La ciclosporine est un traitement immunosuppresseur très utilisé : elle inhibe l'activation des lymphocytes T via la calcineurine. Sa néphrotoxicité limite son utilisation : la ciclosporine induit une augmentation de la vasoconstriction ainsi qu'une augmentation de la réponse des cellules musculaires lisses vasculaires (CMLV) aux agents vasoactifs. Le récepteur minéralocorticoïde (RM), au-delà de ses effets sur la réabsorption sodée, agit sur le tonus vasculaire en modulant la réponse des cellules (endothéliales et musculaires lisses) vasculaires aux agents vasoactifs. Notre hypothèse était que le RM pouvait participer à l'action vasoconstrictrice de la ciclosporine ; son inactivation pourrait limiter la néphrotoxicité de la ciclosporine. Deux modèles de souris ont été invalidés génétiquement pour le RM : dans les cellules endothéliales et les CMLV (KO-RM CMLV). Seules les souris KO-RM CMLV étaient protégées contre la néphrotoxicité de la ciclosporine. Ces effets impliquent une action sur le tonus vasculaire rénal. L'antagonisme pharmacologique du RM (par le canrénoate) administré per os confère la même protection. En revanche, la néphrotoxicité induite par le tacrolimus (une autre anticalcineurine) n'est pas prévenue par l'antagonisme du RM. Utiliser un antagoniste sélectif du RM (l'éplérénone) pourrait prévenir la néphrotoxicité de la ciclosporine. Nous avons prouvé sa bonne tolérance en association à la ciclosporine chez les patients transplantés et insuffisants rénaux chroniques. Une kaliémie supérieure à 4,35mmol/L à l'initiation indique un sur-risque de développer une hyperkaliémie. L'efficacité reste à démontrer au cours d'un essai prospectif et randomisé. / Cyclosporine A (cyclo) is a widely used drug in kidney transplantation: its anticalcineurin actioninhibits T lymphocytes activation and prevents allograft rejection. Despite a huge benefit on graftsurvival, cyclo exerts a side effect that limits its use: nephrotoxicity. Vasculotoxicity appears to becentral: cyclo enhances renal vasoconstriction by altering vasoactive factors and vascular smoothmuscle cells (VSMC) response to vasoactive factors. Beyond its effects on sodium reabsorption,Mineralocorticoid Receptor (MR) acts on vascular tone by modulating both endothelial and VSMCresponses to vasoactive factors. Our working hypothesis was that MR could participate to cycloinducedvasoconstriction and that MR inactivating (pharmacologically or genetically) could alleviatecyclo-induced nephrotoxicity. Two genetically MR-knock out (MR-KO) were generated: inendothelial or VSMC. Only VSMC MR-KO mice were protected from cyclo-induced nephrotoxicity.We also show that such an effect was mediated by vascular tone modulation. This prevention was alsoconferred by the systemic pharmacological antagonism of MR (by canrenoate) in mice but not duringnephrotoxicity induced by tacrolimus (another anticalcineurine drug used in kidney transplantation).Then, we proposed to use MR pharmacological antagonism in humans (by eplerenone) during kidneytransplantation. We first had to prove its safety in such a population. Among 31 cyclo-treated patients,only 9 developed hyperkalemia (>5mmol/L) and none presented serious side effect. We propose akalemia higher than 4.35mmol/L at baseline to be the marker of a higher risk of developinghyperkalemia under treatment. The efficiency of eplerenone to prevent/alleviate cyclo-inducednephrotoxicity during kidney transplantation should be tested during a randomized controlled trial.

Medication is an essential part of health care and enables the prevention andtreatment of many conditions. However, medication errors and drug-relatedproblems (DRP) are frequent and cause suffering for patients and substantial costsfor society. eMedication, defined as information technology (IT) in themedication management process, has the potential to increase quality, efficiencyand safety but can also cause new problems and risks.In this thesis, we have studied the employment of IT in different steps of themedication management process with a focus on the user's perspective. Sweden isone of the leading countries when it comes to ePrescribing, i.e. prescriptionstransferred and stored electronically. We found that ePrescribing is well acceptedand appreciated by pharmacists (Study I) and patients (Study II), but that therewas a need for improvement in several aspects. When the pharmacy market inSweden was re-regulated, four new dispensing systems were developed andimplemented. Soon after the implementation, we found weaknesses related toreliability, functionality, and usability, which could affect patient safety (StudyIII). In the last decade, several county councils in Sweden have implementedshared medication lists within the respective region. We found that physiciansperceived that a regionally shared medication list generally was more complete butoften not accurate (Study IV). Electronic expert support (EES) is a decisionsupport system which analyses patients´ electronically-stored prescriptions in orderto detect potential DRP, i.e. drug-drug interactions, therapy duplication, highdose, and inappropriate drugs for geriatric or pediatric patients. We found thatEES detected potential DRP in most patients with multi-dose drug dispensing inSweden (Study V), and that the majority of alerts were regarded as clinicallyrelevant (Study VI).For an improved eMedication, we need a holistic approach that combinestechnology, users, and organization in implementation and evaluation. The thesissuggests a need for improved sharing of information and support for decisionmaking, coordination, and