<p>Spontaneous reporting systems (SRSs) for adverse drug reactions (ADRs) have been developed as a result of the thalidomide disaster, whereby thousands of children world-wide were born with birth defects. The Swedish Adverse Drug Reactions Advisory Committee was established in 1965. Since 1975, reporting has been compulsory for all suspected serious or new ADRs. International collaboration started in 1968 with countries contributing their ADR reports to an international database set up by the World Health Organization. </p><p>ADRs represent the negative side of the benefit-to-risk balance that in theory needs to be counteracted by perceived or established positive drug effects. All drugs are subject to preclinical and clinical testing prior to marketing authorization. However, these studies are insufficient to detect rare ADRs, ADRs that occur after long-term administration or with latency, ADRs that occur in special patient groups such as children, the elderly, patients with renal or hepatic insufficiency or patients on concomitant drug treatment, and ADRs that represent a modest increase in the risk of diseases (including mortality) that are prevalent in the study population. Postmarketing surveillance of drugs is therefore essential, and regulatory action may be needed on the basis of new ADR information. </p><p>SRSs are important sources of ADR information as exemplified here by the evaluation of peripheral sensory disturbances with fluoroquinolones, hyponatremia with antidepressants, blood dyscrasias with dipyrone, glucose intolerance with atypical antipsychotics, pulmonary embolism with combined oral contraceptives and extrapyramidal symptoms with selective serotonin reuptake inhibitors. SRSs can be used to study clinical manifestations of ADRs (that can give insights into potential ADR mechanisms), risk factors for the ADR or for specific outcomes of the ADR, and ADR reporting incidences when combined with sales data. Signals from SRSs may need to be studied further e.g., by use of large-scale epidemiologic studies based on record linkage between drug prescription databases and health databases. Owing to the rapid availability of information, however, SRSs are likely to remain of major importance for the post-marketing surveillance of drugs.</p>

The WHO database contains more than 2.8 million case reports of suspected adverse drug reactions reported from 70 countries worldwide since 1968. The Uppsala Monitoring Centre maintains and analyses this database for new signals on behalf of the WHO Programme for International Drug Monitoring. A goal of the Programme is to detect signals, where a signal is defined as "Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously." The analysis of such a large amount of data on a case by case basis is impossible with the resources available. Therefore a quantitative, data mining procedure has been developed to improve the focus of the clinical signal detection process. The method used, is referred to as the BCPNN (Bayesian Confidence Propagation Neural Network). This not only assists in the early detection of adverse drug reactions (ADRs) but also further analysis of such signals. The method uses Bayesian statistical principles to quantify apparent dependencies in the data set. This quantifies the degree to which a specific drug- ADR combination is different from a background (in this case the WHO database). The measure of disproportionality used, is referred to as the Information Component (IC) because of its' origins in Information Theory. A confidence interval is calculated for the IC of each combination. A neural network approach allows all drug-ADR combinations in the database to be analysed in an automated manner. Evaluations of the effectiveness of the BCPNN in signal detection are described. To compare how a drug association compares in unexpectedness to related drugs, which might be used for the same clinical indication, the method is extended to consideration of groups of drugs. The benefits and limitations of this approach are discussed with examples of known group effects (ACE inhibitors - coughing and antihistamines - heart rate and rhythm disorders.) An example of a clinically important, novel signal found using the BCPNN approach is also presented. The signal of antipsychotics linked with heart muscle disorder was detected using the BCPNN and reported. The BCPNN is now routinely used in signal detection to search single drug - single ADR combinations. The extension of the BCPNN to discover 'unexpected' complex dependencies between groups of drugs and adverse reactions is described. A recurrent neural network method has been developed for finding complex patterns in incomplete and noisy data sets. The method is demonstrated on an artificial test set. Implementation on real data is demonstrated by examining the pattern of adverse reactions highlighted for the drug haloperidol. Clinically important, complex relationships in this kind of data are previously unexplored. The BCPNN method has been shown and tested for use in routine signal detection, refining signals and in finding complex patterns. The usefulness of the output is influenced by the quality of the data in the database. Therefore, this method should be used to detect, rather than evaluate signals. The need for clinical analyses of case series remains crucial.

