A despeito de suas limitações, os dados do SIHSUS são os mais sistemáticos e abrangentes sobre as Reações Adversas e Intoxicações a medicamentos que provocam hospitalização. Eles demonstram a importância das ações de educação e investigação de casos do Programa Nacional de Farmacovigilância para possibilitar o diagnóstico mais acurado e superação do quadro atual de ocorrência desses agravos, além da possibilidade de o SIH/SUS ser utilizado sistematicamente como fonte de dados na detecção e análise dos problemas relacionados a medicamentos. No período de 1999 a 2007, foram emitidas 6.670.609 AIH (tipo 1), entre as quais 3.611 foram classificadas como internações devidas a RAM e 4.675 como Intoxicações, correspondendo, respectivamente, às taxas médias de 5,41 casos por 104 AIH e 7,2 casos por 104 AIH. Ocorreram 137 óbitos (3,79% das AIH) por RAM e 207 (4,43% das AIH) por Intoxicações na população internada. Tanto as RAM como as Intoxicações tiveram menor chance de levar ao óbito quando comparados às outras causas. Uma característica da distribuição dos RAM foi concentrar 62% das AIH nas faixas etárias de 20 a 59 anos de idade (grupo adulto). Nas Intoxicações merece destaque a elevada proporção de AIH na faixa etária de 0-4 anos (14,29%). As AIH registradas com causas básicas relacionados a RAM foram principalmente de pacientes do sexo masculino, já as Intoxicações foram principalmente de pacientes do sexo feminino. Em ambos tipos de agravos estes pacientes foram internados em hospitais que não faziam parte da Rede de Hospitais Sentinelas do Programa Nacional de Farmacovigilância. No entanto, a probabilidade destes hospitais registrarem as AIH com códigos CID-10 referentes às RAM é maior, o que ocorre provavelmente por estarem mais capacitados em diagnosticar este tipo de agravo. Porém este fato não foi observado para as Intoxicações. Os fármacos que causaram os agravos estudados são psicoativos. Este estudo apresentou algumas evidências sobre a distribuição da morbi-mortalidade provocada por medicamentos entre pacientes internados em hospitais conveniados ao SUS no período de 1999-2007, baseadas nas informações das AIH, que podem ser úteis ao Programa de Farmacovigilância no Estado do Rio de Janeiro. / Despite its limitations, the data SIHSUS are the most systematic and comprehensive on Adverse Reactions and Drug Poisonings causing hospitalization. They demonstrate the importance of these actions and investigation of cases of National Pharmacovigilance Programme to enable the most accurate and overcoming the current frame of event occurrences diagnosis, beyond the possibility of SIH / SUS be systematically used as a data source in the detection and analysis of drug-related problems. In the period 1999-2007, were issued 6,670,609 AIH (type 1), among which 3,611 were classified as hospitalizations due to poisoning as RAM and 4675, corresponding, respectively, at average rates of 5.41 cases per 104 AIH and 7.2 cases per 104 AIH. There were 137 deaths (3.79% of AIH) by RAM and 207 (4.43% of AIH) by poisoning in hospitalized population. Both the RAM as poisoning were less likely to cause death when compared to other causes. A characteristic distribution of RAM was concentrating 62% of AIH in the age groups 20-59 years of age (adult group). In Poisoning deserves the high proportion of AIH aged 0-4 years (14.29%). The AIH registered root causes related ADRs were mostly male patients, since the poisoning were mainly female patients. In both types of injuries these patients were admitted to hospitals that were not part of the Network of Sentinel Hospitals of the National Pharmacovigilance Programme. However, the likelihood of these hospitals register the AIH with ICD-10 codes related to RAM is higher, which is probably because they are better able to diagnose this type of offense. However this was not observed for the poisoning. The drugs that caused the diseases studied are psychoactive. This study presented some evidence on the distribution of morbidity and mortality caused by drugs among patients admitted to the SUS hospitals during the period 1999-2007, based on the information of AIH, which may be useful to Pharmacovigilance Programme in the State of Rio de Janeiro .

