Orientadores: Maria Cristina Volpato, Francisco Carlos Groppo / Dissertação (mestrado profissional) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-11T23:02:37Z (GMT). No. of bitstreams: 1 Gamba_CarlaGoncalves_M.pdf: 490335 bytes, checksum: a284d83f154dafb6d75ba007f7de4dda (MD5) Previous issue date: 2008 / Resumo: A importância do controle da ansiedade está bem estabelecida na literatura, porém há poucas publicações a respeito de sua aplicação em serviço público de saúde. Assim, o objetivo deste trabalho foi comparar dois protocolos farmacológicos de controle da ansiedade em um serviço de atendimento odontológico público. Dentre os usuários do serviço odontológico da rede SUS do município de Vassouras, RJ, que apresentavam necessidade de tratamento odontológico, foram selecionados 103 voluntários com necessidades especiais ¿ PNE, ou doença crônica não transmissível - DCNT, classificados como ASA II, os quais foram submetidos a exodontia de dentes superiores, em estudo randomizado cruzado, sob 3 condições: 1. Midazolam (foram sedados 30 minutos antes do atendimento com 7,5mg de midazolam por via oral), 2. N2O/O2 (foram sedados com a mistura óxido nitroso/oxigênio durante atendimento), e 3. Sem sedação (foram atendidos sem sedação farmacológica). Foram avaliados os seguintes parâmetros: pré-operatório: grau de ansiedade; pré, trans e pós-operatório: pressões arteriais sistólica e diastólica, freqüências cardíaca e respiratória e saturação de oxigênio; pós-operatório: grau de controle de dor e a percepção sobre a ansiedade do paciente pelo cirurgião-dentista que realizou o procedimento odontológico e pelo voluntário. Também foram avaliados o volume de anestésico utilizado, o custo e o tempo dispendido no atendimento e a preferência do cirurgião-dentista e do voluntário com relação às sessões. De acordo com a variável estudada foram aplicados os testes Qui-Quadrado, Friedman, Mann-Whitney e Kruskal-Wallis (a = 0,05). Foram observados emprego de menor volume de solução anestésica e menores valores para as pressões arteriais sistólica e diastólica, freqüências cardíaca e respiratória nas sessões com sedação farmacológica (p<0,05). Os voluntários apresentaram menor (p<0,0001) ansiedade (auto-relato e relato pelo dentista) nas sessões com sedação. A maioria dos dentistas (88%) e dos voluntários (75%) preferiu a sedação com N2O/O2. O tempo de atendimento foi menor (p<0,05) na sessão com midazolam, sem diferença entre as demais (p>0,05). O custo da sedação é menor com uso de midazolam. Conclui-se que ambos os protocolos de sedação farmacológica foram eficazes em reduzir a ansiedade dos voluntários e promoveram atendimento com melhor controle dos parâmetros cardiocirculatórios. A sedação com midazolam pode ser mais vantajosa em serviço público, nas Unidades Básicas de Saúde (atendimento de baixa complexidade), considerando-se o menor tempo dispendido no atendimento e menor custo operacional, enquanto que a via inalatória poderia ser utilizada nos Centros de Especialidades Odontológicas para atendimento de média complexidade. Devido a importância do controle de ansiedade em pacientes com necessidades especiais, as Coordenações de Saúde Bucal deveriam optar pela capacitação de toda a rede para o uso de protocolos de controle da ansiedade. / Abstract: The importance of anxiety control is well established in the literature, but little is published about its application in public health facilities. The aim of this study was to compare two pharmacologic anxiety control protocols in a public health facility. Hundred and three ASA II subjects (controlled chronic diseases and patients with special needs) from the public dental service of Vassouras, RJ, were submitted to maxillary tooth extraction under the following conditions: 1. Midazolam (sedated with 7.5mg midazolam p.o. 30 min before dental treatment), 2. N2O/O2 (sedated with nitrous oxide/oxygen during dental treatment), and 3. (treated without pharmacologic sedation). The systolic and diastolic blood pressures, respiratory and heart rates and oxygen saturation were evaluated before, during and after dental treatment. The anxiety level was evaluated before each treatment; the perceptions about the dental treatment (anxiety and pain control) by the subject and the dentist who performed the treatment were evaluated at the end of each dental treatment. The volume of local anesthetic, cost and time for the procedures in each session were also evaluated. The subjects and dentists were asked what was the preferred session. The results were submitted to Chi-square, Friedman, Mann-Whitney and Kruskal-Wallis according to the parameter studied (a = 0.05). Less anesthetic volumes and lower values of systolic and diastolic pressures, and