Objectives Main objectives of this doctoral thesis were to review available information on pharmacological properties of benzodiazepines and their age-related changes; to evaluate the prevalence of benzodiazepine use in older patients residing in long term care facilities; to investigate the association between use of benzodiazepines and occurrence of falls in acutely hospitalized older patients; and to describe utilization of benzodiazepines in the Czech Republic. Methods A narrative review of literature focused on pharmacokinetics, pharmacodynamics, adverse effects and association of benzodiazepines with falls in older population was conducted. The evaluation of benzodiazepine use in long term care facilities was analysed in a retrospective cross-sectional study using data from the EC 7th Framework Program SHELTER project (Service and Health in the Elderly in Long Term Care). A prospective cohort study data of acutely hospitalized patients in Australia were used to evaluate association between benzodiazepines and falls. To describe utilization of benzodiazepines in the Czech Republic, data from the State Institute for Drug Control and from databases of General Health Insurance Fund were used. This dissertation thesis is a summary of published articles from above stated works and analyses. Results...

Contexte : Les benzodiazépines (BZD) et substances apparentées sont consommées de façon chronique par une large proportion de la population de personnes âgées souffrant d’insomnie chronique. Cet usage dans cette population est cependant critiqué, pour le risque d’effets indésirables associés. La thérapie cognitivo-comportementale pour insomnie (TCC-I) constitue le traitement de première ligne pour lutter contre l’insomnie, en raison de son efficacité et de son innocuité. Objectif : L’objectif de ce projet de recherche est d’évaluer les changements de la qualité du sommeil, de la macroarchitecture et de la microarchitecture du sommeil après un sevrage de BZD chez la personne âgée souffrant d’insomnie chronique. Nous étudierons par la suite l’effet de la TCC-I couplé au sevrage sur les mêmes variables d’intérêts. Nous faisons l’hypothèse que le sevrage s’accompagnera d’une amélioration de la qualité subjective du sommeil (diminution de l’Index de Sévérité de l’Insomnie (ISI) et augmentation de l’efficacité de sommeil (SE)) et d’une modification de certaines variables distinctes : fuseau de sommeil et stade N3 (augmentation du pourcentage au stade N3 et diminution de la densité des fuseaux de sommeil). De plus, nous faisons l’hypothèse que ces changements seront plus prononcés avec la TCC-I couplée au sevrage. Méthodes : 41 participants (âge moyen : 69.39±6.88 ans) ont été randomisés en 2 groupes, stratifiés pour l’âge, la durée et la dose de BZD et apparentés consommés : le groupe sevrage+TCC-I (N=23) et le groupe sevrage (N=18). L’ensemble des participants complètent un plan de sevrage avec suivi de 16 semaines, et dans le même temps, uniquement le groupe sevrage+TCC-I reçoit la TCC-I. L’acquisition des données est réalisée avant et après sevrage à partir de questionnaire (ISI), agenda de sommeil (SE) sur une période de 14 jours, et par enregistrements polysomnographiques (stade N3 et densité des fuseaux de sommeil). Résultats : 60.98% des participants (groupe sevrage+TCC-I: 60.87% ; groupe sevrage: 61.11%) ont réussi une cessation complète de leurs médications après sevrage. Il a été constaté une diminution de l’ISI (F(1,40)=4.36, p=0.01) et de la densité des fuseaux de sommeil (F(1,36)=7.18, p=0.01) après sevrage. Enfin, la TCC-I couplée au sevrage a montré une augmentation plus importante de la SE (F(1,35)=6.75, p=0.01) par rapport au groupe sevrage. Conclusion : Le plan de sevrage avec suivi permet d’obtenir un sevrage complet chez une majorité de participants, sans qu’il ne soit observé d’aggravations significatives de leur qualité de sommeil. L’ajout d’une TCC-I lors d’un sevrage de BZD et apparentés a permis une amélioration plus importante de la qualité du sommeil auto-rapportée (Agenda de sommeil : SE). / Background: Benzodiazepines (BZD) and related drugs are consumed chronically by a large