Introdução: Reação Adversa a Medicamento (RAM) é qualquer resposta prejudicial ou indesejável e não intencional que ocorre com medicamentos em doses normalmente utilizadas no homem para profilaxia, diagnóstico, tratamento de doença ou para modificação de funções fisiológicas. Atualmente, representa uma das principais causas de morbidade e mortalidade na área da saúde. Objetivo: Analisar as reações adversas a medicamentos e fatores associados em pacientes ortopédicos tratados com antibióticos. Método: Coorte prospectiva conduzida com 273 pacientes ortopédicos internados no Instituto Nacional de Traumatologia e Ortopedia, Rio de Janeiro, Brasil. A coleta de dados ocorreu nos anos de 2012 e 2013, por meio de instrumento composto por variáveis demográficas-clínicas e terapia medicamentosa. Para identificação das RAMs realizou-se o monitoramento ativo, composto de: entrevista, análise de prontuários e exames laboratoriais. As RAMs consideradas graves foram analisadas por meio do formulário do Instituto Catalão de Farmacologia, Espanha. Na análise dos dados utilizaram-se os testes Mann-Whitney, Qui-Quadrado, exato de Fisher e regressão logística, com significância de p 0,05. Resultados: A incidência de RAM foi de 41%. O grupo com RAM apresentou maior média de idade (43,3; DP 10,9), tempo de internação (72,7; DP 40,9) e número de medicamentos concomitantes (13,2; DP 4,1). Os fatores associados foram número de medicamentos, uso de antimicobacteriano (OR 2,44; IC 1,3944,270) e carbapenêmicos (OR 2,38; IC 1,167 4,872). Identificaram-se 466 RAM, cuja maioria (67,1%) foi classificada como leve. No grupo de pacientes com RAMs graves identificaram-se leucopenia (46,6%), insuficiência renal aguda (40%) e hepatite medicamentosa (26,6%). Os antibióticos foram os principais medicamentos suspeitos de causar as RAMs graves (76,4%), sendo os mais frequentes (23,5%) formados pela tríade: amicacina + vancomicina + piperacilina com tazobactam. Conclusão: A incidência de RAM é maior quando se incorpora ao serviço de farmacovigilância a técnica de monitoramento contínuo dos pacientes hospitalizados e se utiliza a analise de exames laboratoriais como preditores para suspeitas de RAMs potencialmente graves / Introduction: Adverse Drug Reaction (ADR) is any noxious, undesired or unintended response which occurs in the use of normal dosages of drugs for prophylaxis, diagnosis, treatments or for modifying physiologic functions. Nowadays, ADR represents one of the main causes of morbidity and mortality in the health service area. Objective: To analyze the occurrence of adverse reaction to drugs and factors related to orthopedic patients treated with antibiotics. Method: The prospective cohort study was conducted in 273 orthopedic patients hospitalized at the Brazilian Institute of Traumatology and Orthopedics in Rio de Janeiro. The data collection was made during the years 2012 and 2013, using instruments composed by demographic-clinical variables and drug therapies. With the purpose of identifying occurrences of ADRs, during active monitoring, interviews were conducted, medical charts and exams were analyzed. In addition, the occurrence of ADRs considered harmful was analyzed by using a form provided by the Catalan Institute of Pharmacology, Spain. In the study of the data collected, was made use of Mann-Whitney tests, Chi-Squared test, Fishers exact test and logist regression, with p-value 0,05. Results: The occurrence of ADRs was of 41%. This group was composed by individuals with major age rage (43,3, SD 10,9), major time spent hospitalized (72,7; SD 40,9), and quantity of concurrent drugs used (13,2; SD 4,1). Also, the related factors were the number of drugs, the usage of Antimicobacterial agents (OR 2,44, CI 1,394-4,270) and Carbapenemases (OR 2,38; CI 1,167 4,872). During the study, there were identified 466 ADRs, and the majority (67,1%) was classified as low-grade. Additionally, in the group of patients with harm adverse reactions, it was possible to identify leukopenia (46,6%), acute kidney failure (40%) and drug-induced hepatitis (26,6%). The antibiotics were the main drugs suspected to be the cause of potentially harmful ADRs (76,4%), being the most frequent (23,5%) formed by the triad: amikacin + vancomycin + piperacillin-tazobactam. Conclusion: The occurrence of ADRs is higher when the practice of continuous monitoring of hospitalized patients is incorporated to the pharmacovigilance service, and the analyzes of lab exams are used as predictors for the suspicion of potentially harmful ADRs

