Dissertations / Theses on the topic 'Anticholinergika'

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.<br>Neuroleptic medications are commonly administered in the emergency department but are known to induce extrapyramidal symptoms (EPS) in some patients; typically dystonia and akathisia. This systematic review will examine if adjunctive medications are efficacious when given in conjunction with neuroleptic medications to prevent these extrapyramidal symptoms. The Central, DARE, LILACS, PubMed, CINAHL, and OVID databases were searched for relevant articles between January 2014 and February 2016. Inclusion criteria required the article to be a randomized controlled trial; administer an anticholinergic medication given concurrently or just prior to treatment with medications with known extrapyramidal side effects; and be published in English. The initial search strategy yielded 1222 prospective articles of which 1208 were excluded by title and/or abstract. Fourteen articles were retrieved in full text and independently reviewed by each author. Seven 7 RCTs representing 645 patients were determined to be appropriate for analysis. Meta‐analysis of 5 studies found a significant effect (OR 0.4 with 95% CI 0.23‐0.71) for utilizing anticholinergic adjunct medications in the prevention of EPS for 60 minutes after administration. No reduction was found (OR 1.14 with 95% CI 0.01‐164) in EPS after 60 minutes in meta‐analysis of 2 studies with opposing results. Adjunctive anticholinergic medication was effective in reducing symptoms of dystonia (OR 0.13 with 95% CI 0.04‐0.43) but not in reducing symptoms of akathisia (OR 0.74 with 95% CI 0.27‐1.98). This systematic review found that anticholinergic adjuvant anticholinergic treatment reduced EPS induced by antipsychotic medications during 60 minutes after administration, with the greatest reduction in dystonic symptoms.

This thesis is based on two fundamental questions: Which patients are currently using anticholinergic antiparkinson drugs? Does it matter which anticholinergic antiparkinson drug they are using? These questions were further investigated, using a variety of methods, as follows: Are anticholinergic antiparkinson agents predominantly used to treat Parkinson’s disease or antipsychotic induced extrapyramidal side-effects (EPS)? Is there a high risk of abuse of anticholinergic antiparkinson agents? Can alleged differences in receptor binding profiles of typical first- (FGA) and atypical second (SGA) -generation antipsychotic agents predict concomitant use of anticholinergic agents? Can long-term co-prescription of anticholinergic antiparkinson agents shed some light on the efficacy of antipsychotic agents? Does the literature indicate differences in toxicity and fatality rates of anticholinergic antiparkinson agents? Does an autopsy material indicate differences between anticholinergic agents regarding toxicity and fatality risk? Are warnings in a medical journal against the use of the most toxic anticholinergic agent enough to reduce its use? Can patients stop using anticholinergic agents without further remedies? The thesis has the following conclusions: The overwhelming majority of anticholinergic users were patients concomitantly using antipsychotic agents, presumably for the alleviation of antipsychotic induced EPS. The use of anticholinergics was not particularly skewed and we could not find any other indication of abuse, indicating that concomitant use of anticholinergics can be a proxy for the liability of specific antipsychotic agents to cause EPS. For patients using only one antipsychotic agent, the concurrent use of anticholinergics varied between 0.4% and 26.0%, but largely independently of the distinction between typical and atypical antipsychotics. High D2-receptor antagonism and a high 5-HT2A/D 2- receptor-affinity ratio coincided with the use of anticholinergics. Clozapine and zuclopentixol demonstrated the highest level of prescription persistence in a three-year period. The high prevalence of concomitant use of anticholinergics and zuclopentixol may indicate that the latter was considered efficacious enough to outweigh its probable side-effects. Haloperidol was associated with a mortality three times that of any other antipsychotic agent in the study. Orphenadrine is by far the most toxic anticholinergic antiparkinson agent with a high mortality risk. Warnings in a medical journal against the use of a toxic drug can have an impact on prescription patterns. At least one-third of the patients using anticholinergic antiparkinson agents do not need them.

Class of 2015 Abstract<br>Objectives: The study aimed to increase EPS risk factor assessment when prescribers order prophylactic anticholinergics with antipsychotics. An evidence-based pharmacist checklist card was developed to aid in this decision making process. Methods: A retrospective chart review of patients admitted to the acute inpatient psychiatry units at an academic medical center was conducted to determine baseline prophylactic anticholinergic prescribing habits over a two-month period. Charts were included if the patient was at least 18 years old and ordered at least one scheduled antipsychotic during the admission. An educational intervention session introduced the pharmacist checklist card and shared baseline findings. Post-intervention data was collected during a two-month period following the intervention. The percentage of prophylactic anticholinergic orders based upon pharmacist checklist card parameters pre and post-intervention was analyzed using chi-square test. Results: There was a significant decrease in the total percentage of orders for prophylactic anticholinergics from 72.7% in the pre-intervention period to 50.8% in the post-intervention period (p<0.001). Significant changes in the percentage of orders for prophylactic anticholinergics were also found for patients at no-to-low risk for EPS (56.4% versus 31.8%, p=0.014) and at low-to-moderate risk for EPS (79.6% versus 50.8%, p=0.003). There were no significant changes observed in the percentage of orders for prophylactic anticholinergics for patients at moderate-to-high risk for EPS. A lower percentage of patients prescribed a prophylactic anticholinergic experienced adverse effects in the post versus the pre-intervention period (52.31% versus 75.27%, p=0.003). Conclusions: Significant differences were found between pre and post-intervention anticholinergic medication prescribing habits. This suggests that increased patient risk factor assessment in the form of a pharmacist checklist card is effective in decreasing orders for prophylactic anticholinergic medications not clinically indicated and reducing the incidence of adverse effects.