education, as well as clarification of responsibilitiesamong involved actors in order to employ appropriate IT. We suggestcollaborative strategic work and that the relevant authorities establish guidelinesand requirements for IT in the medication management process. / Läkemedel förbättrar och förlänger livet för många och utgör en väsentlig del av dagens hälso- och sjukvård men om läkemedel tas i fel dos eller kombineras felaktigt med varandra kan behandlingen leda till en försämrad livskvalitet, sjukhusinläggningar och dödsfall. En del av dessa problem skulle kunna förebyggas med rätt information till rätt person vid rätt tidpunkt och i rätt form. Informationsteknik i läkemedelsprocessen har potentialen att öka kvalitet, effektivitet och säkerhet genom att göra information tillgänglig och användbar men kan också innebära problem och risker. Det är dock en stor utmaning att i läkemedelsprocessen föra in effektiva och användbara IT-system som stödjer och inte stör personalen inom sjukvård och på apotek, skyddar den känsliga informationen för obehöriga och dessutom fungerar tillsammans med andra system. Dagens IT-stöd i läkemedelsprocessen är otillräckliga. Till exempel saknar läkare, farmaceuter och patienter ofta tillgång på fullständig och korrekt information om en patients aktuella läkemedel; det händer att fel läkemedel blir utskrivet eller expedierat på apotek; och bristande eller långsamma system skapar frustration hos användarna. Dessutom är det flera delar av läkemedelsprocessen som fortfarande är pappersbaserade. Därför är det viktigt att utvärdera IT-system i läkemedelsprocessen. Vi har studerat IT i olika delar av läkemedelsprocessen, före eller efter införandet, framför allt utifrån användarnas perspektiv. Sverige har lång erfarenhet och tillhör de ledande länderna i världen när det gäller eRecept, det vill säga recept som skickas och lagras elektroniskt. I två studier fann vi att eRecept är väl accepterat och uppskattat av farmaceuter (Studie I) och patienter (Studie II), men att det finns behov av förbättringar. När apoteksmarknaden omreglerades 2009 infördes fyra nya receptexpeditionssystem på apoteken. Vi fann att det efter införandet uppstod problem med användbarhet, tillförlitlighet och funktionalitet som kan ha inneburit en risk för patientsäkerheten (Studie III). I Sverige har man inom flera sjukvårdsregioner infört gemensamma elektroniska läkemedelslistor. I en av studierna kunde vi visa att detta har inneburit en ökad tillgänglighet av information, men att en gemensam lista inte alltid blir mer korrekt och kan innebära en ökad risk att känslig information nås av obehöriga (Studie IV). I två av studierna undersöktes beslutsstödssystemet elektroniskt expertstöd (EES):s potential som stöd för läkare att upptäcka läkemedelsrelaterade problem till exempel om en patient har två olika läkemedel som inte passar ihop, eller ett läkemedel som kanske är olämpligt för en äldre person. Studierna visade att EES gav signaler för potentiella problem hos de flesta patienter med dosdispenserade läkemedel i Sverige (Studie V), och läkarna ansåg att majoriteten av signalerna är kliniskt relevanta och att några av signalerna kan leda till förändringar i läkemedelsbehandlingen (Studie VI). Sammantaget visar avhandlingen att IT-stöd har blivit en naturlig och nödvändig del i läkemedelsprocessen i Sverige men att flera problem är olösta. Vi fann svagheter med användbarhet, tillförlitlighet och funktionalitet i de använda IT-systemen. Patienterna är inte tillräckligt informerade och delaktiga i sin läkemedelsbehandling. Läkare och farmaceuter saknar fullständig och korrekt information om patienters läkemedel, och de har i dagsläget inte tillräckliga beslutsstöd för att förebygga läkemedelsrelaterade problem. Eftersom läkemedelsprocessen är komplex med många aspekter som påverkar utfall behöver vi ett helhetstänkande när vi planerar, utvecklar, implementerar och utvärderar IT-lösningar där vi väger in både tekniska, sociala och organisatoriska aspekter. Avhandlingens resultat visar på ett behov av ökad koordination och utbildning samt förtydligande av ansvaret för inblandade aktörer. Vi föreslår gemensamt strategiskt arbete och att inblandade myndigheter tar fram vägledning och krav för IT i läkemedelsprocessen.

ANALYSIS OF DRUG-RELATED PROBLEMS IN A HEALTHCARE FACILITY V. Author: Thu Thao Truongová Supervisor of the diploma thesis: PharmDr. Martin Doseděl, Ph.D. Consultant: PharmDr. Veronika Měrková Charles University, Faculty of Pharmacy in Hradec Králové, Department of Social and Clinical Pharmacy INTRODUCTION Medication errors are one of the most frequent medicinal errors. They affect patient's safety from the long-term point of view.1 The great part of medication errors occurs on the level of drug administration.2 In healthcare facilities mostly nurses are responsible for medication administration.3 AIM To obtain and evaluate medication errors during drug administration by nurses in a healthcare facility. METHODICS A prospective observational study was conducted in the facility Hamzova léčebna for children and adults focusing on medical rehabilitation. Data collection was performed in May 2019 three consecutive days on each ward, where drugs were administrated by nurse. Direct observation was done in morning, noon and evening drug administrations. Obtained data were recorded into prepared form and were compared with physician's medication order on the patient's record. Afterwards, the forms were transcripted into online database, data were transfered to MS Excel software programme and evaluated by...