Spontaneous reporting systems (SRSs) for adverse drug reactions (ADRs) have been developed as a result of the thalidomide disaster, whereby thousands of children world-wide were born with birth defects. The Swedish Adverse Drug Reactions Advisory Committee was established in 1965. Since 1975, reporting has been compulsory for all suspected serious or new ADRs. International collaboration started in 1968 with countries contributing their ADR reports to an international database set up by the World Health Organization. ADRs represent the negative side of the benefit-to-risk balance that in theory needs to be counteracted by perceived or established positive drug effects. All drugs are subject to preclinical and clinical testing prior to marketing authorization. However, these studies are insufficient to detect rare ADRs, ADRs that occur after long-term administration or with latency, ADRs that occur in special patient groups such as children, the elderly, patients with renal or hepatic insufficiency or patients on concomitant drug treatment, and ADRs that represent a modest increase in the risk of diseases (including mortality) that are prevalent in the study population. Postmarketing surveillance of drugs is therefore essential, and regulatory action may be needed on the basis of new ADR information. SRSs are important sources of ADR information as exemplified here by the evaluation of peripheral sensory disturbances with fluoroquinolones, hyponatremia with antidepressants, blood dyscrasias with dipyrone, glucose intolerance with atypical antipsychotics, pulmonary embolism with combined oral contraceptives and extrapyramidal symptoms with selective serotonin reuptake inhibitors. SRSs can be used to study clinical manifestations of ADRs (that can give insights into potential ADR mechanisms), risk factors for the ADR or for specific outcomes of the ADR, and ADR reporting incidences when combined with sales data. Signals from SRSs may need to be studied further e.g., by use of large-scale epidemiologic studies based on record linkage between drug prescription databases and health databases. Owing to the rapid availability of information, however, SRSs are likely to remain of major importance for the post-marketing surveillance of drugs.

Health care systems in Saudi Arabia and elsewhere play a significant role in the lives of individuals as well as society at large. Although healthcare aims at enhancing the quality of life it can sometimes happen that treatment itself can lead to a diminution of the quality of life due to unexpected adverse effects. These problems may cause therapeutic failures or even drug-related morbidity and mortality. Consequently there is a need to have in place a system, conventionally known as Pharmacovigilance. The aims of Pharmacovigilance are to identify, quantify and continuously monitor all drug use through a system which would enable all health care professionals such as physicians, pharmacists, dentists and nurses to contribute. This thesis investigated the present knowledge of and use of, the Pharmacovigilance system in Makkah, in the Kingdom of Saudi Arabia. A mixed method yielded data that provided depth and breadth to the findings of this study. A questionnaire was designed for 170 community pharmacists and 310 respondents drawn from different medical roles across the seven hospitals in Makkah yielded some useful results. Resistance to change was identified in some groups but it was of interest to discover that 72% of respondents who admitted that their knowledge was insufficient were, nevertheless, agreed about its importance. Key issues from the analysis of the questionnaire were used to design the second phase of the sequential mixed method which involved semi structured interviews with seven senior pharmacists, one from each of the seven hospitals. Analysis yielded three overarching categories: Technology, Internalisation and Motivation. A follow up feedback survey at the end of a lecture, of a group of pharmacy students enhanced the overall findings of the study and revealed a very high degree of interest and acceptance of Pharmacovigilance reporting systems and an expressed desire for its inclusion as a subject in its own right in their training programme. Conflicting epistemological positions inherent in a mixed method are candidly admitted and no attempt is made to circumvent this difficulty. Rather, the enhanced nature of the findings is highlighted despite the opposing knowledge claims of both approaches. A key finding was that 59% of the respondents were unaware of the Saudi National Pharmacovigilance centre (NPC) and reporting arrangements. The problems of lack of internet access and of suitable reporting forms were important contributory reasons for the under-usage of the system. There is a need to raise awareness of all pharmacists of the importance of the knowledge and practice of Pharmacovigilance. Technological solutions should be implemented to facilitate reporting at all levels. Continuing professional development should include Pharmacovigilance. Resistance to change can be addressed by identifying the motivational factors that can lead to a more wholehearted acceptance of the importance of Pharmacovigilance for patient care and well-being. Indeed, these could well be the focus of future studies.