CONTEXT: The seeds from Lupinus mutabilis Sweet, also called “chocho”, are an important part of the diet in several countries in South America. Prior to consumption, processing is required to remove toxic alkaloids. These alkaloids are known to have pharmacological properties as antiarrhythmics, antimuscarinics and hypoglycemics. CASE REPORT: We report a case in which a one-year-old male initially presented with altered mental status and respiratory distress and subsequently developed symptoms of anticholinergic toxicity, after ingesting a large amount of chocho seeds. CONCLUSION: In spite of going through a difficult clinical condition, the subject evolved favorably through receiving supportive treatment. The seeds from Lupinus mutabilis provide nutritional benefits when consumed, but people need to know their risks when these seeds are consumed without proper preparation.

Symptoms commonly associated with terminal phase of disease include pain, nausea, agitation, respiratory symptoms and general fatigue. During the last few days of life, patients may become weak, resulting in difficulty taking oral medication and have periods of unconsciousness. Some patients may require drug administration via subcutaneous infusion. A proportion of patients may develop difficulty clearing respiratory secretions causing a characteristic ‘death rattle’, which although not generally considered to be distressing for the patient, is often treated with a variety of anticholinergic drugs in an attempt to reduce the ‘noisy breathing’ for the benefit of relatives and others who may be closely associated with the patient. This study examined treatment of death rattle in two Hospices focusing on objective and subjective outcome measures in order to determine the efficacy of anticholinergic regimens in current use. Qualitative methods were employed to elicit attitudes of professionals and carers working closely with the patient. The number of patients recruited and monitored were small, many confounding factors were identified which questioned firstly the clinical rationale for administering anticholinergic drugs routinely to treat death rattle and secondly, the ethics of administering drug regimens to patients to treat death rattle with the primary aim of relieving distress for others. Ethnical issues, including those of consent are discussed in relation to their impact on the methodology of end of life studies in medicines management in palliative care.

Background: Alzheimer’s disease (AD) is the most common form of dementia and is characterized by a progressive loss of memory, judgment, and thinking in older adults. The current treatment is cholinesterase inhibitors, which increase acetylcholine at the synapse. Medications with anticholinergic (AC) activity are given for a variety reasons including for the treatment of comorbid conditions or side effects of cholinesterase inhibitors (ChEIs). These drugs inhibit acetylcholine in the brain. Studies have shown the detrimental outcomes of using AC medications with ChEIs in older adults. Moreover, older patients take more medications and have an increased risk of developing AC toxicity as these effects are additive. The association between AC burden with functional, cognitive, and behavioral outcomes bears further evaluation. Methods: This study is a retrospective observational study that investigated the effect of AC medications on function, cognition, and behavior. Data was collected from charts on dementia patients who resided at Piedmont Geriatric Hospital. Descriptive statistics and GEE regression were performed using MS Excel 2007 and SPSS 18.0. Results: There were a total of 83 subjects included in this study with a median age of 77 years old and with a median length of stay of 536 days. 33.7% of the patients were taking cognitive-enhancing medications. The analysis found that AC burden was not a significant predictor of functional, cognitive or behavioral decline. Conclusion: The minimal amount of literature on this association, suggests that AC burden may have negative consequences on function, cognition and behavior in dementia patients. The study results provided inconclusive evidence about the association of AC burden on poorer functional, cognitive and behavioral outcomes. Future research in this field is needed to determine if there is a true association between worsening outcomes and AC burden.

Background. Anticholinergic (ACH) medications are among biologically plausible and potentially modifiable risk factors of delirium. But the epidemiological findings on its role in hospitalized elderly patients are conflicting. Objectives. To evaluate the association between use of ACH medications and delirium severity and the potential effect-modification on this association by dementia. Methods. A cohort of 278 medical inpatients aged 65 years and over with diagnosed delirium was prospectively followed up with the Delirium Index (DI) every 2--7 days up to 3 weeks in a primary acute care hospital. Their DI scores were associated with measures of ACH medication exposure in the previous day using the mixed linear regression model adjusting for potential confounders or effect modifiers. Results . A total of 47 potential ACH medications were used in the cohort (mean: 1.4 per patient per day). An increase in daily ACH medication exposure of one such medication was on average associated with a subsequent increase in delirium severity of 0.52 DI points (95% CI: 0.3--0.8) after adjusting for dementia, baseline DI score, length of follow-up and concurrent use of non-ACH medications. Dementia did not modify the association. Sensitivity analyses using alternative definitions of ACH medications or excluding antipsychotics did not change the results. Conclusions. Exposure to ACH medications is independently and specifically associated with a subsequent increase in symptom severity of delirium among elderly medical inpatients.