respiratory and heart rates were observed in the sessions with pharmacologic sedation (p<0.05). The volunteers presented lower (p<0.0001) anxiety levels (self evaluation and evaluation by dentist) in the sessions with pharmacologic sedation. The N2O/O2 sedation was preferred by most of the dentists (88%) and volunteers (75%). Less time (p<0.05) was expended in the midazolam session with no difference between the two other sessions (p>0.05). The cost of midazolam sedation was lower than that of N2O/O2 sedation. Both pharmacologic sedation protocols were able to reduce the anxiety of the volunteers with a better control of the cardiovascular parameters during the sessions than the observed in the session without pharmacologic sedation. Due to the lower cost and less treatment time offered by midazolam sedation this can be advantageous in public health service. The inhalation sedation with N2O/O2 could be used in public health facilities for medium complexity dental treatment. Public health dental professional should be qualified to offer anxiety control especially to medically compromised patients. / Mestrado / Odontologia em Saude Coletiva / Mestre em Odontologia em Saúde Coletiva

Bakgrund: Akuta krampanfall drabbar många människor, både nationellt och internationellt. Detta behandlas i första hand med Bensodiazepiner, såsom Diazepam och Midazolam. Sveriges prehospitala behandlingsriktlinjer skiljer sig åt vid behandling av akuta krampanfall. Region Halland förnyade behandlingsriktlinjerna år 2011 och införde intranasal administrering av Midazolam Syfte: Att sammanställa behandlingsriktlinjerna angående medicinsk behandling vid kramper prehospitalt i Sverige samt kartlägga användandet av bensodiazepiner vid kramper prehospitalt i Region Halland. Metod: En kvantitativ registerstudie med en retrospektiv design användes. En sammanställning av Sveriges prehospitala behandlingsriktlinjer för medicinsk behandling av kramper utfördes. Chi-Två samt Fishers exakta test användes vid analysen av den insamlade datan från 127 ambulansjournaler i Region Halland. Resultat: Sammanställningen av Sveriges prehospitala behandlingsriktlinjer vid kramper visade att behandlingsriktlinjerna skiljer sig åt nationellt. Resultatet från kartläggningen av användandet med bensodiazepiner vid kramper prehospitalt i Region Halland visade att Diazepam var det vanligast använda läkemedlet samt att det fanns en signifikant skillnad i behandlingen med Diazepam rektalt relaterat till patientens ålder. Flertalet patienter som hade behandlats med Midazolam intranasalt behövde kompletterande behandling med Diazepam intravenöst. Slutsats: Behandlingsriktlinjerna för kramper prehospitalt skiljer sig åt nationellt. Diazepam var det vanligast använda läkemedlet samt en bristfällig följsamhet till behandlingsriktlinjerna framkom i Region Halland. Mer forskning behövs avseende ambulanssjuksköterskors erfarenheter av att behandla pågående kramper prehospitalt för ge patienterna möjlighet till en god omvårdnad på ett säkert sätt. / Background: Acute seizures affects a large number of people both nationally and internationally. Seizures are primarily treated with benzodiazepines, such as Diazepam and Midazolam. Sweden's prehospital treatment guidelines differ in the treatment of acute seizures. Region Halland renewed the treatment guidelines in 2011 and introduced intranasal administration of Midazolam. Objective: To compile the treatment guidelines for medical treatment in prehospital seizures in Sweden and to survey the use of benzodiazepines in prehospital seizures in Region Halland. Method: A quantitative register study with a retrospective design was used. A compilation of Sweden's prehospital treatment guidelines was performed. Chi-Two and Fishers exact test are used in the analysis of the collected data from 127 ambulance journals in Region Halland.  Results: The compilation of Swedish prehospital treatment guidelines for seizures showed that the treatment guidelines differ nationally. The survey of the use of benzodiazepines in prehospital seizures in Region Halland showed that Diazepam was the most commonly used drug, and that there was a significant difference in treatment with Diazepam rectally related to the age of the patient. Most patients treated with Midazolam intranasally needed additional therapy with Diazepam intravenously. Conclusion: The prehospital treatment guidelines for seizures differs nationally. Diazepam was the most commonly used drug and the compliance with the treatment guidelines is inadequate in Region Halland. More research is needed regarding from the ambulance nurse's experiences of treating ongoing prehospital seizures in order to provide patients with proper care in a safe way.