part of the elderly population with chronic insomnia. However, this use in this population is criticized for the risk of associated side effects. Cognitive behavioral therapy for insomnia (CBT-I) is the first-line treatment for insomnia because of its efficacy and safety. Objective: The objective of this project is to assess changes in sleep quality, macroarchitecture and sleep microarchitecture after withdrawal from BZD in the elderly with chronic insomnia. Then, we study the effect of CBT-I coupled with withdrawal on the same variables of interest. We hypothesize that weaning will be accompanied by an improvement in the subjective sleep quality (decrease in Insomnia Severity Index (ISI) and increase in sleep efficiency (SE)) and a modification of certain distinct variables: sleep spindle and stage N3 (increase in the percentage at stage N3 and decrease in the density of sleep spindles). In addition, we hypothesize that these changes will be more pronounced with CBT-I coupled with weaning. Methods: 41 participants (mean age: 69.39 ± 6.88 years) were randomized into 2 groups; stratified for age, duration and dose of BZD and relatives consumed: the weaning+CBT-I group (N = 23) and the weaning group (N = 18). All participants complete a 16-week weaning plan with follow-up, and at the same time, only the therapy group receives CBT-I. Data acquisition is carried out before and after weaning from questionnaire (ISI), sleep diary (SE) over a period of 14 days, and by polysomnographic recordings (stage N3 and density of sleep spindles). Results: 60.98% of participants (weaning+CBT-I group: 60.87%; weaning group: 61.11%) succeeded in completely stopping their medication after withdrawal. A decrease in ISI (F(1.40) = 4.36, p = 0.04) and in sleep spindle density (F(1.36) = 7.18, p = 0.01) was observed after weaning. Finally, CBT-I coupled with weaning showed a greater increase in SE (Sleep Diary; F(1.35) = 6.75, p = 0.01) compared to the control group. Conclusion: The weaning plan with follow-up makes it possible to obtain complete weaning in a majority of participants, without any significant worsening of their quality of sleep being observed. The addition of CBT-I during withdrawal from BZD and related products resulted in a greater improvement in self-reported sleep quality (Sleep Diary: SE).

No description available.

BACKGROUND AND OBJECTIVES: Sexual minority individuals demonstrate disparate rates of substance use. Research suggests that bisexual women are vulnerable to substance use disorders when compared to other sexual minority groups. This study explored differences in prevalence of past-year alcohol use disorder (AUD) with and without concurrent past-year opioid and/or benzodiazepine misuse. METHODS: The present study utilized responses from the National Survey on Drug Use and Health (NSDUH) public dataset between the years 2015-2019 (N = 16,002) to examine the association between sexual orientation and concurrent misuse of opioids and/or benzodiazepines among individuals with past-year AUD, stratified by sex. RESULTS: Bisexual females demonstrated higher rates of concurrent opioid and benzodiazepine use compared to all other groups. Although there was no association between sexual orientation and concurrent substance use patterns among males, female respondents with past-year AUD endorsing past-year misuse of opioids and benzodiazepines, both alone and in combination, were more likely to be bisexual compared to heterosexual. Lesbians were less likely to endorse concurrent misuse of opioids and benzodiazepines compared to bisexual females. DISCUSSION AND CONCLUSIONS: In a national sample, bisexual females demonstrated higher odds of risky concurrent substance use patterns. Identifying sexual minority individuals who exhibit elevated risk of co-occurring alcohol, opioid, and/or benzodiazepine misuse is an important step to targeted prevention efforts and allocation of resources to combat rising overdose deaths. SCIENTIFIC SIGNIFICANCE: For the first time, this study explored risky concurrent alcohol, opioid, and benzodiazepine misuse patterns among individuals of different sexual orientations.