Le lien entre l’usage des médicaments ayant des propriétés anticholinergiques (AC) et les fonctions cognitives a été montré dans plusieurs études. Cependant ces études ont considéré l’ensemble des médicaments étudiés comme un groupe homogène sans prendre en considération le potentiel AC et la classe thérapeutique. La population étudiée dans nos travaux s’appuie sur les participants âgés de 45 ans et plus de la cohorte CONSTANCES ayant passé une batterie de tests neuropsychologiques. Les données concernant la délivrance de médicaments ayant des propriétés AC sont extraites à partir de la base de données du Système National des Données de Santé (SNDS).Les résultats de la 1ère partie de ces travaux montrent que l’association entre l’usage des médicaments ayant des propriétés AC et les fonctions cognitives est hétérogène selon les classes thérapeutiques. En outre, les antipsychotiques contribuent à une grande partie de cette association. Suite à ces résultats, la 2ème partie de ces travaux comparant des psychotropes ayant des propriétés AC avec ceux qui n’en ont pas a conclu qu'il n'y a pas de lien substantiel entre l'activité AC des antidépresseurs et des anxiolytiques et les fonctions cognitives. Ainsi, pour ces deux classes thérapeutiques, le choix du médicament en fonction de son activité AC n’est pas cliniquement pertinent sur le plan du fonctionnement cognitif. Nos résultats sont moins clairs pour les antipsychotiques pour lesquels il pourrait exister un lien entre l'activité AC et les fonctions exécutives basses. Enfin, dans la 3ème partie nous avons pu développer un référentiel cognitif en utilisant une approche multidimensionnelle. Les analyses focalisées sur l’impact de l’usage des benzodiazépines (BZD) sur les fonctions cognitives sont détaillées dans cette partie<br>The relationship between the use of drugs with anticholinergic (AC) properties and cognitive function has been shown in several studies. However, these studies considered all the studied drugs as a homogeneous group without taking into consideration the AC potential and the therapeutic class. The population studied in our work is based on participants aged 45 and over in the CONSTANCES cohort who have undergone a battery of neuropsychological tests. Data concerning the dispensing of drugs with AC properties are extracted from the database of the French National System of Health Data (SNDS).The results of the first section of this work showed that the association between the use of drugs with AC properties and cognitive functions is heterogeneous across therapeutic classes. In addition, antipsychotics contribute to a large part of this association. Based on these results, the second section comparing psychotropic drugs with AC properties with those without, concluded that there is no substantial relationship between the AC activity of antidepressants and anxiolytics and cognitive functions. Thus, for these two therapeutic classes, the choice of drug based on its AC activity is not clinically relevant in terms of cognitive functioning. Our results are less clear for antipsychotics for which there may be a link between AC activity and lower executive functions. Finally, in the 3rd section we were able to develop a cognitive referential using a multidimensional approach. Analyses focusing on the impact of benzodiazepine (BZD) use on cognitive functions are detailed in this section

Asthma is a chronic inflammatory airway disease, and its treatment is frequently challenging despite detailed national and international guidelines. While basic antiinflammatory therapy usually consists of inhaled corticosteroids in doses adapted to the asthma severity, add-on treatment with bronchodilators is essential in more severe asthma. Only recently, the long-acting anticholinergic tiotropium was introduced into the GINA guidelines. This review reports on the studies that have been performed with tiotropium in adult asthmatic patients. Following early proof-of-concept studies, several studies with tiotropium as an add-on therapy to inhaled corticosteroids (ICS), with or without a long-acting beta agonist (LABA), demonstrated convincing clinical benefit for patients. Important lung function parameters and quality of life scores significantly improved shortly after onset of the add-on therapy with tiotropium, and some studies even demonstrated non-inferiority against salmeterol. All studies reported an excellent safety profile of tiotropium. The still growing body of tiotropium studies, both in adults and children, will help to identify the position of tiotropium in future asthma guidelines and might also indicate which patients benefit most from an add-on therapy with tiotropium.

Les psychotropes et les médicaments à propriétés anticholinergiques (anti-muscariniques) ont été associés aux risques de chute et de troubles cognitifs chez les séniors. Nos travaux avaient pour but de mieux comprendre le rôle de ces médicaments dans les phénomènes de troubles de la mobilité et de troubles cognitifs. Dans un premier temps, nous avons montré que la consommation de 2 psychotropes ou plus par jour et/ou d’1 seul médicament à propriétés anticholinergiques par jour, dès la charge anticholinergique minimale, est associée à un déficit lors de tests d’évaluation de la marche et de la cognition chez une population de séniors dès l’âge de 55 ans. En ce qui concerne les médicaments à propriétés anticholinergiques, ces effets néfastes sur la marche et sur la cognition étaient plus prononcés chez les personnes âgées de 75 ans ou plus. Les fonctions exécutives étaient sévèrement affectées par ces deux types de médicaments qui semblaient d’ailleurs affecter la mobilité via ce dysfonctionnement exécutif. Nous avons par ailleurs montré que, parmi les médicaments à propriétés anticholinergiques les plus prescrits dans notre population de séniors, la consommation de tramadol, un antalgique de palier 2, était le plus associé à des effets néfastes sur la marche et la cognition. Il est toutefois difficile d’affirmer que ces effets observés sont dus exclusivement à la consommation du tramadol en raison de la polymédication présente chez les sujets. Pour identifier les médicaments les plus à risque, les études chez l’animal, dans lesquelles l’administration de médicaments peut être contrôlée, peuvent être d’un grand intérêt. C’est ainsi que, dans un second temps, nous avons montré que l’administration chronique de tramadol altère les fonctions exécutives telles que mesurées par un test de flexibilité cognitive chez la souris jeune adulte. L’ensemble de ces résultats devraient alerter les médecins sur le fait qu’il est crucial de réduire la polymédication de psychotropes d’une part, et la prescription de tout type de médicaments à propriétés anticholinergiques d’autre part, chez les séniors, dès l’âge de 55 ans. Il faudrait également prendre des mesures qui visent à prescrire des traitements alternatifs chaque fois que cela est possible. En ce qui concerne le tramadol, ces résultats suggèrent la nécessité de renforcer toutes les mesures qui ont été prises récemment pour lutter contre le mésusage de cet antalgique<br>Psychotropic drugs and drugs with anticholinergic properties (anti-muscarinics) have been associated with risks of falls and cognitive impairment in the elderly. Our work aimed at improving knowledge about the role of these drugs in gait and cognitive impairment. We first showed that daily consumption of 2 or more psychotropic drugs per day and / or only 1 drug with anticholinergic properties, regardless of its anticholinergic burden, is associated with impaired scores on gait and cognitive test in a population of seniors from the age of 55 years. With regard to drugs with anticholinergic properties, these adverse effects were more pronounced in people aged 75 years or older. Executive functions were the severely affected by these drugs consumption. We have also shown that among the most prescribed drugs with anticholinergic properties, the consumption of tramadol, a level 2 analgesic, was the most associated with harmful effects on gait and cognition. However, it is difficult to ascertain that these observed adverse effects are solely driven by the consumption of tramadol due to the polypharmacy in this population. To identify the drugs most at risk, animal studies, in which the administration of drugs can be controlled, may be of great interest. Hence, as a second step, we showed that the chronic administration of tramadol impairs executive functions as measured by cognitive flexibility in young adult mice. Altogether these results should alert physicians on the fact that it is crucial to reduce polypharmacy of psychotropic drugs as well as the prescription of all types of drugs with anticholinergic properties. Alternative treatments should be prioritized as soon as possible. With regard to tramadol, these results suggest the need to strengthen the measures taken recently to combat the misuse of this analgesic