Diabetes is a chronic and debilitating disease that affects nearly half a billion people worldwide with the vast majority of diabetics suffering from Type 2 diabetes mellitus (T2DM), a disease characterized by insulin insensitivity that often requires pharmacotherapy to effectively maintain target blood sugar levels. The thiazolidinedione (TZD) class of drugs consists of oral hypoglycaemic agents used alone or in combination with other antidiabetic drugs to treat T2DM. The drugs within this class, which include rosiglitazone and pioglitazone, were originally heralded as providing novel first and second-line treatment of T2DM with glycaemic control and physiological effects comparable to, and in some cases, better than, first-line treatments such as metformin. However, over time they have also been associated with adverse cardiovascular, osteological, and carcinogenic effects in some, but not all clinical trials, observational studies, and meta-analyses. Given the conflicting evidence to date on the safety of TZD drugs, their role in the treatment of T2DM continues to be debated and epidemiological gaps remain. The objectives of this doctoral research are fourfold: 1) to conduct an in-depth review of the epidemiology of TZD pharmacotherapy including pharmacokinetics and modes of action, the results of previous studies investigating health risks and benefits associated with TZD treatment, and new and future uses for this class of drugs; 2) to determine whether diabetic patients treated with TZDs are at increased risk of adverse cardiovascular outcomes; 3) to assess whether TZD pharmacotherapy is associated with an increased risk of bone fractures and whether risks differ depending on fracture site and patient sex; and, 4) to investigate associations between TZD use and risk of bladder cancer. Specific research questions were investigated using nested case-control analyses designed to capture incident users of antidiabetic drugs and electronic health data from Cerner Health Facts®, an electronic medical record database that stores time-stamped patient records from more than 480 contributing hospitals throughout the United States. Findings from this work are reported in a series of manuscripts, including a published review paper. Key findings include: 1) TZD use was associated with an increased risk of incident myocardial infarction and congestive heart failure compared to never use of TZD drugs with a trend towards a potential early treatment effect within the first year of exposure to pioglitazone; 2) TZD use was associated with an increased risk of closed bone fractures among Type 2 diabetics with use of pioglitazone or rosiglitazone associated with an increased risk across multiple fracture sites in women, but only rosiglitazone use in men and only at peripheral fracture sites; 3) use of either pioglitazone or rosiglitazone were associated with an increased risk of incident bladder cancer compared to never users, however, a low number of bladder cancer cases resulted in underpowered analyses; and, 4) insulin use in a hospital setting may replace a patient's normal course of antidiabetic therapy which, when combined with other potential sources of bias in traditional nested case-control studies using hospital-based data, may lead to overestimation or underestimation of adverse health risks associated with non-insulin antidiabetic therapies. Although these findings warrant replication, the results of the research contained within this dissertation suggest that caution should be exercised when prescribing diabetic patients TZD drugs if they have cardiovascular, osteological, or carcinogenic risk factors. Additional pharmacovigilance studies should also continue to strive to better understand the health risks related to TZD therapy, especially as new therapeutic roles for TZDs in the prevention and treatment of some cancers, inflammatory diseases, and other conditions in non-diabetic populations are being explored.

