysis
eliminates biased estimates of drug efficacy.
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O'Regan, Jordana. "Assessing the Safety of Cholinesterase Inhibitor Discontinuation in Patients with Moderate to Severe Alzheimer’s Disease in a Long Term Care Setting." Thesis, 2014. http://hdl.handle.net/1807/44051.
Full textAbstract:
Cholinesterase inhibitors (ChEIs) are the first line pharmacotherapy for the symptoms of Alzheimer’s disease (AD). Though ChEIs offer modest cognitive benefits in early AD, literature addressing their continued use in severe AD is scarce. This study assessed the safety of discontinuing ChEIs in institutionalized moderate-severe AD patients. Twenty-six patients were randomized, double-blind to ChEI continuation or placebo for 8-weeks. Vitals, weight (kg) and adverse events (AEs) were monitored biweekly. Chi-square test revealed no significant association between semi-blinded treatment allocation and AE occurrence (χ²=(1,26)=0.99, p=0.32). Groups showed no differences on clinically significant weight loss (χ²=(1,26) =1.9, p=0.17), mean weight loss (F=.531, p= .473), pulse rate (F=.624, p=.437), or side effects (F=.224, p=.640). Preliminary results suggest that either ChEIs are well tolerated or that these drugs are no longer providing therapeutic benefit. Study completion (recruitment of 60 patients and unblinding) will generate more comprehensive data for determination of safe ChEI discontinuation guidelines.
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"Study of neuroprotective effect of cryptotanshinone, an acetylcholinesterase inhibitor, in cell and animal models." Thesis, 2009. http://library.cuhk.edu.hk/record=b6074975.
Full textAbstract:
Alzhemier's disease (AD) is a common form of dementia which is characterized by the deposition of amyloids in affected neurons and a cholinergic neurotransmission deficit in the brain. Current therapeutic intervention for AD is primarily based on inhibition of brain acetylcholinesterase (AChE) to restore the brain acetylcholine level. Cryptotanshinone (CT) is a diterprene which is extracted from the root of Salvia miltiorrhiza, an herb that is commonly prescribed in Chinese medicine to treat cardiovascular disease. The present study is aimed at verifying CT's property as an AChE inhibitor using different models. By AChE activity assay, CT was found to be a dual inhibitor which inhibits both human acetylcholinesterase (AChE) and butylcholinesterase (BuChE) with similar IC50. CT inhibited human AChE in a reversible manner, and the inhibition showed the characteristics of mixed-type. To human BuChE, CT is an uncompetitive inhibitor. CT can also inhibit AChE from rat cortical neurons. Apart from AChE inhibition, CT was demonstrated to have ameliorating effect on glutamate excitotoxicity, which is a cause of neuron death in AD. Further study showing that CT treatment can reduce cellular tau phosphorylation, which is the downstream effector of glutamate-induced excitotoxicity. In animal model, the effect of CT on learning impairment in scopolamine-treated rats was also evaluated by the acquisition protocol of Morris water maze. The task learning ability of scopolamine-treated rats was significantly reversed by CT, and the CT-fed rats were able to develop spatial searching strategy comparable to the control animals. Chronic administration of CT at effective doses did not cause significant hepatotoxicity. Cholinergic side effect of muscle weakness was not observed in CT treated rats. On the contrary CT was found to increase the locomotor activity of NIH mice in forced swimming test through reducing the lactic acid in the circulation. Data in this study gives further support on CT's potential as a therapeutic drug for treating AD.<br>by Wong, Kin Kwan Kelvin.<br>Source: Dissertation Abstracts International, Volume: 73-01, Section: B, page: .<br>Thesis (Ph.D.)--Chinese University of Hong Kong, 2009.<br>Includes bibliographical references (leaves 144-167).<br>Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.<br>Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.<br>Abstract also in Chinese.
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"Screening of traditional Chinese medicine for anti-Alzheimer's disease drugs." 2005. http://library.cuhk.edu.hk/record=b5896404.