Abstract With the growing proportion of older people and increasing use of drugs in this population, it is important to study how drugs affect oral health among older people. The aim of this thesis was to study whether sedative load, which represents cumulative exposure to drugs with sedative properties, is associated with oral health among community-dwelling older people. The focus was on a dry mouth, oral health behavior, dental caries, and infection in the periodontium. In addition, sedative load and anticholinergic burden were compared. The present study population was a subpopulation from an intervention study “Geriatric Multidisciplinary Strategy for Good Care of the Elderly”. The study population consisted of 159 community-dwelling, dentate, and non-smoking people aged 75 or older from the city of Kuopio, Finland. Data were collected with interviews, geriatric assessments, and clinical oral examinations. Sedative load was determined by using a previously published method. The study showed that participants with a sedative load were more likely to have dental caries, but not periodontitis, when compared with participants without a sedative load. Sedative load was associated with decreased stimulated salivary secretion and less strongly with unstimulated salivary secretion but not with xerostomia. The results also showed that sedative load was associated with poor or insufficient oral health behavior. Anticholinergic burden was associated with low unstimulated salivary secretion and xerostomia, but not with low stimulated salivary secretion. In conclusion, cumulative exposure to drugs with sedative properties was associated with insufficient oral self-care and poor oral health. The results from this study emphasize the fact that older people using drugs with sedative properties require thorough prophylaxis measures and regular dental check-ups because of their high risk of having poor oral health<br>Tiivistelmä Väestön iäkkäiden henkilöiden osuuden kasvaessa ja heidän lääkkeiden käytön lisääntyessä on tärkeää tutkia, miten lääkkeet vaikuttavat ikääntyneiden suun terveyteen. Tutkimuksen tarkoituksena oli selvittää lääkityksestä aiheutuvan sedatiivikuorman (sedative load) vaikutuksia suun terveyteen kotona asuvilla iäkkäillä henkilöillä. Eritoten tutkimuskohteena oli sedatiivikuorman yhteys kuivaan suuhun, suun terveyskäyttäytymiseen, kariekseen sekä hampaiden tukikudosten sairauteen. Lisäksi tutkittiin antikolinergisen kuorman yhteyttä kuivaan suuhun ja tuloksia verrattiin sedatiivikuormaan. Tutkimuspopulaatio oli osa geriatrista Hyvän Hoidon Strategia -interventiotutkimusta (HHS). Populaatio koostui 159 kotona asuvasta 75-vuotiaasta tai sitä vanhemmasta hampaallisesta, ei-tupakoivasta kuopiolaisesta. Tutkimusmateriaali kerättiin haastattelulla, geriatrisella tutkimuksella sekä kliinisellä suun tutkimuksella. Sedatiivikuorma laskettiin käyttäen aiemmin kehitettyä mallia, jossa määritetään kokonaislääkityksestä aiheutuva sedatiivikuorma. Tutkimus osoitti, että osallistujilla, joilla oli sedatiivikuormaa, oli keskimäärin enemmän kariesta muttei hampaiden tukikudoksen sairautta verrattuna henkilöihin, joilla ei ollut sedatiivikuormaa. Tulokset osoittivat myös, että sedatiivikuorma oli yhteydessä alentuneeseen stimuloidun syljeneritykseen ja vähemmässä määrin alentuneeseen leposyljeneritykseen, mutta ei kuivan suun tunteeseen. Antikolinerginen kuorma oli yhteydessä alentuneeseen leposyljeneritykseen ja kuivan suun tunteeseen, mutta ei alentuneeseen stimuloidun syljeneritykseen. Sedatiivikuorma oli yhteydessä puutteelliseen suun terveyskäyttäytymiseen, kuten vähäiseen hammastahnan käyttöön ja suureen plakkimäärään. Johtopäätöksenä voidaan todeta, että altistuminen väsyttäville lääkkeille on yhteydessä puutteelliseen omahoitoon ja huonoon suun terveyteen. Tämän tutkimuksen tulokset korostavat väsyttäviä lääkkeitä käyttävien ikääntyneiden tarvitsevan perusteellisia ennaltaehkäiseviä toimia sekä säännöllisiä suun tutkimuksia, koska heillä on suurentunut riski huonoon suun terveyteen

