Idiosyncratic drug reactions (IDRs) represent a significant medical problem and pose a great challenge to drug development. Circumstantial evidence suggests that, in most cases, reactive metabolites of the drug are responsible. The major focus of this thesis is the identification of reactive metabolites and the synthesis of analogs required to test several hypotheses related to involvement of metabolism and covalent binding in the mechanisms of IDRs. Minocycline is unique among tetracyclines in causing a significant incidence of a lupus-like syndrome and autoimmune hepatitis. In this study, we demonstrated that minocycline is oxidized to reactive intermediates by myeloperoxidase/H2O2/Cl-, HOCl, horseradish peroxidase/H2O2, or hepatic microsomes. When trapped with N-acetylcysteine (NAC), two adducts with protonated molecular ions at m/z 619 were isolated and analyzed by NMR. One represents attack of the aromatic D ring by NAC meta to the N, N-dimethylamino group, implying that the reactive intermediate was a quinone iminium ion. The other adduct, which was not observed when minocycline was oxidized by hepatic microsomes, indicates that the NAC is attached at the junction of the B and C rings, suggesting that the HOCl added across the double bond of the B ring leading to a reactive molecule, and then NAC displaced the chloride ion. Nevirapine, an anti-HIV drug, is associated with idiosyncratic skin rashes in humans. The goal of this project was to investigate whether the 12-hydroxylation pathway is responsible for the skin rash. To test a part of this hypothesis, 12-trideuteronevirapine, 12-OH-NVP sulfate, and several other analogs of nevirapine were synthesized. D-penicillamine is known to cause idiosyncratic autoimmune reactions in humans. The goal of this project was to test whether D-penicillamine covalently binds to macrophages and triggers downstream events leading to autoimmunity. To test a part of this hypothesis, D-penicillamine conjugated to biotin was synthesized. In summary, reactive metabolites of minocycline were found that likely explain why minocycline has an IDR profile unique among the tetracyclines. In addition, analogs of nevirapine and D-penicillamine required for mechanistic studies of nevirapine and D-penicillamine-induced IDRs were synthesized. These studies provide additional support for the involvement of reactive metabolites in the mechanisms of IDRs.

Abstract Drug misuses result in medical resource wastes and significant society costs. Due to the narrow therapeutic range of vancomycin, appropriate vancomycin dosage is difficult to determine. When inappropriate dosage is used, such side effects as poisoning reaction or drug resistance may occur. Clinically, medical professionals adjust drug protocols of vancomycin based on the Therapeutic Drug Monitoring (TDM) results. TDM is usually defined as the clinical use of drug blood concentration measurements as an aid in dosage finding and adjustment. However, TDM cannot be applied to first-time treatments and, in case, dosage decisions need to reply on medical professionals¡¦ clinical experiences and judgments. Data mining has been applied in various medical and healthcare applications. In this study, we will employ a decision-tree induction (specifically, C4.5) and a backpropagation neural network technique for predicting the appropriateness of vancomycin usage for patients with renal insufficiency and impairment. In addition, we will evaluate whether the use of the boosting and bagging algorithms will improve predictive accuracy. Our empirical evaluation results suggest that use of the boosting and bagging algorithms could improve predictive accuracy. Specifically, use of C4.5 in conjunction with the AdaBoost algorithm achieves an overall accuracy of 79.65%, which significantly improves that of the existing practice, recording an accuracy rate at 41.38%. With respect to the appropriateness category (¡§Y¡¨) and the inappropriateness category (¡§N¡¨), C4.5 in conjunction with the AdaBoost algorithm can achieve a recall rate at 78.75% and 80.25%, respectively. Hence, the incorporation of data mining techniques to decision support would enhance the drug safety, which in turn, would improve patient safety and reduce subsequent medical resource wastes.

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.