Adverse drug reactions are unwanted effects alongside the intended benefit of a drug and might be responsible for 3-7\% of hospitalizations. Finding such reactions is partly done by analysing individual case safety reports (ICSR) of adverse events. The reports consist of categorical terms that describe the event.Data-driven identification of suspected adverse drug reactions using this data typically considers single adverse event terms, one at a time. This single term approach narrows the identification of reports and information in the reports is ignored during the search. If one instead assumes that each report is connected to a topic, then by creating a cluster of the reports that are connected to the topic more reports would be identified. More context would also be provided by virtue of the topics. This thesis takes place at Uppsala Monitoring Centre which has implemented a probabilistic model of how an ICSR, and its topic, is assumed to be generated. The parameters of the model are estimated with expectation maximization (EM), which also assigns the reports to clusters. The clusters are improved with Consensus Clustering that identify groups of reports that tend to be grouped together by several runs of EM. Additionally, in order to not cluster outlying reports all clusters below a certain size are excluded. The objective of the thesis is to improve the algorithm in terms of computational efficiency and quality, as measured by stability and clinical coherence. The convergence of EM is improved using stepwise EM, which resulted in a speed up of at least 1.4, and a decrease of the computational complexity. With all the speed improvements the speed up factor of the entire algorithm can reach 2 but is constrained by the size of the data. In order to improve the clusters' quality, the community detection algorithm Leiden is used. It is able to improve the stability with the added benefit of increasing the number of clustered reports. The clinical coherence score performs worse with Leiden. There are good reasons to further investigate the benefits of Leiden as there were suggestions that community detection identified clusters with greater resolution that still appeared clinically coherent in a posthoc analysis.

The aim of this study was to compare effects of an individualized with a standardized risk assessment for adverse drug reactions to improve drug treatment with antithrombotic drugs in older adults. A randomized controlled trial was conducted in general practitioner (GP) offices. Patients aged 60 years and older, multi-morbid, taking antithrombotic drugs and at least one additional drug continuously were randomized to individualized and standardized risk assessment groups. Patients were followed up for nine months. A composite endpoint defined as at least one bleeding, thromboembolic event or death reported via a trigger list was used. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. In total, N = 340 patients were enrolled from 43 GP offices. Patients in the individualized risk assessment group met the composite endpoint more often than in the standardized group (OR 1.63 [95%CI 1.02–2.63]) with multiple adjustments. The OR was higher in patients on phenprocoumon treatment (OR 1.99 [95%CI 1.05–3.76]), and not significant on DOAC treatment (OR 1.52 [95%CI 0.63–3.69]). Pharmacogenenetic variants of CYP2C9, 2C19 and VKORC1 were not observed to be associated with the composite endpoint. The results of this study may indicate that the time point for implementing individualized risk assessments is of importance.