Full textAbstract:
by Wong Kin Kwan Kelvin.<br>Thesis submitted in: September 2004.<br>Thesis (M.Phil.)--Chinese University of Hong Kong, 2005.<br>Includes bibliographical references (leaves 91-101).<br>Abstracts in English and Chinese.<br>Acknowledgements --- p.i<br>Abstract --- p.ii<br>摘要 --- p.iv<br>Abbreviations --- p.x<br>List of Figures --- p.xiii<br>List of Tables --- p.xiv<br>Chapter Chapter 1 --- Intorduction --- p.1<br>Chapter 1.1 --- Alzheimer，s disease --- p.1<br>Chapter 1.2 --- Histopathological features --- p.1<br>Chapter 1.3 --- Tau protein pathology and AD --- p.4<br>Chapter 1.4 --- Tau protein kinase I (TPKI)- GSK-3β --- p.6<br>Chapter 1.5 --- Tau protein kinase II (TPKII)- Cyclin dependent kinase 5 (Cdk5) --- p.8<br>Chapter 1.6 --- Available treatment --- p.9<br>Chapter 1.7 --- Objectives of the present study --- p.12<br>Chapter Chapter 2 --- Screening for GSK-3p inhibitors from Traditional Chinese Medicine (TCM) --- p.13<br>Chapter 2.1 --- Introduction --- p.13<br>Chapter 2.1.1 --- Phosphorylation of tau in AD --- p.13<br>Chapter 2.1.2 --- Gsk-3p inhibitors --- p.14<br>Chapter 2.1.3 --- Screening of GSK-3β inhibitor from TCM --- p.16<br>Chapter 2.2 --- Material and Methods --- p.18<br>Chapter 2.2.1 --- Preparation of extracts and fractions (AOF1-5) --- p.18<br>Chapter 2.2.2 --- General cell culture techniques --- p.21<br>Chapter 2.2.3 --- "3-(4,5-dimethyltiazoI-2-yl)-2, 5-diphenyl-tetrazolium (MTT) assay of AOF" --- p.23<br>Chapter 2.2.4 --- Recombinant DNA techniques --- p.23<br>Chapter 2.2.5 --- Transfection of GSK-3β and tau cDNA into COS7 cells --- p.28<br>Chapter 2.2.6 --- Extraction of total proteins from culture cells --- p.28<br>Chapter 2.2.7 --- Quantitation of protein by the Bradford method --- p.29<br>Chapter 2.2.8 --- Protein separation by sodium dodecylsulphate polyacrylamide gel electrophoresis (SDS-PAGE) --- p.29<br>Chapter 2.2.9 --- Western blot analysis --- p.31<br>Chapter 2.2.10 --- GSK-3β kinase assay --- p.32<br>Chapter 2.2.11 --- Determination of lithium content by atomic adsorption spectrophotometry --- p.34<br>Chapter 2.3 --- Results --- p.35<br>Chapter 2.3.1 --- Establishment of a co-transfected cell model for GSK-3β induced tau hyperphosphorylation --- p.35<br>Chapter 2.3.2 --- Preliminary screening results of aqueous and ethanol extracts (AOF1 and AOF2) --- p.37<br>Chapter 2.3.3 --- Ethanol extract of AOF inhibits GSK-3p induced tau phosphorylation in COS-7 cells --- p.40<br>Chapter 2.3.5 --- Effect of the essential oils of AOF on GSK-3P induced tau phosphorylation --- p.46<br>Chapter 2.3.6 --- The effect of AOF essential oil on GSK-3P activity in COS7 --- p.50<br>Chapter 2.3.7 --- Lithium content of AOF extracts --- p.52<br>Chapter 2.4 --- Discussion --- p.54<br>Chapter Chapter 4 --- Evaluation of the in vivo efficacy of cryptotenshinone (CT) in Morris Water Maze Task (WMT) --- p.59<br>Chapter 4.1 --- Introduction --- p.59<br>Chapter 4.1.1 --- Involvement of Cholinergic system in cognitive dysfunction in AD --- p.59<br>Chapter 4.1.2 --- Animal model for Alzheimer's disease --- p.60<br>Chapter 4.1.3 --- Morris Watermaze Task (WMT) --- p.61<br>Chapter 4.2 --- MATERIAL AND METHODS --- p.64<br>Chapter 4.2.1 --- Morris Water maze setup --- p.64<br>Chapter 4.2.2 --- Animal model --- p.66<br>Chapter 4.2.3 --- Drug preparation --- p.67<br>Chapter 4.2.4 --- Toxicity test of CT --- p.67<br>Chapter 4.2.5 --- Water maze task (WMT) --- p.68<br>Chapter 4.2.6 --- Visual acuity test --- p.73<br>Chapter 4.3 --- RESULTS --- p.74<br>Chapter 4.3.1 --- Chronic crytotanshinone treatment does not cause hepatic damages to the mice --- p.74<br>Chapter 4.3.2 --- Training Session --- p.76<br>Chapter 4.4 --- DISCUSSION --- p.85<br>Chapter Chapter 5 --- General Discussion and Future Directions --- p.87<br>Chapter 5.1 --- "AOF, the potential GSK-3 inhibitor" --- p.87<br>Chapter 5.2 --- CT´ؤthe AChEI --- p.88<br>References --- p.91<br>Appendix --- p.102<br>Chapter A1 --- Reagents for SDS-PAGE --- p.103<br>Chapter A3 --- Solution components provided by QIAGEN Plasmid Maxipreps kit --- p.108<br>Chapter A4 --- Reagents and medium for cell culture --- p.109<br>Chapter A5 --- Reagents for kinase assay --- p.110<br>Chapter A6 --- Raw data of figures --- p.112<br>Chapter A7 --- Plasmid map of PCI-neo --- p.119
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Čábelová, Pavla. "Syntéza, biologické hodnocení a in silico studie 7-MEOTA-donepezilových inhibitorů cholinesteras." Master's thesis, 2014. http://www.nusl.cz/ntk/nusl-337367.