Syftet med detta arbete är att undersöka hur ett antal läkare ser på problematiken kring läkemedelinteraktioner samt om läkarna anser att ett utvidgat samarbete mellan läkare och farmaceuter kan hjälpa till att minska förekomsten av läkemedelsinteraktioner och hur detta samarbete i så fall skulle se ut. Undersökningen genomfördes genom intervju av ett antal läkare verksamma i södra Sverige. Resultatet visar att de tillfrågade läkarna anser att läkemedelsbehandling kan leda till läkemedelsinteraktioner och att risken för detta ökar i samband med polyfarmaci. För att kunna undvika eventuella läkemedelsinteraktioner använder sig läkarna, förutom av sina kunskaper, av en rad olika hjälpmedel, bland annat datorprogram som varnar för läkemedelsinteraktioner. Läkarna medger att det finns svårigheter också i att upptäcka och särskilja mellan biverkningar och läkemedelsinteraktioner. Förutom behandling med förskrivna läkemedel använder patienterna naturläkemedel, växtbaserade läkemedel eller receptfria läkemedel som kan bidra till uppkomsten av läkemedelsinteraktioner och dessa behandlingar oftast inte är kända av läkarna i samband med förskrivning av en viss medicin. Samarbetet mellan läkare och apotekspersonal anses vara tillräckligt enligt de intervjuade respondenterna. Ett eventuellt utökat samarbete önskas i form av lättare tillgänglighet i samband med svåra situationer där en jourhavande apotekare kan rådfrågas, fler farmakologiska föreläsningar samt mer information från apotekets sida kring nya läkemedel och nya forskningsresultat.

Parkinson disease (PD) is the second most common neurodegenerative disease worldwide, with estimates suggesting that PD prevalence and incidence will increase with aging populations. Therapeutic options and clinical guidelines for PD have significantly changed over the past 15 years; however, pharmacoepidemiology data in PD are lacking, especially regarding adverse effects of non-ergot dopamine agonists (DAs) and outcomes associated with anticholinergic burden. The objectives of this doctoral research are threefold: 1) examine patterns of antiparkinson drug use in relation to clinical guideline publication, drug availability, and emerging safety concerns; 2) determine whether PD patients treated with non-ergot DAs are at increased risk of adverse cardiovascular or cerebrovascular outcomes; and 3) determine whether anticholinergic burden is associated with adverse outcomes in PD. Specific research questions were investigated using epidemiological methods and electronic health data from Cerner Health Facts®, an electronic medical record database that stores time-stamped patient records for more than 300 Cerner subscribing facilities across the United States. Findings from this work are reported in a series of manuscripts, all of which have been published. Key findings include: 1) DA use began declining in 2007, from 34% to 27% in 2012. The decline followed publication of the American Academy of Neurology’s practice parameter refuting levodopa toxicity, pergolide withdrawal, and pramipexole label revisions; 2) heart failure was the only adverse cardiovascular or cerebrovascular outcome that demonstrated a significant association with non-ergot DA use, mainly pramipexole; and 3) anticholinergic burden in PD was associated with the diagnosis of fracture and delirium, and significantly increased the risk of emergency department visit and readmission post inpatient discharge. Reported antiparkinson prescribing trends suggest that safety and best practice information may be communicated effectively in PD. Although findings warrant replication, individuals with PD and independent risk factors for or a history of heart failure may benefit from limited use of pramipexole. Similarly, individuals with PD may benefit from substituting non-PD medications with anticholinergic effects for equally effective non-anticholinergic agents. Additional pharmacovigilance studies are needed to better understand health risks and the impact of population health interventions in PD.

京都大学 / 0048 / 新制・課程博士 / 博士(社会健康医学) / 甲第20289号 / 社医博第78号 / 社新制||医||9(附属図書館) / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 山田 亮, 教授 中山 健夫, 教授 古川 壽亮 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM

No description available.