Substance use disorders cause significant neurological damage, cognitive impairment, and maladaptive behaviors that negatively affect a person's quality of life. The purpose of this study was to explore the effect gender and primary drugs have on locus of control. Generalized expectancy theory helped to explain the behavior of patients diagnosed with substance use disorders and their inability to control ongoing drug use. The research question focused on to what extent drug-related locus of control scores differ by primary drug (narcotic vs. stimulant), gender (male vs. female), and their interaction. Data measuring locus of control from 553 participants provided a subset of 410 participants who identified narcotics or stimulants as their primary drug. A 2x2 full factorial ANOVA was conducted. The results of this study indicated there is a significant interaction between primary drug use and gender. The results could have positive social change implications for the addiction field because of the value of understanding the interdependency of internal-external thought processes related to drug use, the ability to change stigma associated with addiction and gender, and the value of understanding the need for individualized treatment as locus of control shifts from external to internal. It is recommended that the drug-related locus of control instrument become part of treatment protocol along with evidence-based interventions.

Thesis (MA)--Stellenbosch University, 2013. / Bibliography / ENGLISH ABSTRACT: This research study analyzes the Mexican drug war’s impact on the state’s federal political system of shared sovereignty. Transnational criminal organizations (TCOs) such as drug cartels have grown in strength due to shifting dynamics of the global drug trade. This growth in power, both in relation to the use of physical force and the influence over Mexican society, has challenged the state’s authority and monopoly of violence. After the inauguration of President Felipe Calderón in 2006, the government launched an all-in offensive, dedicating the entire state system to ridding the country of the drug cartels. Results of the offensive have been mixed and vary from area to area. However, trends indicate that the offensive has caused power vacuums and increased rivalry among the drug cartels. National homicide statistics show the government offensive has distorted the balance of power among the drug cartels, causing increased competition in an already hypercompetitive market. The majority of Mexico’s modern history consists of the era of single-party dominance, where the Institutional Revolutionary Party (PRI) dominated the political system on both vertical and horizontal levels. The recent growth of federal executive power during Calderón’s administration has caused concern about whether the democratic progress made during the last decade could be reversed – returning the country back to former autocratic practices of governance. This reversal also involves the concentration of power in the center. For the last few decades, the country has been decentralizing its political system in accordance to federal principles laid down by its Constitution. The involvement of the military, a federal instrument of security that has in some cases taken over jurisdiction from state and local authorities, has been causing debate on whether the executive power is violating its constitutional limits of power. With this, the primary research question of this study uses theoretical concepts and is formulated thusly: How do violent non-state actors (VNSAs) impact federalism in Mexico? Mexico was chosen as a case study because of its growing struggle against the drug cartels, a sub-branch of non-state actors (NSAs). The Westphalian state order has changed dramatically with globalization, changing realities with regard to the use of physical violence. This is especially the case in reference to VNSAs, where the use of violence maintains an informal system of order. With the rise of the powerful drug cartels, a direct result of the global drug trade that hides in the shadows of globalization, Mexico’s case is not unique. Colombia struggled with a similar scenario during the 1980s and 1990s. However, the security situation in Mexico has proven to be constantly evolving and very intense during a time of political transition. This study shows that the federal executive branch of the Mexican government has not violated its constitutional limits of the use of power, although the Mexican Constitution of 1917 has proven to be vague in reference to the use of the military in peacetime. This vagueness could undermine regional sovereignty and federal principles laid down by the Constitution. The study also indicates that the increasing levels of violence are affecting the functionality of regional governance, as well as freedom of the press. Homicide statistics show that since the government launched its offensive in 2006, there has been a significant increase in assassinations targeting both mayors and journalists. Overall, there is no indication that the drug war has influenced federalism in Mexico. Rather, the drug war has exposed institutional weaknesses, causing increased demand for and investment in professionalizing state institutions. / AFRIKAANSE OPSOMMING: Hierdie navorsingstudie analiseer die impak van die Meksikaanse dwelmoorlog op Meksiko se federale politieke stelsel van gedeelde soewereiniteit. Transnasionale kriminele organisasies (TKO’s), byvoorbeeld dwelmkartelle, se mag het toegeneem as gevolg van die verskuiwende dinamika in globale dwelmhandel. Die staat se gesag en magsmonopolie word uitgedaag as gevolg van hierdie toename in mag, beide met betrekking tot die owerhede se gebruik van fisieke mag en hul gesag oor die Meksikaanse gemeenskap. Na die inhuldiging van president Felipe Calderón in 2006, het die regering ’n alles insluitende offensief van stapel gestuur om van die land se dwelmkartelle ontslae te probeer raak. Hierdie offensief toon wisselende vordering en die impak daarvan verskil van area tot area. Ten spyte van hierdie mate van vordering, het die offensief egter