<p>Metadon je sintetski agonist opijatnih receptora koji se primenjuje u sklopu supstitucione terapije opijatnih zavisnika metadonom (STM) i u terapiji hroničnog bola. Dugoročna primena STM je praćena blagim, uglavnom prolaznim, neželjenim delovanjima. Međutim, metadon pripada grupi lekova koji mogu da prouzrokuju prolongaciju korigovanog QT intervala (QTc) u elektrokardiogramu (EKG-u) i povećaju rizik za nastanak potencijalno fatalnih aritmija tipa torsades de pointes. Opijatni zavisnici metadon najče&scaron;će koriste u kombinaciji sa benzodiazepinima, i ova kombinacija lekova predstavlja faktor rizika za nastanak smrtnog ishoda. Iako je najveći broj lekara upoznat sa rizikom za razvoj respiratorne depresije prilikom primene opijata u kombinacji sa benzodiazepinima, velika studija otkriva da su ventrikularne aritmije i srčani zastoj najče&scaron;će prijavljivana neželjena delovanja metadona, primenjenog u kombinaciji sa benzodiazepinima. Ciljevi ovoga radu su da se analizom smrtnih slučajeva povezanih sa upotrebom metadona (MRDs) tokom desetogodi&scaron;njeg perioda na teritoriji Vojvodine i sprovođenjem kliničkog ispitivanja kod opijatnih zavisnika na STM proceni kardiolo&scaron;ka bezbednost primene metadona, posebno u kombinaciji sa benzodiazepinima. Sprovedena je retrospektivna studija za određivanje karakteristika MRDs na teritoriji Vojvodine, kao i kliničko ispitivanje u kome su učestvovali opijatni zavisnici koji počinju sa STM. Snimanje EKG-a (za izračunavanje QTc intervala) i uzorkovanje krvi (za određivanje koncentracije metadona i diazepama i vrednosti troponina) je sprovedeno kod svih učesnika istraživanja u 5 vremenskih tačaka (pre početka primene STM, 8. i 15. dana i nakon 1. i 6. meseca primene STM). Koncentracije metadona i diazepama u serumu su određivane metodom tečne hromatografije sa masenom spektrometrijom (LC-MS). U Vojvodini je zapažena rastuća tendencija MRDs, ali ni jedan od umrlih nije bio na STM, i najverovatnije su samoinicijativno koristili metadon i benzodiazepine. Patohistolo&scaron;ki nalaz na srcu može govoriti u prilog kardiotoksičnosti metadona i njegove kombinacije sa benzodiazepinima, pogotovo kod slučajeva sa pronađenim akutnim miokardijalnim o&scaron;tećenjem. &Scaron;to se tiče hroničnih promena na srcu, ne postoji mogućnosti da se potvrdi niti opovrgne uloga psihostimulanasa. Detektovane koncentracije metadona i diazepama kod MRDs su bile u opsegu terapijskih (&lt;1 &mu;g/ml). Poredeći socio-demografske karakteristike opijatnih zavisnika koji su počeli sa STM u ovom istraživanju sa podacima iz sličnih studija sprovedenih &scaron;irom sveta, zapažena je sličnost u pogledu velikog broja karakteristika. Srednje doze metadona 8., 15. dana i nakon 1. i 6. meseca primene STM su bile 40,23&plusmn;17,11 mg, 47,11&plusmn;16,79 mg, 50,00&plusmn;17,55 mg i 78,63&plusmn;18,14 mg, dok su srednje doze diazepama u istim vremenskim tačkama bile 35,92&plusmn;10,47 mg, 33,89&plusmn;9,23 mg, 28,33&plusmn;11,55 mg i 28,12&plusmn;11,67 mg. Srednje koncentracije metadona su u posmatranim tačkama ispitivanja iznosile 153,44&plusmn;111,51 ng/ml, 157,43&plusmn;112,39 ng/ml, 176,77&plusmn;118,56 ng/ml i 342,86&plusmn;181,54 ng/ml, dok su srednje koncentracije diazepama bile 923,00&plusmn;537,89 ng/ml, 923,76&plusmn;739,96 ng/ml, 560,74&plusmn;436,72 ng/ml i 1045,32&plusmn;932,72 ng/ml. Dužina QTc intervala pre primene STM je bila 411,87&plusmn;27,22 ms, tj. 414,64&plusmn;29,38 ms 8. dana STM, 416,97&plusmn;26,39 15. dana, i 425,20&plusmn;17,71 ms nakon 1. meseca tj. 423,50&plusmn;14,72 ms nakon 6. meseca primene STM. Pokazan je statistički značajan porast dužine QTc intervala nakon 1. i nakon 6. meseca primene STM u odnosu na vrednost pre primene STM, kako u grupi svih ispitanika, tako i u podgrupi mu&scaron;kog pola. Pokazano je postojanje statistički značajne korelacije između koncentracije metadona i dužine QTc intervala nakon 15. dana, 1. i 6. meseca primene STM, kako kod svih ispitanika, tako i u podgrupi mu&scaron;kog pola. Ova korelacija ostaje statistički značajna i ukoliko se uključe i drugi faktori &ndash; koncentracija diazepama i dužina perioda upotrebe heroina, kod svih ispitanika i u podgrupi mu&scaron;kog pola nakon 15 dana i mesec dana primene STM, kao i u podgrupi mu&scaron;kog pola nakon 6. meseca STM. Iako nijedan pacijent nije prijavio neko neželjeno delovanje metadona na nivou kardiovaskularnog sistema, najveći broj pacijenata oba pola se nakon prvog meseca primene STM žalio na pojačano znojenje i opstipaciju. Koncentracije metadona i diazepama u uzorcima krvi kod MRDs se nalaze u rasponu koncentracija ovih lekova u krvi ispitanika koji su učestvovali u prospektivnoj studiji. Trećina umrlih je imala samo znake akutnog o&scaron;tećenja srca, dok do porasta troponina i vrednosti QTc intervala preko 500 ms nije do&scaron;lo ni kod jednog ispitanika iz prospektivne studije. Potrebno je sprovesti dalja istraživanja sa ciljem razja&scaron;njenja moguće uloge benzodiazepina u povećanju kardiotoksičnosti metadona kod opijatnih zavisnika na STM.