Les antagonistes cholinergiques interfèrent dans la transmission synaptique au niveau système nerveux central et sont impliqués dans des processus pathologiques chez le sujet âgé, tels que le déclin cognitif, le déclin fonctionnel, les chutes et les symptômes comportementaux et psychologiques de la démence (SCPD). L’objectif de nos travaux était d’étudier l’impact de la réduction de la charge anticholinergique (CA) sur les SCPD chez les patients âgés atteints de démence, hospitalisés en unité aiguë de diagnostic et d’adaptation thérapeutique pour patients souffrant de troubles neurocognitifs, située au Centre Hospitalier Universitaire de Reims. Nos travaux ont permis de mettre en évidence qu’une réduction de la CA de 20% permettait de réduire la fréquence, la sévérité et le retentissement sur l’équipe soignante de SCPD majoritairement perturbateurs. De plus, la réduction de la CA était associée à une diminution des SCPD en termes de fréquence, gravité et retentissement chez les patients présentant des SCPD d’intensité modérée. Etant donné l’absence de consensus clair sur la prise en charge symptomatique des SCPD, une attention particulière doit être portée sur cette iatrogénie souvent évitable chez les patients âgés présentant des troubles neurocognitifs majeurs. Une attitude de déprescription des antagonistes cholinergiques doit être envisagée chez le patient âgé présentant des SCPD<br>Cholinergic antagonists interfere with synaptic transmission in the central nervous system and are involved in pathological processes in the elderly, such as cognitive decline, functional decline, falls, and behavioral and psychological symptoms of dementia (BPSD). The aim of our work was to assess the impact of the reduction of the anticholinergic burden (AB) on BPSD in elderly patients with dementia, hospitalized in a dedicated geriatric care unit specializing in the management of patients with dementia, located at the University Hospital of Reims (France). Our work has shown that a 20% reduction in AB can decrease the frequency, severity and impact of BPSD, which are mostly disruptive. In addition, the reduction in AB was associated with a decrease in BPSD in terms of frequency, severity and impact in patients with moderate-intensity BPSD. Given the lack of clear consensus on the symptomatic management of BPSD, special attention must be paid to this preventable iatrogeny in elderly patients with major neurocognitive disorders. The deprescription of cholinergic antagonists should be considered in elderly patients with BPSD when possible

Streptococcus pneumoniae ist der häufigste Erreger bakterieller Meningitiden. Eine Pneumokokken-Meningitis führt trotz Ausschöpfung aller heute verfügbaren Behandlungsmöglichkeiten in 25 % der Fälle zum Tod. Steigende Antibiotikaresistenzen und die Limitation verfügbarer Vakzine auf einige Serotypen von S. pneumoniae erfordern neue Ansätze in der antimikrobiellen Therapie. Cholin-bindende Proteine (CBPs) sind gemeinsames Merkmal aller Pneumokokkenstämme und für die Virulenz dieses Bakteriums essenziell. Durch Zugabe potenter Anticholinergika können die CBPs von der Bakterienoberfläche abgelöst und damit inhibiert werden. In dieser Arbeit wurde untersucht, ob durch Inhibition von CBPs während des Wachstums der Pneumokokken deren Phagozytose durch Mikrogliazellen in vitro gesteigert werden kann. Während ihres Wachstums wurden die Bakterien dazu mit potenten Anticholinergika inkubiert und am Ende ihrer exponentiellen Wachstumsphase auf murine Mikrogliazellen gegeben. Nicht alle eingesetzten Anticholinergika konnten die Inhibition der CBPs – angezeigt durch die Bildung langer Kokkenketten – bewirken, obwohl für sie alle eine hohe Affinität zu den CBPs in früheren Arbeiten nachgewiesen worden war. Ipratropium, das in höheren Konzentrationen das Pneumokokkenwachstum inhibiert, induzierte in den von uns eingesetzten niedrigen Konzentrationen weder die Bildung von Ketten noch führte es zu einer erhöhten Phagozytoseleistung. Mit DMAE funktionalisiert zeigten PAMAM-Dendrimere der 1. Generation ebenfalls keine Inhibition der CBPs: Es bildeten sich weder Kokkenketten noch zeigte sich eine erhöhte Bakterienaufnahme der Mikroglia. Im Gegensatz dazu stellte sich unter Einfluss von PPI-g2-DMAE neben ausbleibender Kettenbildung ein dosisabhängiger phagozytosehemmender Effekt dar. Einzig durch Co-Inkubation mit dem mit Cholin funktionalisierten PPI-Dendrimer der 2. Generation gelang die Inhibition der CBPs mit resultierender Bildung langer Ketten. Die Phagozytoseleistung zeigte eine dosisabhängige Steigerung sowohl für eine CoInkubation während der gesamten exponentiellen Wachstumsphase als auch nach Co-Inkubation während ihrer letzen 2 Stunden. Dennoch konnte im Sepsismodell der Maus durch intraperitoneale Injektion dieses Dendrimers 15 min vor Infektion mit S. pneumoniae kein protektiver Effekt erzielt werden: Zwischen den mit Dendrimeren behandelten Tieren und denen der Kontrollgruppe zeigten sich keine Unterschiede in Überlebenszeit und Sterblichkeit, dem krankheitsbedingten Gewichtsverlust, dem klinischen Score und der durch Ausplattieren von Milzhomogenaten ermittelten Keimkonzentration im Blut infektionsbedingt verstorbener Tiere. Die von uns eingesetzten Konzentrationen von Ipratropium scheinen für eine Inhibition der CBPs nicht ausgereicht zu haben. Der bislang nicht genau geklärte wachstumsinhibitorische Effekt, der sich in unseren Versuchen bereits ab 5 mM bemerkbar machte, könnte jedoch durch Inhalation von Ipratropium gezielt zur Prophylaxe von Pneumokokken-Pneumonien genutzt werden. Bei an Dendrimere gekoppelten, eigentlich potenten Liganden der CBPs konnte beobachtet werden, dass sie als Teil des Dendrimers ihre Affinität gegenüber den CBPs nicht nur deutlich verändern, sondern auch unerwartete Effekte (Verminderung der Phagozytose) hervorrufen können. Wegen der raschen Elimination scheint die einmalige Gabe eines potenten Dendrimers zur Inhibition der CBPs in vivo nicht auszureichen und erklärt das Versagen im Sepsismodell. Neuere Untersuchungen zur Distribution im Hirnparenchym nach intraventrikulärer oder subarachnoidaler Injektion lassen hoffen, dass durch Gabe subtoxischer Dosen die von uns beobachtete Phagozytosesteigerung in vivo reproduzierbar ist. Durch Inhibition der CBPs ist es möglich, die Virulenz aller Serotypen des Pneumokokkus stark zu reduzieren. Potente Inhibitoren könnten sowohl als Therapeutikum als auch zur Infektionsprophylaxe eingesetzt werden, ohne dass es dabei zur Ausbildung von Resistenzen kommt, da zeitgleich mehrere Virulenzfaktoren inhibiert werden. Es ist daher von großem medizinischen Interesse, Inhibitoren der CBPs zu entwickeln, die in subtoxischen Dosen eine hohe Affinität zu den CBPs aufweisen und diese inhibieren.

