Qian, Shuai. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 265-294). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Acetylcholinesterase inhibition with pyridostigmine has been previously studied in patients with congestive heart failure (CHF), but the effects of this medication on heart rate recovery after exercise and other indices of parasympathetic activity in populations with greater baseline vagal tone has not been fully characterized. Ten healthy, sedentary adults and ten aerobically trained athletes were enrolled in a prospective, double blind, randomized placebo controlled crossover trial. All study subjects were treated with a single dose of oral pyridostigmine 30 mg and matching placebo on separate days. Heart rate variability (HRV) at rest and heart rate recovery (HRR) at one minute after maximal cardiopulmonary exercise stress testing were measured. In sedentary adults, pyridostigmine significantly lowered resting heart rate (mean (SEM) 58.1 (2.4) beats/min versus 66.7 (4.0) beats/min, p = 0.01), increased HRR at one minute (45.1 (2.8) beats/min versus 40.7 (3.4) beats/min, p = 0.02), and lowered both resting mean arterial pressure (80.3 (2.0) mm Hg versus 84.3 (2.7) mm Hg, p = 0.02) and peak exercise mean arterial pressure (103.3 (3.1) mm Hg versus 108.8 (3.2) mm Hg, p < 0.01). In trained athletes, resting heart rate and HRR at one minute were unaffected by pyridostigmine dosing, although a significant increase in VO2 max was observed with the study drug (54.8 (3.5) ml/kg/min versus 53.3 (3.6) ml/kg/min, p = 0.02). Pyridostigmine did not change indices of heart rate variability in either cohort. The difference in resting heart rate and HRR responses to pyridostigmine between athletes and sedentary controls likely reflects training induced modifications of the autonomic nervous system. The inability of acetylcholinesterase inhibition to affect HRV in either sedentary adults or athletes further suggests the improved HRR previously observed in CHF patients treated with pyridostigmine is secondary to parasympathetic augmentation.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.

Thesis (M.Sc. (Environmental Biology))--Mahidol University, 1982.

Orientador: Angelo Zanaga Trape / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-04T03:10:39Z (GMT). No. of bitstreams: 1 Silva_AdaelsonAlves_D.pdf: 4937372 bytes, checksum: 6f3ac3a0b57da499f879075123c2041c (MD5) Previous issue date: 2004 / Resumo: A intoxicação aguda por agrotóxicos inibidores das colinesterases é causa substancial de morbidade e mortalidade em todo o mundo. No Brasil, como nos demais países, os efeitos tardios à saúde humana em decorrência de intoxicação aguda por agrotóxicos continuam não muito bem conhecidos, constituindo um desafio para os pesquisadores. Este trabalho teve como objetivo avaliar a saúde de 33 indivíduos, 20 homens e 13 mulheres, que softeram intoxicação aguda por agrotóxicos inibidores das colinesterases, entre janeiro de 1994 e dezembro de 2000, notificados no Centro de Controle de Intoxicações de Maringá e que necessitaram de tratamento hospitalar. Para a avaliação compareceram 36 indivíduos, que consentiram participar da pesquisa. Foram excluídos do estudo três deles: dois por serem portadores de doença psiquiátrica, anterior ao episódio de intoxicação, e uma criança, portadora de distúrbio neurológico, também anterior à intoxicação. Quanto ao tempo decorrido após o episódio de intoxicação, 19 (57,6 %) tinham 6 anos ou mais, sendo que 8 (24,2%) situavam-se na faixa entre 9 e 10 anos pós-intoxicação. A tentativa de suicídio foi a circunstância da intoxicação mais &eqüente no grupo estudado (60,6% ). Em relação à profissão, 33,3% eram agricultores. A faixa etária era predominantemente de jovens e aduhos (66,7%), com idade entre 16 e 40 anos. Os inseticidas organofosforados foram responsáveis por 20 intoxicações (60,6%) e os inseticidas carbamatos por 13 intoxicações (39,7%). A necessidade de internamento em UTI (42,4%) caracterirou a gravidade das intoxicações. Quanto aos sinais e sintomas referidos pelos indivíduos no momento da investigação, encontrou-se cefaléia (33,3%), insônia (33,3%), epigastralgia (27,3%), irritabilidade (18,9%) e fraqueza muscular (15,1%). A incidência de hipertensão arterial (42,4%) foi maior no grupo investigado que na população geral A av~li:lção laboratorial mostrou que a função renal estava normal em todos os indivíduos e anormalidades bioquímicas hepáticas, avaJi9das pelas dosagens séricas da alanino aminotransferase (AST), aspartato aminotransferase (ALT) e gama glutamil transferase (GAMA GT), estavam presentes em 30,3% dos indivíduos do grupo: três pacientes em duas e um nas três en7.ima~. O exame neurológico estava normal e quatro indivíduos apresentaram aherações eletroencefalográficas. As dosagens das colinesterases séricas apresentaram pequenas alterações. Diante dos resuhados, concluiu-se que o protocolo utilizado não foi capaz de evidenciar aherações significativas na saúde dos pacientes examinados, sendo que as anormalidades bioquímicas hepáticas e a alta incidência de hipertensão arterial encontradas apontam a necessidade de estudo complementar ,para o estabelecimento do nexo causal / Abstract: Acute intoxication by cholinesterase-mJnõiting pesticide causes substantial morbidity and mortality worldwide. In Brazil and other countries, the Jate efIects to human health due to acute intoxication by pesticides continue not well known, which is a challenge to researchers. The current writing aimed at to evaluate the heahh conditions of 33 individuaIs, 20 men and 13 women, that were exposed to acute intoxication by cholinesterase-inlnõiting pesticide within January 1994 and December 2000, notified at the Intoxication Control Centre from Maringá and that needed hospital treatment. For the study, 36 individuaIs agreed to take part ofthe research. Three ofthem were excluded: two by having psychiatric diseases prior to intoxication and a child with neurologicaI disturb aIso prior to intoxication. As for the time after the intoxication episode, 19 (57,6%) had been intoxicated 6 years before the research, 8 (24,2%) had intoxicated between 9 and 10 years before. Suicide attempt was the main intoxication cause within the group studied (60,6%). As for the profession, 33,3% were agricuhurists. The main age group was young, with ages from 16 to 40 years (66,7%). Organophosphate pesticides caused 20 intoxications (60,6%), and carbamate pesticides caused 13 intoxications (39,7%). The necessity ofICU internment (42,4%) demonstrated the gravity of intoxications. As for the signaIs and symptoms related by individuaIs at the investigation, could have been found headaches (33,3%), insomnia (33,3%), stomach-aches (27,3%), irritability (18,9%) and muscle weakness (15,1%). The incidence ofhyper blood pressure (42,4%) was greater at the study group than at the ordinary population. LaboratoriaI investigation showed that renal function was normal within all individuaIs, and hepatic function, assessed by the blood dosage of aIanine aminotransferase (AST),aspartate aminotransferase (ALT) and gama glutamil transferase (GAMA GT), modified in 30,3% of individuaIs ITomthe group: three patients in two and one in the three enzymes. The neurologicaI exam was normal and four individuaIs presented electroencephalographic modifications. The dosages of blood cholinesterase showed little aherations. From the resuhs of the research, it can be concluded that the protocol applied could not evidence significant changes on the heaIth of patients examined. The hepatic biochemicaI abnormalities and the high incidence of hyper blood pressure suggest the necessity of complimentary studies in order to establish causal nexus / Doutorado / Saude Coletiva / Doutor em Saude Coletiva