</p> / <p>Methadone is a synthetic agonist of opioid receptors which is used in methadone maintenance tratment (MMT) of opiate addicts as well as in the treatment of chronic pain. A long-term use of MMT is followed by mild, mostly transient, adverse effects. However, methadone belongs to a group of medicines which can provoke a prolongation of QTc (corrected QT) interval in electrocardiogram (ECG) and thus increase the risk from the development of potentially fatal arrhythmias &ndash; torsades de pointes. Moreover, methadone is widely associated with benzodiazepines use in heroin addicts, and this combination is considered as a risk factor for lethal outcome. Despite the fact that most of health care professionals are aware of possible respiratory depressant effect of methadone and benzodiazepines co-administration, recently published data reveal that ventricular arrhythmia and cardiac arrest are currently the most frequent adverse event attributed to methadone and benzodiazepine co-medication. The aim of this study is to assess cardiac safety of methadone use, especially in combination with benzodiazepines, by analyzing characteristics of methadone-related deaths (MRDs) during 10-year period as well as by conducting a clinical trial among opiate addicts in MMT. A retrospective study to determine the characteristics of MRDs in Vojvodina, as well as a clinical trial in which participated opiate addicts at the start of MMT were performed. ECG (to calculate QTc interval) and blood sampling (to determine methadone and diazepam concentrations and troponin values) were performed in all study participants at five time points (before the introduction of MMT, on 8th, on 15th day, after 1 and 6 months of MMT). Methadone and diazepam concentrations in serum were determined by using liquid chromatography-mass spectrometry (LC-MS). An increasing tendency of MRDs was observed in the region of Vojvodina, but none of the victims were under healthcare professionals&rsquo; control, and, most commonly, they used methadone and benzodiazepines, on their own initiative. Pathohistological findings in the heart in MRDs might support cardiac adverse effects of methadone and its combination with benzodiazepines, especially in cases with acute myocardial damage. As for the chronic heart changes, we can neither confirm nor exclude the role of psychostimulants. Detected concentrations of methadone and diazepam were in therapeutic range (&lt;1 &mu;g/ml). Comparing socio-demographic characteristics of opiate addicts who started with MMT in this study with data from similar studies conducted worldwide, the similarity in terms of large number of features was observed. The mean methadone dose on the 8th, 15th days, and after 1 and 6 months of MMT was 40.23&plusmn;17.11 mg, 47.11&plusmn;16.79 mg, 50.00&plusmn;17.55 mg and 78.63&plusmn;18.14 mg, respectively, while the mean diazepam dose at the same time points was 35.92&plusmn;10.47 mg, 33.89&plusmn;9.23 mg, 28.33&plusmn;11.55 mg and 28.12&plusmn;11.67 mg, respectively. The mean methadone concentration at observed time points was 153.44&plusmn;111.51 ng/ml, 157.43&plusmn;112.39 ng/ml, 176.77&plusmn;118.56 ng/ml and 342.86&plusmn;181.54 ng/ml, respectively, while the mean diazepam concentration was 923.00&plusmn;537.89 ng/ml, 923.76&plusmn;739.96 ng/ml, 560.74&plusmn;436.72 ng/ml and 1045.32&plusmn;932.72 ng/ml, respectively. The length of QTc interval before the introduction of MMT was 411.87&plusmn;27.22 ms, 414.64&plusmn;29.38 ms on the 8th day of MMT, 416.97&plusmn;26.39 on the 15th day of MMT, after 1 month of MMT 425.20&plusmn;17.71 ms and after 6 months of MMT 423.50&plusmn;14.72 ms. There was a statistically significant increase in the length of QTc interval after 1 and 6 months of MMT in comparison to the value before the application of MMT, within the