aanleiding gegee tot magsvakuums en ’n toename in wedywering tussen dwelmkartelle. Nasionale moordsyfers dui daarop dat hierdie regeringsoffensief die magsbalans tussen dwelmkartelle versteur het, wat gelei het tot ’n toename in kompetisie in ’n reeds uiters kompeterende mark. Meksiko se moderne geskiedenis bestaan hoofsaaklik uit ’n era van eenpartydominansie, waar die Institusionele Rewolusionêre Party (Institutional Revolutionary Party, IRP) die politieke stelsel op beide vertikale en horisontale vlak gedomineer het. Die onlangse opkoms van die federale uitvoerende mag tydens die Calderón-administrasie wek kommer dat die vordering wat in die laaste dekade gemaak is ten opsigte van demokratisering van die politieke stelsel, omvergewerp sal word en dat Meksiko die gevaar sal loop om terug te keer na sy voormalige outokratiese en gesentraliseerde regeerpraktyke. Oor die afgelope paar dekades het die land juis pogings aangewend om sy politieke stelsel te desentraliseer na aanleiding van federale beginsels soos neergelê in die grondwet. Die weermag – ’n federale instrument vir sekuriteit – het alreeds op sekere plekke jurisdiksie by staats- en plaaslike owerhede oorgeneem. Dit het gelei tot debatte oor of die uitvoerende mag sy grondwetlike magsbeperkinge oorskry. Na aanleiding van Meksiko se huidige politieke situasie, asook teoretiese konsepte soos die staat, federalisme, nie-staatsakteurs en globale dwelmhandel, word die primêre navorsingsvraag vir hierdie studie soos volg geformuleer: Hoe beïnvloed gewelddadige nie-staatsakteurs federalisme in Meksiko? Om hierdie vraag te beantwoord, word daar gebruik gemaak van sekondêre bronne, (beperkte) insig oor die dwelmkartelle se handelspraktyke en ’n ondersoek na die linguistiese beperkinge op die gebruik van amptelike Meksikaanse regeringspublikasies. Meksiko is as gevallestudie vir hierdie navorsingsprojek gekies vanweë die land se toenemende stryd teen dwelmkartelle, ’n subvertakking van nie-staatsakteurs. Die Westfaalse staatsorde wat eeue lank die wettige gebruik van fisieke geweld beheer het, het dramaties verander met die opkoms van globalisering. Dit is veral die geval by gewelddadige nie-staatsakteurs, waar die gebruik van geweld tans ’n informele stelsel van orde handhaaf. Die opkoms van Meksiko se magtige dwelmkartelle, ’n direkte gevolg van globale dwelmhandel (wat in die skadu van globalisering skuil), is egter nie enig in sy soort nie. Alhoewel Colombië byvoorbeeld in die 1980’s en 1990’s ’n soortgelyke probleem ondervind het, het die sekuriteitstoestand in Meksiko getoon dat dit steeds ontwikkelend van aard en hewig ten tye van politieke oorgang is, wat dit toepaslik vir hierdie studie maak. Die gevolgtrekking waartoe daar in hierdie studie gekom word, is dat die federale uitvoerende tak van die Meksikaanse regering tot dusver nie sy grondwetlike beperkinge ten opsigte van die uitoefening van mag oorskry het nie. Die Meksikaanse grondwet van 1917 is egter vaag oor die weermag se bevoegdheid om gesag af te dwing tydens vredestye. Hierdie vaagheid kan moontlik die streeksoewereiniteit en federale beginsels wat deur die grondwet verskans word, ondermyn. Daar is ook bepaal dat die toenemende geweld sowel die funksionaliteit van die streeksregering as die vryheid van die pers, beïnvloed. Moordsyfers in Meksiko dui daarop dat daar sedert 2006 ’n beduidende toename in sluipmoordaanvalle op burgemeesters en joernaliste was. Alles in ag genome, is daar egter geen aanduiding daarvan dat die dwelmoorlog wel federalisme in Meksiko geraak het nie. Die impak wat dit wel gemaak het, is om institusionele swakheid in die regering te openbaar, wat tot ’n toename in die aanvraag na en investering in die professionalisering van staatsinstellings gelei het.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

INTRODUÇÃO: Hemangioma Infantil (HI) é o tumor vascular mais comum da infância. Em 1992 a International Society for the Study of Vascular Anomalies (ISSVA) definiu o hemangioma infantil como tumor benigno de células endoteliais, com características clínicas, radiológicas e imuno-histoquímicas específicas. A origem do HI ainda é desconhecida. É sabido que apresentam potencial involutivo espontâneo e que o tratamento é indicado em 10% a 20% dos casos, podendo ter caráter emergencial ou eletivo. As indicações emergenciais compreendem situações de ameaça à função ou vida. As indicações eletivas são reservadas aos casos de hemangiomas localizados em áreas que podem levar à deformidade e/ou cicatriz permanente, quando apresentam complicações locais ou pequenas lesões em áreas expostas, podendo o tratamento ser clínico ou cirúrgico. A terapêutica medicamentosa tem sido a rotina e historicamente a opção mais utilizada foi o corticosteroide, cuja a eficácia é variável e os eventos adversos são frequentes. Em 2008 uma descoberta fortuita introduziu os betabloqueadores como nova opção para o tratamento do HI, com resultados estáveis e posteriores evidências clínicas do benefício da droga no tratamento do HI. Neste contexto, propôs-se avaliar o uso do propranolol, quantificando sua eficácia, segurança e incidência de eventos adversos, comparando-se ao uso da prednisolona (PRED). MÉTODO: Estudo intervencionista prospectivo randomizado com 50 portadores de HI, atendidos no complexo do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Os pacientes selecionados tinham idade inferior a 2 anos e indicação eletiva de tratamento. Os indivíduos incluídos foram aleatoriamente alocados em 2 grupos, sendo o primeiro grupo de tratamento com prednisolona e o outro de tratamento com propranolol (PROP), ambos por via oral, por 2 meses. Os pacientes foram seguidos semanalmente para mensuração de parâmetros clínicos incluindo peso, pressão arterial (PA), frequência cardíaca (FC) e saturação de oxigênio, além de avaliação objetiva da ocorrência de eventos adversos. A resposta ao tratamento foi avaliada de forma quantitativa por meio de medidas diretas da lesão e por 3 avaliadores independentes segundo critérios de melhora do aspecto clínico geral, volume, cor e envolvimento funcional. Os eventos adversos foram avaliados quanto a sua incidência