Pendant plus de six décennies, les antivitamines K (AVK) ont été la seule classe d’anticoagulants oraux disponibles sur le marché. L’arrivée des Anticoagulants Oraux Directs (AOD) en 2008 a marqué un réel tournant dans l’anticoagulation par voie orale. La première partie de ce travail s’est intéressée aux caractéristiques des patients traités par anticoagulants, et les conséquences en termes d’hospitalisations pour évènement hémorragique ou ischémique. Au sein d’une cohorte de patients hospitalisés pour AVC (cohorte BIOSTROKE, Lille), aucun facteur d’influence particulier, intervenant sur la survenue et l’évolution (mortalité, de déclin cognitif, et de handicap à 3 mois) de l’AVC n’était mis en évidence. En parallèle, une étude menée dans le service d’urgences du Centre Hospitalier de Béthune sur 3 années (2012, 2014, 2016) pour suivre l’évolution des prescriptions d’anticoagulants oraux et observer l’impact de la mise sur le marché des AOD, montrait une population dont certaines caractéristiques semblaient être associées à une utilisation plus volontiers des AOD ou des AVK. Le nombre d’évènements hémorragiques et thrombotiques sous AVK restait cependant stable sur les trois périodes d’étude (770 patients inclus au total). Forts de ces données rassurantes, la deuxième partie de ce travail s’est intéressée aux pratiques de prescription et au bon usage des anticoagulants, avec un focus particulier sur les AOD, à travers trois études : la première réalisée auprès des médecins généralistes du Nord et du Pas de Calais qui montrait une population de prescripteurs plutôt méfiants envers les AOD et ayant une préférence pour les anti-Xa. Les deux autres études portaient sur le bon usage des AOD, à partir de prescriptions à l’officine (grâce à la participation des étudiants en pharmacie de la faculté de Lille en stage d’officine) et à l’hôpital (Centre Hospitalier Régional de Lille). Ces études retrouvaient globalement des chiffres de prescriptions d’AOD transposables aux données françaises, avec cependant des disparités ville/hôpital. En termes de bon usage, les prescriptions étaient pour moins d’un tiers d’entre elles non-conformes aux recommandations en vigueur, avec une forte proportion de situations de sous-dosages. En conclusion, ce travail de thèse a permis de mettre à jour des pistes de formation/information des professionnels de santé sur ces nouvelles molécules anticoagulantes qui vont participer à une prise en charge avisée et optimale des patients. / For over six decades, vitamin K antagonists (VKAs) were the only class of oral anticoagulants available on the market. The arrival of Direct Oral Anticoagulants (DOAs) in 2008 marked a real turning point in the oral anticoagulation. The first part of this work was interested in the characteristics of patients treated with anticoagulants and the consequences in terms of hospitalizations for ischemic or hemorrhagic events. In a cohort of patients hospitalized for stroke (cohort BIOSTROKE Lille), no particular influencer, on the onset and course (mortality, cognitive decline, and disability at 3 months) of stroke was highlighted. In parallel, a study conducted in the emergency department of the Hospital of Bethune on three years (2012, 2014, 2016) to observe oral anticoagulants prescriptions and the impact of DOAs arriving, showed a population where many characteristics appear to be associated with a more readily using DOAs or VKAs. The number of bleeding and thrombotic events with VKAs remained stable during the three study periods (in total 770 patients were included). With these reassuring data, the second part of this work has focused on prescribing practices and the appropriate use of anticoagulants, with a particular focus on DOAs, through three studies: one conducted among general practitioners of Nord and Pas de Calais departments, which showed a rather wary about DOAs but with a preference for anti-Xa. The other two studies focused on the appropriate use of DOAs, estimated from pharmacy (with the participation of pharmacy students of the Faculty of Lille) and hospital (Lille Regional Hospital Center) prescriptions. Data about DOAs prescriptions were transposable to French data, albeit with city / hospital disparities. Non-appropriate prescriptions were observed in less than one-third file, with a high proportion of under dosing situations. In conclusion, this work has allowed updating training tracks / information for health care professionals on these new anticoagulant molecules to improve information and optimal patients’ care.

One of the objectives of the U.S. Food and Drug Administration is to protect the public health through post-marketing drug safety surveillance, also known as Pharmacovigilance. An inexpensive and efficient method to inspect post-marketing drug safety is to use data mining algorithms on electronic health records to discover associations between drugs and adverse events. The purpose of this study is two-fold. First, we review the methods and algorithms proposed in the literature for identifying association drug interactions to an adverse event and discuss their advantages and drawbacks. Second, we attempt to adapt some novel methods that have been used in comparable problems such as the genome-wide association studies and the market-basket problems. Most of the common methods in the drug-adverse event problem have univariate structure and thus are vulnerable to give false positive when certain drugs are usually co-prescribed. Therefore, we will study applicability of multivariate methods in the literature such as Logistic Regression and Regression-adjusted Gamma-Poisson Shrinkage Model for the association studies. We also adopted Random Forest and Monte Carlo Logic Regression from the genome-wide association study to our problem because of their ability to detect inherent interactions. We have built a computer program for the Regression-adjusted Gamma Poisson Shrinkage model, which was proposed by DuMouchel in 2013 but has not been made available in any public software package. A comparison study between popular methods and the proposed new methods is presented in this study.