whole group of patients and in the subgroup of men. A statistically significant correlation between the concentration of methadone and QTc interval length after 15 days, 1 and 6 months of MMT, both in the whole group and in the subroup of men was observed. The correlation remained statistically significant if the other factors, such as concentration of diazepam and the length of heroin use, were included, in all patients and in the subgroup of men after 15 days and one month of MMT as well as in the subgroup of men after 6 months of MMT. Although none of the patients reported any cardiac adverse effect of methadone, the majority of them complained of sweating and constipation after the first month of MMT. Concentrations of methadone and diazepam in blood samples in MRDs were within the range of concentrations of these drugs in blood of patients who participated in the prospective study. In one third of MRDs only signs of acute myocardial damage were detected, while an increase in troponin values and the length of QTc interval over 500 ms did not occur in any patient in the prospective study. Further studies could clarify the possible role of benzodiazepines in the increasing cardiotoxicity of methadone in opiate addicts in MMT.</p>

L’insomnie, commune auprès de la population gériatrique, est typiquement traitée avec des benzodiazépines qui peuvent augmenter le risque des chutes. La thérapie cognitive-comportementale (TCC) est une intervention non-pharmacologique ayant une efficacité équivalente et aucun effet secondaire. Dans la présente thèse, le coût des benzodiazépines (BZD) sera comparé à celui de la TCC dans le traitement de l’insomnie auprès d’une population âgée, avec et sans considération du coût additionnel engendré par les chutes reliées à la prise des BZD. Un modèle d’arbre décisionnel a été conçu et appliqué selon la perspective du système de santé sur une période d’un an. Les probabilités de chutes, de visites à l’urgence, d’hospitalisation avec et sans fracture de la hanche, les données sur les coûts et sur les utilités ont été recueillies à partir d’une revue de la littérature. Des analyses sur le coût des conséquences, sur le coût-utilité et sur les économies potentielles ont été faites. Des analyses de sensibilité probabilistes et déterministes ont permis de prendre en considération les estimations des données. Le traitement par BZD coûte 30% fois moins cher que TCC si les coûts reliés aux chutes ne sont pas considérés (231$ CAN vs 335$ CAN/personne/année). Lorsque le coût relié aux chutes est pris en compte, la TCC s’avère être l’option la moins chère (177$ CAN d’économie absolue/ personne/année, 1,357$ CAN avec les BZD vs 1,180$ pour la TCC). La TCC a dominé l’utilisation des BZD avec une économie moyenne de 25, 743$ CAN par QALY à cause des chutes moins nombreuses observées avec la TCC. Les résultats des analyses d’économies d’argent suggèrent que si la TCC remplaçait le traitement par BZD, l’économie annuelle directe pour le traitement de l’insomnie serait de 441 millions de dollars CAN avec une économie cumulative de 112 billions de dollars canadiens sur une période de cinq ans. D’après le rapport sensibilité, le traitement par BZD coûte en moyenne 1,305$ CAN, écart type 598$ (étendue : 245-2,625)/personne/année alors qu’il en coûte moyenne 1,129$ CAN, écart type 514$ (étendue : 342-2,526)/personne/année avec la TCC. Les options actuelles de remboursement de traitements pharmacologiques au lieu des traitements non-pharmacologiques pour l’insomnie chez les personnes âgées ne permettent pas d’économie de coûts et ne sont pas recommandables éthiquement dans une perspective du système de santé. / Insomnia is common in the geriatric population, typically treated with benzodiazepine drugs which can increase the risk of falls. Cognitive behavioral therapy (CBT) is a non-pharmacological intervention with equivalent efficacy and no adverse events. This thesis compares the cost of benzodiazepines versus CBT for the treatment of insomnia in older adults, with and without consideration of the additional cost of falls incurred by benzodiazepine use. A decision tree model was constructed and run from the health payer’s perspective over 1 year. The probability of falls, ER visits, hospitalisation with and without hip fracture, cost data and utilities were derived from a comprehensive literature review. Cost consequence, cost utility and potential cost saving analyses