e gravidade, utilizando-se a classificação do Common Terminology Criteria for Adverse Events. RESULTADOS: Vinte e seis pacientes foram alocados no grupo PRED e 24 no grupo PROP. Da casuística 37 indivíduos completaram as 8 semanas de seguimento. Em 8 casos houve interrupção precoce do tratamento em função de eventos adversos, em 1 caso por falha terapêutica e em 4 casos houve perda de seguimento. A idade média no grupo PRED foi de 6,46 meses e no grupo PROP de 7,25 meses. O gênero feminino foi predominante em ambos os grupos. A face foi a localização anatômica mais acometida, seguido do tronco. A resposta ao tratamento foi efetiva e sem distinção entre os grupos, com redução significativa das medidas avaliadas. Quanto as avaliações clínicas de acordo com o coeficiente de correlação interclasses, houve concordância interna excelente entre os avaliadores. As notas atribuídas para os pacientes mostraram melhora com o tratamento e no quesito cor mostrou-se diferença significativa em favor do grupo PROP. Quanto aos parâmetros clínicos mensurados, o percentil de peso mostrou elevação progressiva no grupo PRED sendo a diferença significativa em relação ao grupo PROP. A diferença nas medidas de PA sistólica entre os grupos foi significativa e a análise multivariável evidenciou uma elevação significativa no grupo PRED ao passo que no grupo PROP não houve alteração dos níveis pressóricos. A avaliação da FC revelou um significativo declínio no grupo PROP na 6º semana, não se mantendo no restante do período. Não foram identificadas alterações nas medidas de saturação de oxigênio. Quanto a incidência os eventos adversos (EA) a diferença entre os grupos foi significativa. No grupo PRED 22 pacientes apresentaram 35 EA sendo os mais frequentes o aspecto cushingoide, elevação da PA e infecções. No grupo PROP 10 pacientes apresentaram 10 EA incluindo hipotensão e distúrbios respiratórios. Quando a gravidade dos EA foi avaliada não foram observadas diferenças. CONCLUSÃO: Prednisolona e propranolol foram igualmente efetivos em reduzir o tumor. Considerando-se os eventos adversos, o uso do propranolol se mostrou como tratamento mais tolerável em relação ao uso do corticosteroide / INTRODUCTION: Infantile hemangioma (HI) is the most common vascular tumor of childhood. In 1992 the International Society for the Study of Vascular Anomalies (ISSVA) defined infantile hemangioma as a benign endothelial cell tumor with specific clinical, radiological and immunohistochemical characteristics. The origin of HI is still unknown. It is known that they have spontaneous involutive potential and that the treatment is indicated in 10% to 20% of the cases, and it can be emergency or elective. Emergency indications include life threatening situations. Elective indications are reserved for cases of hemangiomas located in areas that may lead to permanent deformity and/or scarring, when they present local complications or small lesions in exposed areas, and this treatment may be clinical or surgical. Drug therapy has been the routine and historically the most widely used option was the corticosteroid, whose efficacy is variable and the adverses events are frequent. In 2008 a fortuity finding introduced beta-blockers as a new option for HI treatment, with stable results and subsequent clinical evidence of drug benefit in the treatment of HI. In this context, it was proposed to evaluate the use of propranolol, quantifying its efficacy, safety and incidence of adverse events, compared to the use of prednisolone. METHODS: Prospective randomized interventional study with 50 patients with HI from the \"Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo\". The patients selected were younger than 2 years and had an elective indication of treatment. Patients included were randomly allocated into 2 groups, the first group being treated with predinisolone (PRED) and the other with propranolol (PROP), both orally, for 2 months. Patients were followed weekly to measure clinical parameters including weight, blood pressure (BP), heart rate (HR) and oxygen saturation, as well as an objective evaluation of the occurrence of adverse events. The response to treatment was quantitatively assessed by means of direct measures of the lesion and by 3 independent evaluators according to criteria of improvement of general clinical appearance, volume, color and functional involvement. Adverse events were evaluated for their incidence and severity, using the classification of the Common Terminology Criteria for Adverse Events. RESULTS: Twenty-six patients were allocated to the PRED group and 24 to the PROP group. Overall, 37 patients completed the 8-week follow-up. In 8 cases there was an early interruption of treatment due to adverse events, in 1 case due to therapeutic failure and in 4 cases there was loss of follow-up. The mean age in the PRED group was 6.46 months and in the PROP group of 7.25 months. The female gender was predominant in both groups. The face was the most affected anatomic location, followed by the trunk. The treatment response was effective and without distinction between groups, with a significant reduction of the measures evaluated. Regarding the clinical evaluations according to the interclass correlation coefficient, there was excellent internal agreement among the evaluators. The scores attributed to the patients showed improvement with the treatment and in the item color there was a significant difference in favor of the PROP group. Regarding the clinical parameters measured, weight percentile showed progressive elevation in the PRED group, presenting significant difference in relation to the PROP group. The difference in systolic BP measurements between groups was significant and multivariate analysis showed a significant increase in the PRED group, whereas in the PROP group there was no change in pressure levels. The HR evaluation revealed a significant decline in the PROP group in the 6th week, not remaining in the remainder of the period. No changes in oxygen saturation measurements were identified. Regarding the incidence and adverse events (AE), the difference between the groups was significant. In the PRED group 22 patients presented 35 AEs, the most frequent being cushingoid appearance, elevated BP and infections. In the PROP group 10 patients presented 10 AEs including hypotension and respiratory disorders. When the severity of AE was assessed, no differences were observed. CONCLUSION: Prednisolone and propranolol were equally effective in reducing the tumor. Considering the adverse events, the use of propranolol was shown as a more tolerable treatment in relation to corticosteroid use