碩士<br>國立陽明大學<br>國際衛生碩士學位學程<br>105<br>Introduction: Datura species have been used for its hallucination effects in the United State and Europe, whereas Asian countries have used it as herbal medicine. This study was conducted to further understand Datura poisoning in Asian context. Methods: This is a case-series study that included all cases with Datura exposure reported to the National Poison Center of Taiwan between 1986 and 2015. Logistic regression analysis was used to find any potential predictors of severity; while Fisher’s exact test was used to assess the effectiveness of physostigmine in terms of the days of full recovery of delirium, severe agitation and coma. Results: Totally 203 cases involving 114 Datura spp exposures and 89 Brugmansia suaveolens exposures were eligible for analysis. Herbal medicine accounted for 84.5% of reported exposures. The most frequently reported clinical effects were mydriasis (53.2%), confusion (40%), tachycardia (35.5%), dizziness (34%), delirium (31%), hypertension (19.2%), hallucination (16.7%), agitation and coma (6.4%). Seventy-three cases (36%) had severe effects without mortality. Misidentification of the plants and leaf, seed, stem, root consumption were found to be the potential predictor of severity. Forty patients (19.7%) received physostigmine therapy and it seemed to lead to an earlier resolution of central nervous system signs. Conclusion: Herbal medication overdose is the main reason of Datura poisoning in Taiwan as well as other Asian countries. Consumption of seeds, stems, roots and leaves and misidentification of the plants would be predictors for severity in our study. Physostigmine is an effective and safe antidote in the management of herb-related anticholinergic toxicity.

碩士<br>中國醫藥大學<br>醫務管理學系碩士在職專班<br>105<br>Background: In the end of 2018, the population aged 65 or older had approached 14% in Taiwan. The more population aging, may also increases the risk of anticholinergic medication. Anticholinergic-effected agents are widely used in clinical treatments of various diseases, especially for the elderly. Few studies have been conducted to investigate the risk of Pneumonia in Taiwan. Therefore, it is necessary to investigate the association between the prevalence of anticholinergic medication use and the occurrence of Pneumonia in elder Objectives: To examine the risk factors of anticholinergic medication and the association with Pneumonia. Methods: This research was a retrospective cohort study using the 2008-2013 Longitudinal Health Insurance Database (LHID2010), a nationally representative database established by the National Health Research Institutes. All participants were the elderly with age above 65 years old (n = 22,914), but without Pneumonia. Any participants medication with steroid, ACEI, amiodarone,amantadine from January 2008 to June 2013 were excluded. A 6-month follow-up was performed for each prescription to identify pneumonia from July 2008 to December 2013. Conditional logistic regression was applied to evaluate the odds ratio (OR) for the risk of Pneumonia associated with anticholinergic agents. In order to eliminate the potential confounders, OR was adjusted by gender, age, comorbidities and medication history. Results: Among a total of 22,914 participants prescriptions, 6.6% of them were anticholinergic medications. Approximately 76.1% of participants had received at least one anticholinergic medication between July 2008 and June 2013. The patients, facility and physician characteristics were the risk factors associated with anticholinergic medications. After adjusting for age, gender, chronic disease and covariates, it was found that patients had anticholinergic medication were at higher risks to have Pneumonia (odds ratio [OR]= 1.16; 95% confidence interval [CI], 1.04-1.31) compared to those who had never received anticholinergic agents. Conclusions: Overall use of anticholinergic medication was associated with greater risk of pneumonia compare to no use after adjusted for other factors. The result of our study suggest that physicians should be cautious when prescribing anticholinergic medication for the elder people in order to reduce the risks of pneumonia and improve the elder’s medication safety.

碩士<br>國立陽明大學<br>醫務管理研究所<br>101<br>Background: Aging is a global health issue for many economical developed countries. There are 10.9% elderly population in Taiwan and the aging index is as high as 72.2%. The elderly often have multiple chronic diseases because of aging and the degradation of physiological functions. They visit different hospitals in different divisions where polypharmacy problems may exist and, therefore, may produce inappropriate prescription or inappropriate medication, resulting in high hospitalization rates and/or mortality. Anticholinergic-effected agents are widely used in clinical treatments of various diseases, especially for the elderly. The purpose of this study is to investigate the related factors that could cause the anti-cholinergic effect such as delirium, dementia and cognitive dysfunction after the elderly whose were over 65 years old taking this type of drugs. Methods: We used NHIRD which contains one million insurance beneficiaries to conduct a retrospective cohort study which focused on the elderly who were over 65 years old to explore the role of anticholinergic agents for the exposure factors using Anticholinergic Cognitive Burden Scale (referred ACB) which is used to assess the activity of anticholinergic drugs. We defined case group as having anticholinergic agents and use age, gender, average number of medications as control variables to track two-year observational study . Results: In demographic characteristics, the study showed that in terms of gender, the women taking anticholinergic effects agents have a higher probability of occurrence of cognitive dysfunctions and other adverse effects. In terms of age, for each additional age, the probability of occurrence of cognitive dysfunctions has increased by 1.071-fold, reaching a statistically significant difference (HR = 1.071; P <0.0001). In term of health condition, the elderly having cognitive dysfunctions in the degree of disease burden (4, 5-level) is higher than those of non-cognitive dysfunction and there is a statistically significant difference (P = 0.0018). As the role of agents in the use of anticholinergic delirium, dementia and other cognitive dysfunction related studies, the results show that in those without cognitive dysfunction, there are 1,914 people (50.37%) not using anticholinergic agents and 1,886 people (49.63%) using the agents. In those with cognitive dysfunctions, there were 35 people (35.71%) not using anticholinergic agents and 63 people (64.29%) using the agents. And there was a significant difference (P = 0.0042). It could be found that in the use of anti-cholinergic agonist, the proportion (64.29%) of the elder with cognitive dysfunction and using anticholinergic effects agent was significantly higher than those without cognitive dysfunction and using anticholinergic effects agent in a proportion (49.63%). Conclusions: As the population growing old, inappropriate medication problems in the elderly have attracted increasing attention in recent years. The study showed that in terms of gender, the probability of adverse effects occurrence in women is higher than men. The age for each additional one year, the probability of occurrence of cognitive dysfunction has increased by 1.071-fold, while those with poor physical conditions and using high activity of anticholinergic drugs, had a higher probability of occurrence of cognitive dysfunction. Anticholinergic drugs are still widely used in clinical practice without any form of warning and lead to less health-related attention. The relevant units and authorities should urgently develop counter-measures for the use of this type of drugs to improve the safety of medicines.