Quinolones are a group of antibiotics that have gained significant popularity on a global scale since the end of the last century. This popularity was predominantly based on their proven potency, broad coverage against a wide range of bacteria, in addition to possessing a favorable pharmacologic profile. Whereas quinolone-associated adverse reactions are generally tolerable and self-limiting, some reactions have generated heightened concerns due to their serious nature, which have resulted in label changes or even market withdrawal in some instances. This thesis investigates the association between quinolone antibiotics and two adverse reactions of an acute and serious nature: acute liver failure and retinal detachment. Each adverse reaction is investigated through integrating evidence from three studies utilizing different designs based on data from different sources, with each source offering a unique perspective on this issue. The first study type (chapter 2 for acute liver failure ‘ALF’ and Chapter 5 for retinal detachment ‘RD’) analyzes spontaneous reports submitted to the US Food & Drug Administration (FDA) adverse event reporting system database. Chapters 3 and 6 systematically identified all relevant (published and unpublished) clinical trials for occurrences of ALF and RD, respectively, among trial participants. Finally, chapters 4 (ALF) and 7 (RD) involved case-control analysis of a major US database of electronic health records for nearly 70 million inpatients admitted to more than 500 hospitals between 2000 and 2016. The FAERS analysis revealed a positive ALF signal with ciprofloxacin and a marginal signal for RD with moxifloxacin. Examination of the evidence from clinical trials revealed only two cases of ALF, one associated with gemifloxacin and one with moxifloxacin. No cases of RD were reported in any of the identified clinical trials. Primary analyses of the Health Facts® data revealed no overall association between quinolones and the risk of ALF or RD. However, elevated risk was identified in some subgroups, including African Americans (ALF, RD), Caucasians (ALF), women (ALF, RD), men (ALF), those ≤60 years of age (ALF) or 56-70 years of age (RD), and those with no or few comorbidities (ALF). Evidence from analyses of data from spontaneous reports and clinical trials provided some evidence for an elevated risk of ALF or RD following the systemic administration of quinolone antibiotics. Some evidence of elevated risk was also identified in the case-control analyses of inpatient EHR records. Findings from our six epidemiologic studies are in line with current advisories by FDA and Health Canada.

Submitted by Nuzia Santos (nuzia@cpqrr.fiocruz.br) on 2016-10-17T11:27:29Z No. of bitstreams: 1 Tese_SC_MarianaMartinsGonzagadoNascimento.pdf: 218266 bytes, checksum: 09bb50de7e46f75bfeee14bd0625a861 (MD5) / Approved for entry into archive by Nuzia Santos (nuzia@cpqrr.fiocruz.br) on 2016-10-18T13:10:31Z (GMT) No. of bitstreams: 1 Tese_SC_MarianaMartinsGonzagadoNascimento.pdf: 218266 bytes, checksum: 09bb50de7e46f75bfeee14bd0625a861 (MD5) / Made available in DSpace on 2016-10-18T13:10:31Z (GMT). No. of bitstreams: 1 Tese_SC_MarianaMartinsGonzagadoNascimento.pdf: 218266 bytes, checksum: 09bb50de7e46f75bfeee14bd0625a861 (MD5) Previous issue date: 2016 / Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Belo Horizonte, MG, Brasil. / O uso de medicamentos potencialmente inadequados (MPI) para idosos pode estar associado a mais riscos que benefícios e sua utilização tem sido documentada internacionalmente. Nesta perspectiva, os objetivos deste trabalho foram: (1) numa abordagem transversal, estimar a prevalência de utilização de MPI entre idosos residentes na Região Metropolitana de Belo Horizonte (RMBH), Minas Gerais, e os fatores associados a essa prática; (2) longitudinalmente, investigar se o uso de MPI constitui fator de risco independente para a mortalidade entre idosos residentes em comunidade. A abordagem transversal foi baseada nos dados coletados junto a uma amostra representativa da população idosa com 60 anos ou mais residentes na RMBH (n=1.158); no cumprimento do segundo objetivo, utilizou-se os dados coletados junto à coorte idosa do Projeto Bambuí (n=1.586), composta em 1997 e acompanhada, anualmente, até 