O envelhecimento da população implica em aumento da prevalência de doenças crônicas não transmissíveis (DCNT) e uso de polifarmácia (uso de 5 ou mais medicamentos concomitantemente). Porém, o uso de medicamentos pode ter um efeito negativo em pacientes com multimorbidade. Entende-se como competição terapêutica (CT) a interação medicamento-doença em que o tratamento recomendado para certa condição pode alterar negativamente (competir com) outra condição coexistente. Neste âmbito, o objetivo principal deste trabalho foi estimar a prevalência de CT e avaliar características associadas à CT em idosos da comunidade. O presente estudo usou como base o estudo populacional de idosos do município de São Paulo: Estudo Saúde, Bem-estar e Envelhecimento, onda 2015. As CTs foram definidas a partir de guias de prática clínica (GPCs) com alta qualidade, selecionados a partir de revisão sistemática e avaliação da qualidade. Somente cerca de um quarto dos GPC apresentaram alta qualidade e foram usados para extração das CTs. A média de idade dos 1.224 idosos do SABE foi 70,8, 56,2% eram mulheres, 84% viviam acompanhados, 27,5% estudaram 9 anos e mais, quase 50% declararam renda insuficiente para cobrir com as despesas diárias, metade autoavaliaram a saúde como regular ou ruim, cerca de 40% relataram polifarmácia. Estatinas, inibidores da enzima de recaptação de angiotensina e inibidores da bomba de próton foram as classes de medicamentos mais relatadas. Multimorbidade foi reportada por 61,7% dos idosos. A prevalência de CT foi de 13,2%. Entre idosos com multimorbidade, a prevalência de CT foi de 21,4%. No modelo final de regressão logística, CT foi associada com polifarmácia (OR: 4,70; IC 95% 3,00 7,36), hospitalização no último ano (OR: 1,75; IC 95% 1,07 2,87), queda no último ano (OR: 1,57; IC 95% 1,04 2,36) e pior autoavaliação de saúde (OR: 1,92; IC 95% 1,23 2,99). Profissionais de saúde devem ter cautela ao selecionar GPC e ao prescrever medicamentos a idosos com multimorbidade. / Aging implies in an increasing prevalence of noncommunicable diseases (NCDs) and polypharmacy use (use of 5 or more medications concomitantly). However, medications may have a negative effect on patients with multimorbidity. Therapeutic competition (TC) is known as a drug-disease interaction in which the treatment recommended for a certain condition can negatively alter (compete with) another coexisting condition. In this context, the main objective of this study was to estimate the prevalence of TC and evaluate characteristics associated with TC in community dwelling older adults. The present study used the population-based study of older adults living in the city of São Paulo (SABE study, 2015 survey). TCs were identified by using clinical practice guidelines (CPGs) with high quality. A systematic review and critical appraisal of CPGs were conducted to identify high-quality CPGs. Only about a quarter of CPGs were of high quality and were used for CT extraction. A total of 80 CTs were identified from the high-quality CPGs. The mean age of the 1,224 SABE participants was 70.8, 56.2% were women, 84% did not live alone, 27.5% studied 9 years and over, almost 50% declared insufficient income to cover daily expenses, half self-assessed health, such as regular or poor, about 40% reported polypharmacy. Statins, angiotensin-reuptake enzyme inhibitors and proton pump inhibitors were the most commonly reported drug classes. Multimorbidity was reported by 61.7% seniors. The prevalence of TC was 13.2%. Among seniors with multimorbidity, the prevalence of TC was 21.4%. In the final logistic regression model, TC was associated with polypharmacy (OR: 4.70, 95% CI 3.00 - 7.36), hospitalization in the last year (OR: 1.75, 95% CI 1.07-2 , 95% CI 1.04 - 2.36) and worse health self - assessment (OR: 1.92, 95% CI 1.23 - 2.99), a decrease in the last year (OR: 1.57; Health professionals should be careful when selecting CPGs and prescribing medications to older adults with multimorbidity.

Introdução: Vancomicina, considerada o antibiótico de primeira escolha para o tratamento de infecções estafilocócicas, é eliminada por filtração glomerular, e a sua administração deve ser individualizada de acordo com a função renal. As diretrizes atuais recomendam doses e níveis séricos maiores, para aumentar as chances de bons resultados clínicos. Questiona-se se esta estratégia causaria maior nefrotoxicidade. Objetivos: Comparar a frequência de injúria renal aguda (IRA) em pacientes com suspeita de infecção estafilocócica tratados com vancomicina ou com outros antimicrobianos com o mesmo perfil terapêutico em um hospital terciário. Analisar a associação do uso de vancomicina com o desenvolvimento de IRA nestes pacientes. Avaliar os fatores de risco associados ao desenvolvimento de IRA nos pacientes tratados com vancomicina. Identificar os fatores de risco associados à letalidade precoce e tardia nos pacientes com suspeita de infecção estafilocócica tratados com vancomicina ou outros antimicrobianos com o mesmo perfil terapêutico. Métodos: Foram analisados os prontuários dos pacientes com suspeita de infecção estafilocócica que receberam os antimicrobianos vancomicina, teicoplanina, oxacilina, daptomicina ou linezolida por pelo menos três dias nos anos de 2010 e 2011 em um hospital terciário. Analisou-se a frequência de IRA associada ao uso de vancomicina (critério KDIGO) e. por regressão logística, se o uso de vancomicina foi associado ao desenvolvimento de IRA. Avaliou-se por regressão logística os fatores de risco associados ao desenvolvimento de IRA no grupo de pacientes tratados com vancomicina. Analisou-se por regressão de Cox