碩士<br>中國醫藥大學<br>醫務管理學系碩士在職專班<br>99<br>Background: Beers’ criteria indicated that some anticholinergic agents are inappropriate for treating the elderly people, but those medicines are still used by 12% to 21% to older continuously in the United States. This study aimed to explore the appropriation of anticholinergic agents’ descriptions and the possible adverse outcomes of using those medicines in the elder in Taiwan. Methods: A cross-sectional study was conducted by analyzing ” Longitudinal Health Insurance Database (LHID2005)” from 2007 to 2008 of “National Health Insurance Research Database (NHIRD)” to investigate all the prescriptions of the elder above 65 years old and explore the risk factors of “Anticholinergic Risk Scale (ARS)” and the associated factors adverse outcomes. The adverse events included emergency visit, hospitalization, as well as side effects like constipation. Results: By analyzing in unit of “person”, the prevalence of elderly exposing to inappropriate prescribing of anticholinergic agents was 75.56%. On the other hand, by using “prescription” as the unit, the prevalence became 18.67%. The characteristics of patients, facilities and physicians were considered associated with the risk factors of inappropriate prescription of anticholinergic agents. After adjusting for age, gender and severity of disease, it was found that patients had inappropriate person of anticholinergic agents were at higher risks to have emergency visit (odds ratio [OR]= 1.85), hospitalization(OR= 1.06), constipation(OR= 1.87), hyperplasia of prostate(OR= 1.51), delirium(OR= 1.51), cardiac dysrhythmia unspecified (OR= 1.16) and cognitive impairment (OR= 1.29) compared to those who had never received inappropriate prescribing of anticholinergic agents. Conclusions： This study discovered that over 75 % of the elder with diseases had received inappropriate anticholinergic agents’ treatment in Taiwan that was much higher than western countries. The significant associations between inappropriate prescriptions of anticholinergic agents and adverse outcomes suggest that physicians should be cautious when prescribing medication for the elder people in order to reduce the risks of adverse outcomes and improve the elder’s medication safety. Keywords: Elder, Anticholinergic Agents, Inappropriate Prescription, Adverse Outcomes

碩士<br>高雄醫學大學<br>藥學系臨床藥學碩士班<br>104<br>Introduction: Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease. Guideline recommended that the first choice of pharmacotherapy was inhaled bronchodilators. The association between myocardial infarction (MI) and anticholinergic agents were still in debate. The aim of this study was to investigate the prescribing patterns of bronchodilators among COPD patients and evaluate the association between anticholinergic agents and MI. Methods: (1) Prescribing patterns: This cross-sectional study used Health and Welfare Data Science Center (HWDC) database to analyze annual prescribing patterns of bronchodilators in COPD patients from 2008 to 2013. (2) Anticholinergic agents and MI: A nested-case control study was conducted by HWDC database. A cohort of 142,437 COPD patients was identified from 2008 to 2013. Case group was defined the first diagnosis of MI after COPD diagnosis. Any use of anticholinergic agents within 6 months before MI occurred was analyzed. From this cohort, 1,583 cases were matched to 1,583 controls by one-to-one propensity score matching (PSM). PSM was based on gender, age, comorbidities and medication history. Conditional logistic regression was applied to evaluate the odds ratio (OR) for the risk of MI associated with anticholinergic agents. In order to eliminate the potential confounders, OR was adjusted by gender, age, comorbidities and medication history. Results: (1) Prescribing patterns: A total of 143, 133 patients were included in the study. The first three common prescriptions were xanthines, short-acting beta-2 agonists (SABA) and muscarinic antagonists (MA). However, the utilization of xanthine declined with time. Among of all SABA prescriptions, the utilization of oral form was more than inhaled form. (2) Anticholinergic agents and MI: Case group showed an increase risk of MI compared with control group. [aOR = 1.55, 95% confidence interval (CI): 1.29-1.85] Conclusion: Although guideline recommended that inhaled bronchodilator was first choice for treatments, our study showed that the prescription patterns of Taiwan were different. Future research is to investigate the reasons and preferences of prescriptions. The use of anticholinergic agents in COPD patients was associated with the risk of MI. Clinicians should be alert this drug safety issue.