2011. Para definição do uso de MPI, variável dependente no estudo transversal e exposição de interesse no estudo longitudinal, utilizou-se o critério de Beers 2012. Variáveis sociodemográficas, de condições de saúde, de utilização de serviços de saúde e número de medicamentos foram utilizadas em caráter exploratório no estudo dos fatores associados ao uso de MPI (etapa transversal) e como variáveis de ajuste na investigação da associação entre uso de MPI e mortalidade (vertente longitudinal). A análise da prevalência e dos fatores associados ao uso de MPI foi baseada no modelo de regressão de Poisson; a investigação da associação do uso de MPI e mortalidade foi realizada por meio do modelo dos riscos proporcionais de Cox, adotando-se em ambos os casos, o nível de significância estatística de 5%. Na RMBH, a prevalência do uso de MPI foi de 43,3%. O sexo feminino, o número de doenças crônicas e a polifarmácia apresentaram-se positiva e independentemente associadas ao uso de MPI, sendo a última a variável mais fortemente associada. Em Bambuí, o uso de MPI mostrou-se como fator de risco para mortalidade entre os idosos da coorte. Nossos resultados apontam para a necessidade da seleção de alternativas terapêuticas mais seguras para idosos. / Potentially inappropriate medications (PIMs) for the elderly can be associated with greater risks than benefits and its use has been reported internationally. Having this into consideration, the objectives of this study were: (1) in a cross-sectional study, to estimate the prevalence of PIMs use among elderly residents of the Metropolitan Region of Belo Horizonte (MRBH), Minas Gerais, and the associated factors; (2) in a longitudinal study, to investigate if the PIM use constitutes a risk factor for mortality among community dwelling elderly. The cross-sectional approach was based on data from a representative sample of the elderly population (60 years or older) living in the MRBH (n=1.158). To fulfill the second objective, data from Bambuí elderly cohort (composed in 1997 and followed annually until 2011) study was used. Beers criteria (2012) were used to define PIM use, which was the dependent variable in the crosssectional study and exposition factor in the longitudinal study. Socio-demographic variables, health status, healthcare services use and number of medications were used as exploratory variables in the study involving associated factors (crosssectional study), and as adjustment variables in the investigation of association between PIM use and mortality (longitudinal study). Prevalence analysis and associated factors were performed using Poisson regression model. To investigate the association between PIMs use and mortality, Cox proportional hazards model was used. A 0.05 significance level was adopted for all analyzes. The prevalence of PIM use was 43.3% in the MRBH. Female gender, number of chronic conditions and polypharmacy were positively and independently associated with PIM use, the latter having been the most strongly associated factor. In Bambuí, PIM use was identified as a risk factor for mortality among the elderly in the cohort. These results indicate the need for selection of safer therapeutic alternatives for elderly patients.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-09-20T13:55:36Z No. of bitstreams: 1 elisabethcamposdeandrade.pdf: 10436022 bytes, checksum: ee61c000d375df1c659ffc7041f3103f (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-09-22T15:12:59Z (GMT) No. of bitstreams: 1 elisabethcamposdeandrade.pdf: 10436022 bytes, checksum: ee61c000d375df1c659ffc7041f3103f (MD5) / Made available in DSpace on 2017-09-22T15:12:59Z (GMT). No. of bitstreams: 1 elisabethcamposdeandrade.pdf: 10436022 bytes, checksum: ee61c000d375df1c659ffc7041f3103f (MD5) Previous issue date: 2017-07-31 / FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais / A testosterona é frequentemente utilizada no período pré-operatório da cirurgia nos casos de hipospádia grave. Estudos anteriores demonstraram a presença de receptores androgênicos em miócitos cardíacos que podem modular o fenótipo. O uso de doses suprafisiológicas de andrógenos pode levar à toxicidade no músculo cardíaco e, em alguns casos, à hipertrofia ventricular esquerda. Este ensaio clínico