os fatores de risco para letalidades intra-hospitalar, seis meses e até um ano após a internação. Resultados: Foram incluídos 591 pacientes, dos quais 508 foram expostos à vancomicina e 83 foram expostos a teicoplanina, oxacilina, linezolida, ou daptomicina. IRA ocorreu em 28,5% dos pacientes que utilizaram vancomicina e em 14,5% dos que utilizaram outros antimicrobianos (p < 0,001). O grupo de pacientes tratados com vancomicina apresentou parâmetros sugestivos de maior gravidade, como maior frequência de culturas positivas para estafilococos, hipotensão grave, contagem de leucócitos em sangue periférico mais elevada e níveis séricos maiores de lactato, procalcitonina e PCR. Quando pacientes que desenvolveram IRA foram comparados com pacientes que mantiveram a função renal estável, observou-se que o uso de vancomicina, a duração do tratamento e nível sérico de vancomicina foram significativamente maiores entre os primeiros. Vancomicina foi identificada como fator independente para o desenvolvimento de IRA na regressão logística. Os fatores de riscos independentes para o desenvolvimento de IRA no grupo exposto à vancomicina foram uso de medicamentos nefrotóxicos ou que alteram a função renal, uso de medicamento vasopressor e concentração sérica de vancomicina >= 20 mg/L. Vancomicina não se associou a letalidade em nenhum dos períodos estudados, enquanto IRA se associou de forma independente à letalidade precoce e tardia. Conclusões: Estes resultados indicam que a vancomicina apresenta nefrotoxicidade significativa e que os seus níveis séricos devem ser obrigatoriamente avaliados. O uso de medicamentos nefrotóxicos ou que alteram a função renal deve ser, quando possível, evitado ou suspenso em pacientes tratados com vancomicina. O desenvolvimento de IRA, mas não o uso de vancomicina, foi fator independente para letalidade, reforçando que este antimicrobiano pode ser utilizado quando indicado, desde que se previna o desenvolvimento de IRA / Introduction: Vancomycin is considered the first choice antibiotic for treatment of staphylococcus infection. Vancomycin is eliminated through glomerular filtration, and so it is administration must be individualized according the renal function. Current treatment guidelines recommend higher doses and blood levels in order to increase the odds for an adequate clinical outcome. On the other hand, this strategy might cause higher vancomycin-associated nephrotoxicity. Objectives: To analyze the frequency of acute kidney injury (AKI) development in patients with suspicion of staphylococcus infection treated with vancomycin, or other antibiotics with the same therapeutic profile in a tertiary hospital. To analyze the association of vancomycin with AKI development in those patients. To analyze the risk factors for AKI development in vancomycin-treated patients. To identify the risk factors associated to early and late mortality in patients with suspicion of staphylococcus infection treated with vancomycin, or other antibiotics with the same therapeutic profile in a tertiary hospital.Methodology:We analyzed the files of all the patients with suspicion of staphylococcus infection treated with vancomycin, teicoplanin, oxacillin, daptomycin, or linezolid antibiotics for at least three days during the years of 2010 and 2011 in a tertiary hospital.The frequency of AKI development (KDIGO criteria) was assessed. Using logistic regression we assessed if vancomycin use was an independent risk factor for AKI development and the risk factors for AKI development in the group of patients treated with vancomycin. We assessed, using Cox regression, the risk factors for in-hospital, six months and one year after hospitalization mortality. Results: We included 591 patients in the final analysis, 508 using vancomycin and 83 using other antibiotics (teicoplanin, oxacillin, daptomycin, or linezolid). AKI developed in 28.5% of the vancomycin group compared with 14.5% in the other antibiotics group (p < 0.001). Patients treated with vancomycin showed parameters suggesting higher clinical severity, such as higher percent of staphylococcus positive cultures, severe hypotension, higher leukocytes blood count, higher serum levels of lactate, procalcitonin and CRP. When patients developing AKI were compared with patients maintaining preserved renal function, the first group showed a statistically significant higher frequency of vancomycin use, longer vancomycin treatment and higher vancomycin through levels. Using logistic regression vancomycin was identified as an independent risk factor for AKI development. The independent risk factors for AKI development in the vancomycin group were simultaneous use of vancomycin and other nephrotoxic drugs or drugs that influence renal function, vasopressor drugs use and blood levels of vancomycin >= 20 mg/L. Vancomycin was not associated with mortality in any studied time, whereas AKI was an independent risk factor for early and late mortality. Conclusions: These results indicate that vancomycin is associated with significative nephrotoxicity and that its blood levels must be mandatorily assessed. The use of drugs that are nephrotoxic or influence renal function must be, when feasible, avoided or halted in vancomycin-treated patients. AKI development, but not vancomycin use, was an independent risk factor for mortality, reinforcing the perception that vancomycin can be used when necessary, since AKI development is prevented