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.

La prise en charge de la démence est un défi pour les cliniciens tant ces patients constituent une population hétérogène. Dans le cadre de cette prise en charge, l’intérêt des antidémentiels (anticholinestérasiques et mémantine) est débattue : l’efficacité clinique semble discutable et les effets indésirables non négligeables. En 2010, des recommandations de bonnes pratiques ont laissé libre choix aux médecins de prescrire ou non ces médicaments. Depuis des questions restent en suspens : 1/ quelle est l’évolution des taux de prescription de ces médicaments depuis ces recommandations, en d’autres termes comment l’expertise clinique des médecins, un des piliers du tryptique de l’evidence based medicine, s’est-elle exprimée ? 2/ quels sont les facteurs qui restent associés aujourd’hui au fait de prescrire ou non ces médicaments ? et 3/ y a-t-il une sur-hospitalisation liée à leurs effets indésirables ?La question de la surmédicalisation est au cœur de notre problématique de thèse. Dans ce travail, nous avons répondu à ces 3 questions posées qui ont constitué nos 3 objectifs. Nous avons pu montrer que les médecins semblaient de moins en moins confiants vis-à-vis des antidémentiels avec une diminution de leur prescription depuis 2010 et des conséquences importantes en termes de coûts évités. Lorsqu’ils continuaient d’être prescrits, ces traitements l’étaient essentiellement chez les patients les plus jeunes ou en meilleur état de santé. Enfin, les anticholinestérasiques, essentiellement la rivastigmine, augmentaient le risque d’hospitalisation via des effets indésirables cardiaques et digestifs. Nos résultats plaident en défaveur de la prescription d’antidémentiels tant du point de vue de la morbidité que des dépenses de santé. La question du point de vue du patient reste posée. / Patients with dementia raise therapeutic challenges, as they constitute a heterogeneous population. As part of this management, the interest of antidementia drugs (cholinesterase inhibitors and memantine) is debated: the clinical efficacy seems questionable and the adverse effects appear to be significant. The 2010 recommendations gave to cliniciens the choice to prescribe or not these drugs. Since questions remain unanswered: 1 / what is the evolution of prescription rates of these drugs since these recommendations, in other words how the clinical expertise of cliniciens, one of the pillars the evidence based medicine, is expressed? 2 / what are the factors that remain today associated with prescribing these drugs or not? and 3 / Is there over-hospitalization related to their side effects?The question of medical overuse is a central point of our thesis problem. In this work, we answered these 3 questions which constituted our 3 objectives. We were able to show that cliniciens seemed less and less confident about antidementia drugs with a decrease in their prescription since 2010 and significant consequences in terms of avoided costs. When they continued to be prescribed, these treatments were mainly used in the youngest or most healthy patients. Finally, cholinesterase inhibitors, mainly rivastigmine, increased the risk of hospitalization via cardiac and digestive side effects. Our results argue against the prescription of antidementia drugs both from the point of view of morbidity and health expenditures. The question from the patient's point of view remains.