Ce travail porte sur l’étude du risque de démence chez les personnes âgées ayant consommé des benzodiazépines. Ces médicaments méritent une attention particulière du fait de (i) leur utilisation trop systématique et le plus souvent chronique contrairement aux recommandations préconisant des durées d’utilisation courtes (ii) leurs effets délétères sur la cognition demeurant mal évalués à long terme. La plupart des études conduites sur ce sujet ont conclu à une augmentation du risque de démence chez les sujets ayant utilisé des benzodiazépines. Un biais protopathique pouvait cependant, en partie du moins, avoir expliqué ces résultats : la prescription de benzodiazépines pouvait avoir été motivée par des prodromes souvent observés au cours des années précédant le diagnostic de la maladie. Afin de mieux prendre en considération ce biais, le projet BENZODEM a utilisé les ressources de la cohorte PAQUID (3777 sujets ≥ 65 ans tirés au sort sur les listes électorales de Dordogne et Gironde bénéficiant d’un suivi de plus de 20 ans). Ce projet, combinant deux études de cohorte et une étude cas-­‐témoins, a conclu à un risque de démence augmenté de 46 à 62% chez les utilisateurs de benzodiazépines et retardé de 5 à 15 ans par rapport à l’initiation du traitement. La seconde partie du programme (BENZODEM2) a consisté en une étude cas-­‐témoins conduite sur un large échantillon de sujets de plus de 65 ans enregistrés sur la base de données de la Régie de l’Assurance Maladie du Québec (RAMQ). Ce programme a permis (1) de valider les précédents résultats (risque augmenté de 30 à 80% en fonction de la dose, la durée du traitement et la nature des molécules) (2) d’identifier les profils de consommation associés à un excès de risque : consommateurs de plus de 3 mois avec une relation dose-­‐effet marquée et molécules à longue demi-­‐ vie d’élimination. Des explorations complémentaires ont permis de conclure que cet excès de risque n’était pas expliqué par une mortalité différentielle entre groupes comparés ni par la prescription d’autres médicaments psychotropes. Une autre étude menée sur PAQUID montrait une absence de différence entre consommateurs et non consommateurs de benzodiazépines vis-­‐à-­‐vis de l’évolution des scores mesurant les fonctions cognitives. Ces résultats ont permis d’émettre des hypothèses concernant le mécanisme de l’association entre utilisation de benzodiazépines et démence: (1) les benzodiazépines pourraient constituer des marqueurs précoces de la maladie ; (2) les benzodiazépines pourraient aussi diminuer les capacités de recours à la réserve cognitive en réponses aux lésions précoces de la maladie au stade préclinique ; (3) il est aussi possible que ces deux explications soient combinées. / This work deals with the risk of dementia in elderly individuals who have used benzodiazepines. These drugs deserve particular attention because (i) their use appears to be too systematic and most often chronic despite good practice guidelines recommending short durations of use (ii) their deleterious effects on cognition remain underevaluated for the long-­‐term. Most of the studies conducted concluded that there was an increased risk of dementia among benzodiazepine users. In fact, a protopathic bias could, at least in part, have explained these results. Indeed, the prescription of benzodiazepines could have been motivated by the prodromes often observed several years before the clinical diagnosis of a dementia. With the aim of better controlling for this bias, the BENZODEM project used the resources of the PAQUID cohort (3777 subjects ≥65 years randomly sampled from electoral lists in South-­‐West France, with a 20-­‐ year follow-­‐up). This project combined two cohort studies and one case-­‐control. These studies concluded in a risk of dementia increased by 46 to 62% in benzodiazepine users and delayed by 5 to 15 years after treatment initiation. The second part of the programme (BENZODEM2) consisted of a case-­‐control study conducted