Datura metel is a herbaceous plant found in almost all tropical parts of the world. It belongs to the family Solanaceae whose members, viz. Duboisia, Atropa, Hyoscyamus and Datura plants are known to produce tropane alkaloids- hyoscyamine and scopolamine which are most noted for their therapeutic use as anti-cholinergic agents. Since these alkaloids are produced in very low amounts in plants, alternative sources and methods of production for these alkaloids have been crucial in meeting the demands for these drugs. Endophytic fungi inhabiting a plant may have the potential to produce the same compounds as the host plants. The aim of the present study was to search for tropane alkaloid producing endophytic fungal isolates from Datura metel. Eighteen endophytic fungi were isolated from various tissues of Datura metel and screened for the presence of three tropane alkaloid biosynthetic genes- putrescine N-methyltransferase (PMT), tropinone reductase I (TRI) and hyoscyamine 6β-hydroxylase (H6H) using PCR-based screening approach. Six endophytic fungal isolates were found to possess the PMT, TR1 and H6H genes. The fungi were identified using molecular taxonomy as Col letotrichum boninense, Phomopsis sp., Fusarium solani, Col letotrichum incarnatum, Col letotrichum siamense and Col letotrichum gloeosporioides and the identity was confirmed using colony and spore morphology. The production of tropane alkaloids hyoscyamine and scopolamine by the fungi has been ascertained using various techniques like TLC, HPLC and ESI-MS/MS by comparison with the authentic reference standards. The amount of tropane alkaloids produced by all six fungi in liquid cultures was quantified using HPLC analysis. Among the six tropane alkaloid-producing fungi Col letotrichum incarnatum gave the highest yields of hyoscyamine and scopolamine which were 3.906 mg/L and 4.13 mg/L, respectively. With an aim to characterize the tropane alkaloid biosynthetic genes in these fungi, the PMT gene was isolated from five of the endophytic fungi- Col letotrichum boni-nense, Fusarium solani, Col letotrichum incarnatum, Col letotrichum siamense and Col-letotrichum gloeosporioides for the first time and the sequence analysis showed high ho-mology (98%) to the Datura metel PMT cDNA. The gene was found to be devoid of introns in the fungi. Further phylogenetic analysis of the full length PMT sequence from the fungi strongly supports the hypothesis of horizontal gene transfer between the host plant and endophytic fungi. For further in detail characterization of fungal PMT, the Col letotrichum boninense PMT gene was taken as a representative. CbPMT gene was cloned in pRSET A expres-sion vector and heterologously expressed in E. coli and biochemically characterized. For optimal yield of soluble protein upon heterologous expression different conditions such as IPTG concentration, temperature and time post induction were optimized. Optimal yield was obtained by inducing the culture by 0.25 mM IPTG once it had reached and O.D. of 0.6 and incubating at 37◦ C for 3 h. The recombinant CbPMT enzyme expressed as histidine tagged fusion protein was purified using Ni-NTA affinity chromatography. Gel elution studies were carried out to determine molecular weight of the protein and it was found that the protein exists as a homodimer in solution with some amount also present as a monomer. Catalytic activity of the purified recombinant enzyme was studied for its dependence on both substrates putrescine as well as S-adenosylmethionine (SAM). The Km and Vmax values for putrescine were found to be 464 µM and 18.55 nkat/mg, respectively, while those for S-adenosylmethionine were found to be 628 µM and 18.63 nkat/mg, respectively. Optimum temperature for activity was found to be 37◦ C and optimum pH range was found to be 8-9. Fluorescence spectroscopy was used to study the binding affinity of both the sub-strates to the enzyme. Fluorescence quenching data for each substrate was analysed by using a nonlinear regression curve fit and Kd values were found to be 0.309 mM for pu-trescine and 0.118 mM for SAM, respectively. Circular dichroism spectrum of the enzyme indicated a pattern typical for alpha helix in the secondary structure. Binding of either substrate led to increase in ellipticity of the protein. Fluorescence quenching studies with collisional quenchers- acrylamide, potassium iodide, and cesium chloride indicated that the native protein is folded in a conformation that allows tryptophan residues to be acces-sible for quenching. The fraction of tryptophan residues (fa ) accessible for quenching by acrylamide (1.06) was found to be higher than that for potassium iodide (0.54) while that cesium ions was the least (0.38). The neutral quencher acrylamide could access all the tryptophans meaning that none of tryptophans are completely buried inside hydrophobic cores. the differential accessibility to the charged quenchers, however, indicates that more of the tryptophans are surrounded by positively charged amino acids. The unfolding of the protein was studied with the aid of chaotropic agents guanidine-HCl and urea and thermodynamic parameters were determined. The denaturant m-values were found to be 2.313 kcal/mol/M for Gdn-HCl and 2.345 kcal/mol/M for urea respectively. The free energy of unfolding was estimated to be 2.635 kcal/mol for Gdn-HCl and 4.630 kcal/mol for urea. Since no reports are available about the thermodynamics of folding and unfolding of PMT from any plant source, this study contributes towards the understanding of protein stability. Although a lot of reports are available on the biochemical characterization of PMT from different plant sources, the crystal structure of PMT is not yet available. In the current work, homology based modelling studies on CbPMT were carried out to get some idea about the protein tertiary structure. Homology based modelling studies showed that a significant amount of protein is present as α-helices which are present on the surface while the β-sheets are present in the interior of the protein. Each monomer of the protein is capable of binding both the substrates and hence the dimerization property of the enzyme could be a purely structural one leading to more stability and solubility of the protein. In conclusion, this study has shown for the first time that endophytic fungi have significant potential to be used for tropane alkaloid production and six such fungal strains have been identified. Although the production of tropane alkaloids by endophytic fungi is not very high, it can be scaled up by over-expressing the biosynthetic gene putrescine N-methyltransferase in the highest producer- Col letotrichum incarnatum to further increase the yield. These endophytic fungi have significant potential to be applied in fermentation technology to meet the demands for these drugs economically.