abstract: Proliferation of social media websites and discussion forums in the last decade has resulted in social media mining emerging as an effective mechanism to extract consumer patterns. Most research on social media and pharmacovigilance have concentrated on Adverse Drug Reaction (ADR) identification. Such methods employ a step of drug search followed by classification of the associated text as consisting an ADR or not. Although this method works efficiently for ADR classifications, if ADR evidence is present in users posts over time, drug mentions fail to capture such ADRs. It also fails to record additional user information which may provide an opportunity to perform an in-depth analysis for lifestyle habits and possible reasons for any medical problems. Pre-market clinical trials for drugs generally do not include pregnant women, and so their effects on pregnancy outcomes are not discovered early. This thesis presents a thorough, alternative strategy for assessing the safety profiles of drugs during pregnancy by utilizing user timelines from social media. I explore the use of a variety of state-of-the-art social media mining techniques, including rule-based and machine learning techniques, to identify pregnant women, monitor their drug usage patterns, categorize their birth outcomes, and attempt to discover associations between drugs and bad birth outcomes. The technique used models user timelines as longitudinal patient networks, which provide us with a variety of key information about pregnancy, drug usage, and post- birth reactions. I evaluate the distinct parts of the pipeline separately, validating the usefulness of each step. The approach to use user timelines in this fashion has produced very encouraging results, and can be employed for a range of other important tasks where users/patients are required to be followed over time to derive population-based measures. / Dissertation/Thesis / Masters Thesis Computer Science 2016

Introdução: A automedicação é uma prática frequente em diferentes culturas, que pode ser usada como estratégia para resolução de pequenos problemas de saúde, especialmente em populações cujo acesso a serviços de saúde é restrito. No entanto, essa prática pode, também, ocasionar reações adversas graves, resistência microbiana, interações medicamentosas e gastos desnecessários, especialmente em grupos economicamente desfavorecidos e socialmente excluídos como ocorre com os povos ribeirinhos. Objetivo: Analisar a prática de automedicação e fatores associados entre ribeirinhos da região do Médio Solimões - Amazonas. Método: Estudo transversal de base populacional realizado nas comunidades ribeirinhas do município de Coari - Amazonas. A amostra probabilística foi composta por 492 ribeirinhos adultos. A coleta de dados foi realizada nas comunidades por meio de um questionário composto por variáveis independentes: socioeconômicas, demográficas, de acesso aos serviços de saúde, consumo de drogas lícitas, enfermidades autorrelatadas e informações sobre o consumo de medicamentos. A variável dependente automedicação foi avaliada pelo uso de pelo menos um medicamento sem prescrição médica ou de dentista, nos últimos 30 dias. Na análise dos dados utilizou-se testes do Qui-quadrado ou exato de Fischer, teste t de Student ou de Wilcoxon-Mann-Whitney e regressão logística binária hierarquizada. Resultados: A prevalência da automedicação foi de 76,3%. Dor de diferentes origens (58,1%) foi o principal motivo que levou à automedicação. Analgésicos (57,5%) e antimicrobianos (13,0%) foram os medicamentos mais utilizados. Os fatores associados à automedicação foram sexo masculino (OR=2,20; IC=1,21-4,01), faixa etária entre 18 a 39 anos (OR=2,50; IC=1,06-5,91), não procura por serviços de saúde (OR=2,90; IC=1,66-5,09), tempo de deslocamento da comunidade à zona urbana entre 1 a 4 horas (OR=2,84; IC=1,26-6,41) e maior que 4 horas (OR=5,27; IC=2,18-12,74), ter o hábito de consumo de medicamentos alopáticos por conta própria (OR=3,14; IC=1,49-6,61). Conclusões: Na população ribeirinha, a prática elevada da automedicação reflete a necessidade de busca de autocuidado pelas pessoas, sobretudo decorrente do restrito acesso aos serviços de saúde. / Introduction: Self-medication is a