were performed. Both probabilistic and deterministic sensitivity analyses were conducted to account for uncertainty around the data estimates. Benzodiazepine treatment costs 30% less than the price of CBT when the costs of falls are not considered (CAN $231 vs. CAN $335 per individual per year). When the cost of falls is considered, CBT emerges as the least expensive option (absolute cost-saving CAN$ 177 per person per year, CAN $1,357 with benzodiazepines vs. $1,180 for CBT). CBT dominated benzodiazepines, with a mean cost saving of CAN $ 25,743 per QALY gained with CBT due to fewer falls. The cost savings analysis shows that if the CBT were to completely replace benzodiazepine therapy, the expected annual direct cost savings for the treatment of insomnia would be $ 441 million CAD dollars, with a cumulative cost savings of $112 billion CAD dollars over 5-years. The PSA report shows that even at different varying parameters, benzodiazepines cost CAD$ 1,305, S.D $ 598 (range 245-2,625) on average / person / year vs. CAD$ 1,129, S.D $ 514 (range 342-2,526) on average / person / year for CBT. Current treatment reimbursement options that fund pharmacologic therapy instead of non-pharmacologic therapy for geriatric insomnia are neither cost-saving nor ethically recommendable from the health system’s perspective.

Les patients admis aux soins intensifs (SI) souffrent de comorbidités qui affectent leur pronostic. Deux problèmes sont potentiellement associés aux sédatifs et compliquent le séjour de 35 à 50% des malades : le délirium, un état confusionnel aigu; et le coma ‘iatrogénique’, une altération de la conscience induite pharmacologiquement. L’importance de l’association entre clinique et médicaments a un intérêt pour prévenir ces syndromes cliniques morbides. Nous voulions étudier le délirium et le coma iatrogénique, les doses administrées de midazolam et de fentanyl, leurs niveaux plasmatiques, les variantes génétiques de métabolisme et de transport et les facteurs inflammatoires et ce, chez 100 patients admis aux soins intensifs. Nos données soulignent l’importance des interactions médicamenteuses dans l’incidence du coma iatrogénique, et réfutent l’association entre les benzodiazépines et le délirium. Ces résultats clarifient la pathophysiologie du délirium, corroborent le manque d’association délirium-benzodiazépines avec un marqueur biologique, c.-à-d. les niveaux sériques, et ouvrent le débat quant aux agents les plus utiles pour traiter l’anxiété et le délirium. Finalement, plusieurs caractéristiques pharmacocinétiques des benzodiazépines administrées aux soins intensifs publiées récemment complètent les données de notre étude quant à la sédation en soins critiques. Un chapitre sur l’importance de la pharmacogénomique en soins intensifs et un débat publié quant au pro et con de l'utilisation des benzodiazépines aux SI, sont soumis en complément de l’étude clinique décrite ci-haut effectuée dans le cadre de cette maîtrise. / Critically ill patients suffer from co-morbid conditions that impact on their prognosis. Two problems complicate Intensive Care Unit (ICU) stay in 35-50% of patients and are potentially associated with sedatives: delirium, an acute confusional state, and 'iatrogenic' coma, when consciousness is altered pharmacologically. Establishing the association between these clinical syndromes and administering sedatives is key in planning effective prevention of these morbid complications. We studied iatrogenic delirium and coma in 100 ICU patients given midazolam and/or fentanyl, and tallied drug doses, measured plasma levels, genetic variations in metabolism and transport and inflammatory factors. Our data highlight the role drug-drug interactions play in iatrogenic coma, and refute the association between benzodiazepines and delirium. These results clarify the pathophysiology of delirium, corroborate the lack of delirium-benzodiazepine association with a benzodiazepine biological marker, i.e. serum levels, and open the debate as to which agents are useful for treating anxiety and delirium. Recent publications addressing benzodiazepine pharmacokinetics in critical care complement our data in the field of critical care sedation. A chapter on the importance of pharmacogenomics in intensive care, and a published pro-con debate as to benzodiazepine use in critical care are submitted in addition to the clinical study mentioned above as part of this master’s thesis.