Full textAbstract:
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Pavla ábelová Supervisor: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Supervisor specialist: PharmDr. Jan Korábe ný, Ph.D. Title of diploma thesis: Synthesis, biological evaluation and in silico studies in the series of novel 7-methoxytacrine-donepezile like compounds Alzheimer's disease (AD) is an irreversible neurodegenerative disorder of the brain characterized clinically by loss of memory, deterioration of activities of daily living and cognition. The pathological hallmarks of AD include neuritic plaques composed of extracellularly stored fibrils of amyloid- peptide, intracellular deposits of hyperphosphorylated tau and neurotransmitter deficits. The aim of the study was to design and synthesize 7-methoxytacrine-donepezil-like compounds as potential inhibitors of acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BChE, EC 3.1.1.8). New compounds consist of 7-methoxytacrine representing less toxic derivative of tacrine and benzylpiperazine moiety corresponding to donepezil fragment. To determine the potential of new derivatives, AChE and BChE inhibitory activities of the new molecules were assessed in vitro according to the method of Ellman et al....
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Yang, Yuan-Han, and 楊淵韓. "Evaluating the Therapeutic Response of Acetyl-cholinesterase Inhibitor in Alzheimer''s Disease." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/02642912644336345663.
Full textAbstract:
博士<br>高雄醫學大學<br>醫學研究所<br>99<br>The prevalence and incidence of Alzheimer’s disease (AD) is
increasing with aging. Pathological hallmarks for AD are mainly senile plaque, neurofibrillary tangle, and neuronal loss eventually. Currently the treatment of AD is mainly focused on acetyl-cholinesterase inhibitors(AChE-I)However, not every AD patient will respond to the treatment of AChE-I. Therefore, we conducted a study to measure and analyze the plasma concentration of AChE-I: donepezil in relation to the clinically therapeutic response. We have found that higher plasma concentration of doenepzil did not provide better therapeutic response. AD patients with their higher initial sum of boxes for clinical dementia rating (CDR) were
not good respond to the treatment as well as the higher initial Mini-Mental Status Examination (MMSE) score. In general, 58-60% of our AD patients will respond to these treatments regardless of age,education, gender, and their apo-lipoprotein E genotypes (ApoE),although ApoE genotype is a putative genetic factor to AD. Beyond ApoE gene, given to Angiotensin converting enzyme (ACE) can degrade the beta-amyloid, ACE gene is a putative genetic factor to AD, but its 5 effect was varied with races. We have recruited 257 AD patients and 137 non-demented Taiwanese to examine the genetic association and the ACE plasma protein level in relation to the various ACE genotypes. Our study has shown ACE insertion homozygote was a protective factor to AD
(p=0.040, OR=0.584, 95%CI: 0.349-0.976), for its lower ACE plasma protein level (114.79±31.32 ng/mL, p=0.023) compared to other genotypes.
The early diagnosis of AD is related to the therapeutic response. In order to diagnose AD at its early stage, we have translated and validated the AD8 questionnaire developed by Washington University in St Louis. We have recruited 239 normal cognitive and AD subjects into analyses. Our results have shown that the cut-off values were both 2 in differentiating normal (CDR=0) from very mild dementia (CDR=0.5) with the sensitivity 95.9% and specificity 78.7% and in differentiating normal (CDR=0) from dementia (CDR≧0.5) with the sensitivity 97.6% and specificity 78.1%, respectively.
My study began at evaluating clinically therapeutic response of acetyl-cholinesterase inhibitors to AD, validating AD8 questionnaire to screen early AD in order to have better therpaetic response in AD patients 6 in their early stage, and examining the association of ACE gene and AD.
Current study results are not sufficient to answer the questions for the treatment of donepezil to AD, especially in the difference of plasm concnetration, if any, between single dose and multiple doses of donepezil in AD patients. We also have to clarify whether cytochrome P450 will effect the donepezil concentration, and the various cognitive
responses, if any, under current dosage of donepezil 5 mg and coming higher dosage, 10 mg or 23 mg in the future.
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Osman, Wesseem. "Design, Synthesis, and Evaluation of Tacrine-Based Derivatives: Potential Agents to Treat Alzheimer’s Disease." Thesis, 2013. http://hdl.handle.net/10012/7666.