frequent practice in different cultures, and it can be used as a strategy to solve minor health problems, especially among populations with restricted access to health care services. However, such a practice may cause serious adverse reactions, microbial resistance, drug interactions and unnecessary expenses, mainly for economically disadvantaged and socially excluded groups like the riverside communities. Objective: To analyze the self-medication practice and its related factors among riverside communities in the region of the Middle portion of the Solimões River Amazonas State, Brazil. Method: Cross-sectional, population-based study carried out among riverside communities in the municipality of Coari Amazonas State, Brazil. The probability sampling comprised 492 adult riverside dwellers. Data collection was held in the communities by means of a questionnaire including independent variables: socioeconomic, demographic ones, access to health care services, drug therapy, self-reported illnesses, and information on medication use. Medication dependent variable was assessed by the use of at least one drug without medical or dentists prescription in the past 30 days. For the data analysis, Chi-square test or Fischers exact test, Students t or Wilcoxon-Mann-Whitney tests, and hierarchical binary logistic regression were used. Results: Self-medication prevalence was 76.3%. Pain from different origins (58.1%) was the main reason for self-medication. Painkillers (57.5%) and antimicrobial medication (13.0%) were the most used drugs. Self-medication related factors were males (OR=2.20; CI=1.21-4.01), age range between 18 and 39 years (OR=2.50; CI=1.06-5.91), not search for health care services (OR=2.90; IC=1.66-5.09), travel time from the community to the urban center between 1 and 4 hours (OR=2.84; CI=1.26-6.41), and over 4 hours (OR=5.27; CI=2.18-12.74), habit of self-medication for allopathic drugs (OR=3.14; CI=1.49-6.61). Conclusions: High self-medication practice among the riverside population reflects the need for turning to self-medication, mainly due to the restricted access to health care services.

Problemas relacionados a medicamentos (PRMs) compreendem erros de medicação (EMs) e reações adversas a medicamentos (RAMs). Este estudo teve por objetivo analisar, classificar, quantificar e intervir nos PRMs ocorridos em pacientes idosos internados. Este estudo prospectivo descritivo de uma série de casos clínicos abrangeu 28 pacientes e 100 prescrições aleatórias a eles destinadas. A identificação dos PRMs se deu por métodos de farmacovigilância ativa e as intervenções farmacêuticas (IFs) foram realizadas diretamente junto à equipe médica. Medicamentos de uso potencialmente inapropriado para idosos foram utilizados por 21,4% dos pacientes; 19% das prescrições possuíam rasuras. Foram encontrados 924 PRMs, sendo 920 EMs e 4 possíveis RAMs, sendo uma delas confirmada. A maioria dos EMs foi classificada como sem prejuízo ao paciente. Foram realizadas 143 IFs em 73 prescrições de 92,9% dos pacientes, sendo a maioria (77,6%) acatada pela equipe médica. Apesar das limitações, demonstrou-se a importância do farmacêutico na investigação, prevenção e solução de PRMs. / Drug related problems (DRPs) include medication errors (MEs) and adverse drug reactions (ADRs). The objective of this study was to analyze, classify, quantify and intervene in DRPs occurred in hospitalized elderly patients. This prospective descriptive study of a case series included 28 patients and 100 random prescriptions to them addressed. The identification of DRPs was carry out by methods of active pharmacovigilance and the pharmaceutical interventions (PIs) were performed directly with the medical staff. Drugs potentially inappropriate for the elderly were used by 21.4% of the patients; 19% of the prescriptions had rasures. There were 924 DRPs, with 920 MEs and 4 possible ADRs 4, one of which confirmed. The majority of MEs was classified as \"without harm to the patient\". Were carried out 143 PIs on 73 prescriptions of 92.9% of the patients, being the majority (77.6%) fully embraced by the medical staff. Despite the limitations, it was possible to demonstrate the pharmacist importance in research, prevention and resolution of DRPs.