4-Alkyl-L-proline derivatives (APD) are specialized precursors involved in the biosynthesis of at least three groups of different natural compounds: some pyrrolo-1,4-benzodiazepines with antitumor activity, bacterial hormone hormaomycin and clinically used lincosamide antibiotic lincomycin. These compounds share a biosynthetic pathway encoded by 5 or 6 homologous genes present in the biosynthetic gene clusters of the producing organisms. Similarities in biosynthesis and differences between APD structures of these compounds could be used to prepare a hybrid producing strain of biologically more effective lincomycin derivative. Unusual amino acid 4-propyl-L-proline (PPL) is the APD precursor of lincomycin. The originally proposed scheme of the PPL pathway does not comply with our current knowledge. Therefore, it was necessary to revise this scheme according to new results. The first two steps of the PPL pathway are functionally proved. Probing the next step was the main aim of this work. The protein LmbW was overproduced and its methyltransferase activity was confirmed in vitro. LmbW is able to directly methylate intermediate of second step of the pathway while the originally scheme proposed methylation at a later stage of biosynthesis. LmbW is also able to attach a longer alkyl chain to its substrate. This...

O avanço econômico, científico e tecnológico, vem levando a um aumento da expectativa de vida e consequente envelhecimento da população. Assim, o idoso requer atenção especial pela maior incidência de doenças crônicas e degenerativas e pelo aumento concomitante no uso de fármacos, podendo ocasionar complicações pela sua maior vulnerabilidade à eventos adversos (EAs), uso inapropriado e abusivo, exposição à interações medicamentosas sérias, e casos de iatrogenias. Acrescenta-se o fato particular de um aumento abusivo no uso de benzodiazepínicos (BDZs). O objetivo deste trabalho foi rever e sintetizar as evidências geradas por ensaios clínicos controlados e randomizados sobre a incidência de EAs relacionados ao uso de BDZs em idosos com ansiedade ou insônia em comparação àqueles que, sob as mesmas condições clínicas, não o utilizaram. Desenvolveu-se a recuperação de artigos em cinco bases de dados eletrônicas na área da saúde (PubMed, SCOPUS, Web of Science, Cochrane Central, e LILACS), para posterior análise combinada (metanálise) dos resultados evidenciados. / The economic, scientific and technological progresses have provided an increase in life expectancy and the consequent process of aging. Thus, the elderly requires special attention due to the higher incidence of chronic and degenerative diseases and the higher concomitant increase in the drugs use that may cause complications by increasing ulnerability for adverse events (AEs); nappropriate and abusive use; exposition to serious drug interactions, and iatrogenic cases. Add to these the particular abusive increase in benzodiazepine (BDZ) use. The objective of this study was to review and synthesize the evidence generated by randomized controlled trials on the incidence of AEs related to therapy with BDZs in elderly with anxiety or insomnia compared to those under the same clinical conditions, not medicated. The articles were recovered in five healthcare electronic databases (PubMed, SCOPUS, Web of Science, Cochrane Central, and LILACS), for subsequent combined analysis (meta-analysis) of the results.