in a large sample of subjects >65 years registered in the Quebec Health care database (Régie de l’Assurance Maladie du Québec, RAMQ). It was thus possible(1) to validate the previous results by using a different population (the risk was found to be increased by 30 to 80% depending on the patterns of use regarding dose, duration and type of molecule), (2) to identify the patterns of use which appeared to be at risk; excess risk was only apparent for uses of more than three months with a marked dose-­‐effect relationship, and was higher for molecules with a long elimination half-­‐life. Complementary explorations using the PAQUID cohort indicated that the excess risk in exposed was not explained by a differential mortality rate between the groups compared. Other studies suggested that the link found remained independently of the prescription of other psychotropics. Another analysis in the PAQUID cohort showed that, in the absence of dementia, no difference was observed between benzodiazepine users and non-­‐users with regards to the evolution of scores evaluating cognitive functions. These results led to several assumptions about the putative mechanism explaining the relationship found between benzodiazepine use and dementia: (1) benzodiazepines could be early markers of symptoms such as anxiety, depression or insomnia, which are potential prodromes or risk factors for this disease, (2) these drugs could also reduce the ability to use cognitive reserve in order to cope with early lesions of the disease during the preclinical stage, (3) the association found could also result from these two mechanisms.

Development and validation of methods for analysis of several drugs or their metabolites are decribed in this thesis. The document is presented as a commentary to the original papers, which were published in peer reviewed journals. Discussion on the optimization of each method is presented and covers also method development and influence of preanalytical aspects. Additionally, examples of the application of the developed methods in clinical pharmacology and toxicology are shown. This dissertation consists of three parts: enantiomeric determination of tramadol and its metabolite, determination of some antihypertensive drugs, and qualitative analysis of benzodiazepines. Development of a method for chiral analysis of tramadol and its desmethylated metabolite O- desmethyltramadol (ODT) in human urine and plasma is described in the first part of the thesis. Tramadol is a centrally acting analgetic drug, which is used as racemate in clinical practise. Each enantiomer displays different binding properties for various receptors: (+)-tramadol preferentially inhibits serotonin reuptake while (-)-tramadol mainly inhibits noradrenalin reuptake. (+)-tramadol is considered 10-times more potent than (-)-tramadol. Major active metabolite (ODT), which is considered to be the main agent responsible for the...

Tranquilizer misuse is a behavior associated with substance use disorder. As of now there is only one published article that includes a predictive model on misuse of subscription tranquilizers. The aim of this study is to predict ongoing tranquilizer misuse whilst comparing three different methods of classification; (1) regularized logistic regression, (2) adaptive boosting and (3) support vector machines. Data from the National Survey of Drug Use and Health (NSDUH) from 2019 is used to predict misuse among the individuals in the sample from 2020. The regularized logistic regression and the support vector machines models both yield an AUC of 0.88, which is slightly higher than the adaptive boosting model. However, the support vector machine model yields a higher level of sensitivity, meaning that it is better at detecting individuals who misuse. Although the difference in performance between the methods is relatively small and is most likely caused by the fact that different methods perform differently depending on the characteristics of the data.