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. / by Wong, Kin Kwan Kelvin. / Source: Dissertation Abstracts International, Volume: 73-01, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 144-167). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Orientador: Hideko Yamanaka / Coorientador: Flávio Santos Damos / Banca: Cecilio Sadao Fugivara / Banca: Eder Tadeu Gomes Cavalheiro / Banca: Carla dos Santos Riccardi / Banca: Silvia Helena Pires Serrano / Resumo: Os pesticidas estão entre os poluentes mais preocupantes, devido à toxicidade e presença significativa no ambiente. A sua toxicidade é baseada na capacidade de inibir irreversivelmente a enzima acetilcolinesterase (AChE) que é chave na transmissão de impulsos nervosos. Este trabalho descreve o desenvolvimento de sensor contendo hexapeptídeo, bioinspirado em enzima acetilcolinesterase, para detecção de pesticidas organofosforados e carbamatos. A sequência peptídica (NH3+ - His - Glu - Trp - Arg - Pro - Ser - COO-) foi imobilizada sobre nanopartículas magnéticas (Fe3O4) previamente sintetizadas, modificadas com quitosana e posteriormente funcionalizadas com 1,12-diaminododecano. As condições experimentais de imobilização do peptídeo foram otimizadas, sendo estas: concentração 5,0 x 10-5 mol L-1 e tempo de incubação de 30 minutos a 25 ºC. O grupo carboxílico presente na sequência peptídica foi ativado com o uso de agentes de acoplamento 1-etil-3-(3-dimetilaminopropil) carbodiimida (EDC) e N-hidróxisuccinimida (NHS). A razão de concentração otimizada de EDC/NHS foi de 18,6/12,5 mmol L-1, respectivamente, e tempo de ativação de 60 minutos. O sinal eletroquímico do peptídeo foi monitorado pelo pico de oxidação da histidina, cujo valor é diminuído ao interagir com o pesticida. O perclorato de sódio (NaClO4) 0,1 mol L-1 pH 7,5 foi selecionado como eletrólito suporte. Os parâmetros da voltametria de onda quadrada foram otimizados (frequência de 100 Hz, amplitude de 90 mV e incremento ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Pesticides are among the most worrying pollutants due to toxicity and significant presence in the environment. Its toxicity is based on the ability to irreversibly inhibit the enzyme acetylcholinesterase (AChE) which is key in the transmission of nerve impulses. This work describes the development of a sensor containing hexapeptide, bioinspiring enzyme acetylcholinesterase, for the detection of organophosphorus pesticides and carbamates. The peptide sequence (NH3+ - His - Glu - Trp - Arg - Pro - Ser - COO-) was immobilized on previously synthesized magnetic nanoparticles (Fe3O4), modified with chitosan and subsequently functionalized with 1,12 - diaminododecane. The experimental conditions of immobilization of the peptide were optimized, being: 5,0 x 10-5 mol L-1 concentration and incubation time of 30 minutes at 25 ºC. The carboxyl group present in the peptide sequence was activated with the use of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS) coupling agents. The optimum concentration ratio of EDC / NHS was 18.6 / 12.5 mmol L-1, respectively, and activation time of 60 minutes. The electrochemical signal of the peptide was monitored by the histidine oxidation peak, whose value is decreased when interacting with the pesticide. Sodium perchlorate (NaClO4) 0.1 mol L-1 pH 7.5 was selected as supporting electrolyte. The parameters of the square wave voltammetry were optimized (frequency of 100 Hz, amplitude of 90 mV and increment of sweep of 6 mV) using a matrix of factorial planning. The preconcentration time of the peptide with the pesticide was fixed in 5 minutes. The sensor presented linear response in the studied concentration ranges, with detection limits of 6.0 x 10-11 mol L-1 and 4.0 x 10- 10 mol L- 1 for carbofuran and chlorpyrifos, respectively. The storage in the refrigerator at ± 4 °C allowed 85% stability of the immobilized peptide after a period of... / Doutor

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.