L’insomnie, commune auprès de la population gériatrique, est typiquement traitée avec des benzodiazépines qui peuvent augmenter le risque des chutes. La thérapie cognitive-comportementale (TCC) est une intervention non-pharmacologique ayant une efficacité équivalente et aucun effet secondaire. Dans la présente thèse, le coût des benzodiazépines (BZD) sera comparé à celui de la TCC dans le traitement de l’insomnie auprès d’une population âgée, avec et sans considération du coût additionnel engendré par les chutes reliées à la prise des BZD. Un modèle d’arbre décisionnel a été conçu et appliqué selon la perspective du système de santé sur une période d’un an. Les probabilités de chutes, de visites à l’urgence, d’hospitalisation avec et sans fracture de la hanche, les données sur les coûts et sur les utilités ont été recueillies à partir d’une revue de la littérature. Des analyses sur le coût des conséquences, sur le coût-utilité et sur les économies potentielles ont été faites. Des analyses de sensibilité probabilistes et déterministes ont permis de prendre en considération les estimations des données. Le traitement par BZD coûte 30% fois moins cher que TCC si les coûts reliés aux chutes ne sont pas considérés (231$ CAN vs 335$ CAN/personne/année). Lorsque le coût relié aux chutes est pris en compte, la TCC s’avère être l’option la moins chère (177$ CAN d’économie absolue/ personne/année, 1,357$ CAN avec les BZD vs 1,180$ pour la TCC). La TCC a dominé l’utilisation des BZD avec une économie moyenne de 25, 743$ CAN par QALY à cause des chutes moins nombreuses observées avec la TCC. Les résultats des analyses d’économies d’argent suggèrent que si la TCC remplaçait le traitement par BZD, l’économie annuelle directe pour le traitement de l’insomnie serait de 441 millions de dollars CAN avec une économie cumulative de 112 billions de dollars canadiens sur une période de cinq ans. D’après le rapport sensibilité, le traitement par BZD coûte en moyenne 1,305$ CAN, écart type 598$ (étendue : 245-2,625)/personne/année alors qu’il en coûte moyenne 1,129$ CAN, écart type 514$ (étendue : 342-2,526)/personne/année avec la TCC. Les options actuelles de remboursement de traitements pharmacologiques au lieu des traitements non-pharmacologiques pour l’insomnie chez les personnes âgées ne permettent pas d’économie de coûts et ne sont pas recommandables éthiquement dans une perspective du système de santé. / Insomnia is common in the geriatric population, typically treated with benzodiazepine drugs which can increase the risk of falls. Cognitive behavioral therapy (CBT) is a non-pharmacological intervention with equivalent efficacy and no adverse events. This thesis compares the cost of benzodiazepines versus CBT for the treatment of insomnia in older adults, with and without consideration of the additional cost of falls incurred by benzodiazepine use. A decision tree model was constructed and run from the health payer’s perspective over 1 year. The probability of falls, ER visits, hospitalisation with and without hip fracture, cost data and utilities were derived from a comprehensive literature review. Cost consequence, cost utility and potential cost saving analyses were performed. Both probabilistic and deterministic sensitivity analyses were conducted to account for uncertainty around the data estimates. Benzodiazepine treatment costs 30% less than the price of CBT when the costs of falls are not considered (CAN $231 vs. CAN $335 per individual per year). When the cost of falls is considered, CBT emerges as the least expensive option (absolute cost-saving CAN$ 177 per person per year, CAN $1,357 with benzodiazepines vs. $1,180 for CBT). CBT dominated benzodiazepines, with a mean cost saving of CAN $ 25,743 per QALY gained with CBT due to fewer falls. The cost savings analysis shows that if the CBT were to completely replace benzodiazepine therapy, the expected annual direct cost savings for the treatment of insomnia would be $ 441 million CAD dollars, with a cumulative cost savings of $112 billion CAD dollars over 5-years. The PSA report shows that even at different varying parameters, benzodiazepines cost CAD$ 1,305, S.D $ 598 (range 245-2,625) on average / person / year vs. CAD$ 1,129, S.D $ 514 (range 342-2,526) on average / person / year for CBT. Current treatment reimbursement options that fund pharmacologic therapy instead of non-pharmacologic therapy for geriatric insomnia are neither cost-saving nor ethically recommendable from the health system’s perspective.