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Institution/department: Charles University, Faculty of Pharmacy in Hradec Králové, Department of Social and Clinical Pharmacy Title of diploma thesis: Rationality of benzodiazepine use in older patients Supervisor: Assoc. Prof. Daniela Fialová, PharmDr. Ph.D. Author: Adriana Magátová Introduction: Benzodiazepines are one of the most commonly prescribed potentially inappropriate drugs (PIMs) in geriatric patients in Europe and are responsible for common problems associated with risky drug prescription in older age (eg, cognitive impairment, falls, orthostatic hypotension, drug dependence, and others). Physiological and pathophysiological changes associated with the aging process, as well as frequent polymorbidity and polypharmacotherapy, are associated with more frequent occurrence of drug-related complications in older age. With the growing proportion of geriatric population, the importance of preventing drug complications in older adults increases. The aim of this study was to compare prescribing habits in the use of BZD and in the use of drug combinations with sedative potential and to determine the association of their use with drug-related risks in geriatric patients in community pharmacy practice in Spain (SP) and the Czech Republic (CZ) and in groups of patients assessed in various healthcare settings...

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GABA is the main inhibitory neurotransmitter of the central nervous system. GABA[subscript A]Rs are multimeric transmembrane receptors, which are composed of 5 subunits. It is known that there are 19 subunits that can make up the GABA[subscript A]Rs, allowing for a vast array of receptor subtypes. In addition to the GABA binding site GABA[subscript A]Rs have distinct allosteric binding sites for benzodiazepines, barbiturates, ethanol, certain general anaesthetics and neuroactive steroids. The molecular heterogeneity of the GABA[subscript A]R is accompanied by distinct pharmacological profiles of the different receptor subtypes. The advance of transgenic mouse models has allowed the functional significance of this heterogeneity to be studied in vivo. Therefore, this thesis utilises a variety of transgenic mouse models carrying either mutations or deletions of certain subunits to study the functional significance of the receptor heterogeneity. Mice lacking the α1 subunit (α1[superscript(-/-)]), carrying a point mutation of the α1 subunit (α1H101R), and mice lacking the δ subunit (δ[superscript(-/-)]) have been utilised to investigate the role of these subunits in the sedative actions of benzodiazepines and the GABA[subscript A]R agonist THIP. Although there are limitations to the interpretation of these results due genetic background of the α1[superscript(-/-)] and α1H101R, experiments suggest that the α1H101R mutation is not behaviourally silent as previously suggested and provide further evidence that the α1 subunit mediates the sedative properties of benzodiazepines. These experiments also reveal that the extrasynaptic δ containing receptors are responsible for mediating the sedative effects of THIP, and these findings combined with evidence from collaborators, implicates the thalamus as an anatomical mediator of these effects. An investigation of the putative cognitive enhancing effects of THIP using an attentional set-shifting task for mice suggested that pre-treatment with THIP reduces the number of errors to reach criterion. δ[superscript(-/-)] mice could not be trained to perform the task, therefore further behavioural investigation of these mice was performed, which suggested a heightened level of anxiety and reduced motivation for a food reward. This thesis has furthered our understanding of the functional role of GABA[subscript A]R subtypes. With the advance in genetic manipulations that allow for regionally selective mutations of the receptor the anatomical structures involved in these functions can be identified.

Our research aim was to design, synthesize, and study the competitive enzyme inhibition kinetics of pyrrolo[2,1-c][1,4]benzodiazepine (PBD) derivatives as potential non-²-lactam ²-lactamase inhibitors. All compounds (1-13) passed the Lipinski’s rule of 5 test and were docked into the active site of TEM-1 ²-lactamase. PBD derivatives 1-7 were synthesized in high yields and tested for their potency against TEM-1 and P99 ²-lactamases. Kinetic data showed that compounds 1, 4, 5, and 7 possessed inhibitory activity against TEM-1 ranging from 4-34 %. Docking results revealed significant interactive spanning of the active site of TEM-1 by PBDs. The limited inhibitory activity of the compounds, 1-7 could be attributed to the lack of solubility and bulky nature of the molecules, thus limiting the optimal ligand-enzyme interactions. 1,2,4- Oxadiazolinones (8-13) were further synthesized to reduce the steric hindrance of the PBD scaffolds while promoting the electrophilicity of the potentially active lactam and also evaluated for potency.