Os sistemas de farmacovigilância fundamentam as decisões sobre segurança no uso de medicamentos regulamentados por autoridades de saúde. Estudá-los e propor estratégias de melhorias contribuem para fortalecer os sistemas de saúde, aperfeiçoando a qualidade da assistência à saúde e assegurando a segurança do paciente e coletividade. A Tese objetivou analisar a evolução e desempenho do sistema brasileiro de farmacovigilância, denominado de SINAF, e as notificações dos pacientes com suspeitas de reações adversas a medicamentos (RAMs) registradas no Notivisa-medicamento no período de 2008 a 2013 e propor uma lista-referência de códigos da CID-10 para vigilância de RAMs e intoxicações medicamentosas (IMs). A Tese compreende seis artigos científicos organizados para publicação. No primeiro, uma revisão de escopo apresentou uma perspectiva histórica para caracterizar a evolução do SINAF e lacunas identificadas no processo, como a ausência de comissão de farmacovigilância que atenda aos requisitos mínimos de um sistema de farmacovigilância propostos pela Organização Mundial da Saúde. Os artigos 2, 3 e 4 analisaram características relacionadas com o desempenho do SINAF. O artigo 2 revelou que não há preferência digital da idade na base de dados das notificações de eventos adversos a medicamentos (EAMs) do Notivisa-medicamento. Mediante uma análise comparativa, o artigo 3 mostrou diferenças entre o formulário para notificação de EAMs utilizado no SINAF e de outros doze países latinoamericanos (Argentina, Bolívia, Chile, Colômbia, Costa Rica, Cuba, Guatemala, México, Panamá, Peru, Uruguai e Venezuela), sobretudo na quantidade de variáveis para preenchimento, podendo contribuir com a subnotificação de casos. No artigo 4 – um estudo de avaliação de sistemas de vigilância de saúde pública –, revelou que o desempenho do Notivisa-medicamento foi considerado satisfatório para três atributos (flexibilidade, validade e erro preditivo positivo) e deficitário para a maioria deles (simplicidade, aceitabilidade, representatividade, completude, consistência, oportunidade e clareza metodológica). O artigo 5, mediante estudo descritivo e retrospectivo, encontrou uma taxa de notificação de RAMs de 22,8/ 1 milhão de habitantes/ano. Trata-se de taxa bastante inferior a países de alta renda como Nova Zelândia, Suécia, Austrália e Suíça que possuem mais de 300 notificações por milhão, como em relação a países de média renda, como a África do Sul, com taxa de 77 por milhão de habitantes. A população feminina (60,5%) prevaleceu no total de pacientes (26.554), assim como, a raça/cor branca (58,1%). A idade variou de 0 a 112 anos (mediana = 46 anos). Quase 1/3 (32,5%) das suspeitas de RAMs ocorreram em populações vulneráveis (idosos e crianças). Foram avaliados 54.288 pares de medicamento-reação adversa, onde prevaleceram as reações adversas graves (59,2%), com destaque para as que resultaram em efeito clinicamente importante (83,1%). O estudo 6 propôs uma lista-referência com 691 códigos da CID-10, sendo 360 (52,1%) relacionados com RAMs e 331 (47,9%) com IMs. Um total de 511 (73,9%) códigos estão relacionados com casos de admissão hospitalar e/ou óbito. Os achados da Tese evidenciam a necessidade de mudanças em diferentes aspectos estudados do SINAF, como forma de contribuir na produção de informações completas, fidedignas e mais representativas sobre danos ocasionados por medicamentos comercializados no país. / The pharmacovigilance systems support the decisions on safety when using medications regulated by health authorities. Analyzing them and proposing improvement strategies are ways to make healthcare systems stronger, improving the quality of healthcare assistance, making sure the patient is safe and that the population is ensured. The dissertation was aimed at analyzing the evolution and performance of the Brazilian pharmacovigilance system, SINAF, and the notification of patients with suspected adverse drug reactions (ADRs) registered with the notification system NOTIVISA/medication from 2008 through 2013, as well as proposing a reference list of ICD-10 codes for surveillance of ADRs and intoxication due to medication (IDM). The dissertation is comprised of six scientific articles ready to be published. The first one, a scoping review, presents a historical perspective to demonstrate the development process of SINAF and the gaps identified during the process, such as the absence of a pharmacovigilance commission that complies with the minimum requirements of a pharmacovigilance system as proposed by World Health Organization. Articles 2, 3 and 4 presents an analysis of the performance-related characteristics of SINAF. Article 2 reveals that there is no digital age preference in the adverse drug events (ADEs) database belonging to NOTIVISA/medication. Using a comparative analysis, article 3 shows differences between the form for ADEs notification using SINAF and in other twelve Latin-American countries (Bolivia, Chile, Colombia, Costa Rica, Cuba, Guatemala, Mexico, Panama, Peru, Uruguay and Venezuela), highlighting the number of variables to complete, and it may collaborate with the sub-notification of cases. Article 4 – a study on the evaluation of public health surveillance systems over time – reveal that the performance of NOTIVISA/medication was considered satisfactory regarding three attributes (flexibility, validity and positive predictive error) and deficient regarding most of the others (simplicity, acceptability, representability, integrality, consistency, opportunity and methodological clarity). Article 5, by means of a descriptive and retrospective study, found an ADR notification rate of 22.8/million inhabitants/year. This is a much lower rate than in high income countries, such as New Zealand, Sweden, Australia and Switzerland, which have over 300 notifications per million, when compared against average income, such as South Africa, with a rate of 77/million inhabitants. Female population (60.5%) prevailed in the total number of patients (26,554), as well as white race/color (58.1%). Age was between 0 - 112 years old (median = 46 years). Almost 1/3 (32.5%) of the suspected ADRs occurred in vulnerable populations (elderly and children). 54,288 pairs of medication/adverse reactions were assessed. Severe adverse reactions prevailed (59.2%), and attention is drawn to those resulting in clinically important effect (83.1%). Study 6 proposes a reference list with 691 ICD-10 codes; 360 (52.1%) out of them are ADRs-related and 331 (47.9%) out of them are IDM. A total of 511 (73.9%) codes are related to cases of hospital admission and/or death. The dissertation findings prove the need of changes across different aspects in SINAF as a way to contribute to production of complete, reliable and representative information on damages caused by commercially available drugs in Brazil.