Full textAbstract:
With the incidence of Alzheimer’s disease (AD) growing worldwide and in Canada along with the growing economic and social burdens, the need for more effective therapies becomes of great importance. Since the discovery of AD, a number of proposed theories have arisen to explain the pathophysiology including the i) cholinergic theory, ii) oxidative stress pathways, and iii) metal ion imbalance. The major class of drug therapies to treat AD are cholinesterase inhibitors; however, the “one drug, one target” approach has not proven fruitful and generally becomes ineffective in later stages of disease progression. In this project, we synthesized a library of 1,2,3,4-tetrahydroacridine derivatives (10a-d, 11a-e, 12a-e, and 13a-f) as potential agents to target the cholinergic and oxidative stress pathways of AD. Chapter I provides background information on the role of AChE and BuChE enzymes in AD. Furthermore, this chapter describes the neurotoxicity of reactive oxygen species (ROS) and metals in AD. Chapter II provides a summary of project hypothesis and rationale. Chapter III describes the synthetic details regarding the synthesis of target small molecules. It further describes the principles involved in carrying out biological evaluation such as AChE and BuChE inhibition, antioxidant properties via DPPH stable radical scavenging, iron chelation capacity using ferrozine and in vitro cell viability data in neuroblastoma cells. Chapter IV describes the SAR details on ChE inhibition, antioxidant activities, iron chelation and cell viability profiles and molecular modeling details. A brief conclusion and future directions are included in Chapter V and the final section, Chapter VI provides experimental details for synthetic chemistry including analytical data of synthesized compounds and protocols for biological evaluations. This study identified
novel tetrahydroacridine derivatives with nanomolar inhibition of both human AChE and human BuChE enzymes that were more potent relative to the reference agent tacrine. Compound 10d[N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine] was identified as a potent inhibitor of BuChE (IC50 = 24.0 nM) and compound 13c [6-chloro-N-(pyridine- 2-ylmethyl)-1,2,3,4-tetrahydroacridin-9-amine] was identified as a potent inhibitor of AChE (IC50 = 95.0 nM) with good inhibition of BuChE (IC50 = 1.61 μM) whereas compound 11e [6-chloro-N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine] was identified with an optimum combination of dual AChE and BuChE inhibition (AChE IC50 = 0.9 μM; BuChE IC50= 1.4 μM). In conclusion, our studies provide new insight into the design and development of novel tetrahydroacridine derivatives to target multiple pathological routes of AD.
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Dhar, Devjani. "Rational Design of sym-Triazines For Multitarget-directed Modulation of Cholinesterases and Amyloid-beta in Alzheimer’s Disease." Thesis, 2013. http://hdl.handle.net/1807/35601.
Full textAbstract:
Alzheimer’s disease (AD), a progressive age-related neurodegenerative disorder is characterized by impairments in memory and cognitive functions. The two main pathogenic hallmarks associated with the progression of this multifactorial disease include accumulation of amyloid-beta (Aβ) plaques and the deterioration of the cholinergic system in the brain. Using cost-effective synthetic procedures, mono-, di-, and tri- substituted sym-triazine derivatives incorporating acetylcholine substrate analogues and aromatic phenyl moieties were synthesized for the targeted modulation of Aβ aggregation and acetylcholinesterase (AChE) activity. A subset of these sym-triazines demonstrated dual inhibition of Aβ fibrillization and AChE hydrolytic activity in vitro studies. These highly effective compounds were also shown to be well tolerated by differentiated human neuronal cells in cell viability tests. These novel compounds have the potential to undergo future in vivo pharmaceutical analysis and have a positive impact on the quality of life of the people living with this devastating disease and their caretakers.
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Vašíčková, Alžběta. "Alkaloidy Vinca minor L. a jejich biologická aktivita (inhibice lidských cholinesteras) V." Master's thesis, 2020. http://www.nusl.cz/ntk/nusl-412256.
Full textAbstract:
Vašíčková A.: Alkaloids of Vinca minor L. and their biological activity (inhibition of human cholinesterases) V. Diploma thesis, Charles University, Faculty of Pharmacy in Hradec Králové, Department of Pharmaceutical Botany, Hradec Králové 2020. From the selected fraction VM 215-258 were isolated 3 alkaloids by flash chromatography followed, preparative thin layer chromatography and crystallization. Their structure was determined by mass spectroscopy, NMR and optical rotation, and the obtained data were compared with those in literature. Strictamine and minovincinine belong to alkaloids previously isolated, the alkaloid AV-3 has not been isolated yet. These alkaloids were tested for their ability to inhibit human cholinesterases and their inhibitory activity was compared to standards galanthamine and physostigmine. Compound AV-3 showed mild inhibitory activity against BChE (IC50 μM > 86.3 ± 2.3), other alkaloids were considered inactive, their IC50 values against cholinesterases were > 100 μM. Key words: Vinca minor L. (Apocynaceae), vinca alkaloids, minovincinine, strictamine, Alzheimer's disease, acetylcholinesterase, butyrylcholinesterase.