randomizado duplo-cego controlado visa avaliar o efeito do uso de testosterona tópica sobre o pênis no índice de massa ventricular esquerda em meninos com hipospádia. Foram incluídos meninos com hipospádia de 6 meses a 9 anos. Os meninos foram divididos em dois grupos: G1 - meninos que receberam creme de propionato de testosterona 1%, duas vezes ao dia, durante 30 dias e G2 - meninos que receberam creme placebo na mesma posologia. Todos os meninos foram submetidos à avaliação ecocardiográfica bidimensional para medir o índice de massa ventricular esquerda e a exame físico para avaliação da pressão arterial e do índice de massa corporal antes do tratamento, ao seu término e 60 dias após. Foram determinados os níveis de testosterona sérica, LH e FSH. Trinta e cinco meninos foram analisados, sendo 17 no G1 e 18 no G2. Não foram encontradas diferenças no índice de massa do ventrículo esquerdo (massa ventricular esquerda indexada pela área de superfície corporal) antes do tratamento. O índice de massa do ventrículo esquerdo foi de 59,21 ± 11,91 g/m² em G1 e 55,12 ± 8,29 g/m² em G2 (p=0,244) ao final do tratamento e 61,13 ± 11,69 g/m² em G1 e 62,84 ± 35,99 g/m² em G2 (p=0,852) 60 dias após. Os níveis séricos de testosterona foram 12 [7-80] ng/dL em G1 e 5 [5-7] ng/dL em G2 (p=0,018) ao final do tratamento e 10 [5-11] ng/dL em G1 e 5 (4-5) ng/dL em G2 (p=0,155), 60 dias após. Houve um pequeno aumento na pressão arterial sistólica (PAS) ao final do tratamento (83,82 ± 7,18 mmHg) no grupo que recebeu testosterona (G1) comparado com o grupo que recebeu placebo (G2), 77,5 ± 6,69 mmHg (p=0,010). Após 60 dias, os níveis de PAS retornaram aos níveis basais em G1 (82,35 ± 5,62 mmHg) e em G2 (81,38 ± 4,79 mmHg) (p=0,588). A testosterona tópica pode ser considerada segura no período pré-operatório de meninos com hipospádias sem risco de hipertrofia ventricular esquerda. Houve um aumento dos níveis de PAS durante o uso da testosterona, que foi transitório, retornando a níveis normais 60 dias após a suspensão da droga. / Testosterone is often used in the preoperative period of surgery in cases of severe hypospadias. Previous studies have demonstrated the presence of androgen receptors in cardiac myocytes that can modulate the phenotype. The use of supraphysiological doses of androgens can lead to toxicity on the heart muscle and, in some cases, to left ventricular hypertrophy. This randomized double blind controlled clinical trial aims to evaluate the effect of topical testosterone on left ventricular mass index in boys with hypospadias. Boys with hypospadias aged 6 months to 9 years were included. Boys were divided into two groups: G1 - boys who received testosterone propionate 1% ointment twice a day for 30 days, and G2 - boys receiving placebo ointment in the same regimen. All boys were submitted to bidimensional echocardiographic evaluation to compare the left ventricular mass index, blood pressure, and body mass index before treatment, at its ending and 60 days later. Levels of serum testosterone, LH, and FSH were measured. Thirty-five boys were analyzed: 17 in G1 and 18 in G2. No differences were found in left ventricular mass index (left ventricular mass indexed by body surface area) prior to treatment. Left ventricular mass index was 59.21 ± 11.91 g/m² in G1 and 55.12 ± 8.29 g/m² in G2 (p=0.244) at the end of the treatment and 61.13 ± 11.69 g/m² in G1 and 62.84 ± 35.99 g/m² in G2 (p=0.852) 60 days later. Serum testosterone levels were 12[7-80] ng/dL in G1 and 5[5-7] ng/dL in G2 (p=0.018) at the end of the treatment of treatment and 10[5- 11] ng/dL in G1 and 5[4-5] ng/dL in G2 (p=0.155), 60 days later. There was a small increase in systolic blood pressure (SBP) at the end of the treatment (83.82 ± 7.18 mmHg) in the group who receive testosterone (G1) compared with controls (G2), 77.5 ± 6.69 mmHg (p=0.010). Passing 60 days, SBP levels returned to basal levels in G1 (82.35 ± 5.62 mmHg) and in G2 (81.38 ± 4.79 mmHg) (p=0.588). Topical testosterone can be considered safe in the preoperative period of boys with hypospadias with no risk of left ventricular hypertrophy. An increase in systolic blood pressure occurs while using testosterone but it is transitory, returning to normal levels 60 days after the discontinuation of the drug.