Antiretroviral drugs are successful in controlling HIV/AIDS and reducing disease progression. Antiretroviral regimens are stopped in up to 25% of all patients during their initial treatment therapy as a result of adverse drug effects, failing treatment and nonadherence within the initial eight months of treatment (Sharma et al., 2007: 235). A pharmacovigilance surveillance system makes it possible for physicians, pharmacists and other healthcare providers to report suspected ADRs. The purpose of this system is to operate as a guide in identification of new ADRs and predisposing risk factors to known ADRs. The objective of this study was to assess the prevalence and documentation of adverse drug reactions (ADR) in the private and public antiretroviral clinics in Maseru district, with special reference to zidovudine (AZT) and tenofovir (TDF) - based regimens. The empirical investigation was divided into two phases. The first phase was a cross-sectional quantitative retrospective drug utilisation review study which focused on the occurrence of adverse drug reactions in patients taking zidovudine (AZT) and tenofovir (TDF). The second phase, a survey in a form of questionnaires for the health professionals. Drug utilisation review: The sample size of patients was 300. Of the 44 patients who experience ADRs, 72.73% (n = 32) were female and 27.27% (n = 12) were male. A greater number of patients who experienced ADRs were females with 43.18% (n = 19) presenting with skin rash, 27.27% (n = 12) with nausea/vomiting, and 2.27% (n = 1) with diarrhoea. In male patients, 2.27% (n = 1) had peripheral neuropathy, 18.18% (n = 8) skin rash, 2.27% (n = 1) Fanconi syndrome, 2.27% (n = 1) nausea/vomiting, and 2.27% (n = 1) diarrhoea. Patients whose ART regimen changed due to ADRs were five. 60% (n = 3) of the patients were females and 40% (n = 2) were males. There was an estimated increase of 0.0025 cell/mm³, 0.0026 cell/mm³, 0.0024 cell/mm³, 0.0025 cell/mm³, and of 0.0019 cell/mm³ in CD4 cell count per day according to sex, age group, weight group, initial ART regimen, and ADRs, respectively. An estimated increase of 0.00021 g/dL, 0.00022 g/dL, 0.00018 g/dL, 0.00022 g/dL, and of 0.00020 g/dL in Hb profile per day occurred according to sex, age group, weight group, initial ART regimen, and ADRs, respectively. There was an estimated increase of 0.000062%, 0.000046%, 0.000068%, 0.000062%, and of 0.00017% in neutrophil count according to sex, age group, weight group, initial ART regimen, and ADRs per day, respectively. There was an estimated increase of 0.000044 IU/L, 0.000043 IU/L, 0.000046 IU/L, and of 0.000028 IU/L in ALT according to sex, age group, weight group, and initial ART regimen per day, respectively. An estimated decrease of 0.000013 IU/L in ALT according to ADRs per day also occurred. There was an estimated decrease of 0.00038 μmol/L, 0.00039 μmol/L, 0.00040 μmol/L, 0.00040 μmol/L, and of 0.00028 μmol/L in serum creatinine per day according to sex, age group, weight group, initial ART regimen, and ADRs, respectively. There was an estimated decline of 0.00023 mmol/L, 0.00022 mmol/L, 0.00023 mmol/L, 0.00024 mmol/L, and of 0.00015 mmol/L per day in urea according to sex, age group, weight group, initial ART regimen, and ADRs, respectively. Health professional’s questionnaire: 49 health professionals responded to the questionnaire. 100% (n= 49) of the participants showed that they did not use the yellow card scheme to report ADRs. 34.65% (n = 17) use the individual case safety reports. 57.14% (n = 28) used the structured databases to report ADRs. 85.71% (n = 42) documented in the patient bukana, and 6.12% (n = 3) used the HIV/AIDS ART card to document ADRs occurrence. 91.84% (n = 45) of the health professionals never filled the ADR reporting form in their working environment. In conclusion, adverse drug reactions occurring in a hospital or healthcare facility should be recorded and reported by the medical practitioners, nurses, pharmacists, and the pharmacy technicians. Therefore, it is important to assess the continuous evaluation of the benefits and harm of medicines which will help in achieving the ultimate goal of making safer and more effective treatment available for patients. As well as to help the health professionals to participate in the very important process of continuous surveillance of safety and efficacy of pharmaceutical products used in clinical practice. / MPham (Pharmacy Practice), North-West University, Potchefstroom Campus, 2014

Antiretroviral drugs are successful in controlling HIV/AIDS and reducing disease progression. Antiretroviral regimens are stopped in up to 25% of all patients during their initial treatment therapy as a result of adverse drug effects, failing treatment and nonadherence within the initial eight months of treatment (Sharma et al., 2007: 235). A pharmacovigilance surveillance system makes it possible for physicians, pharmacists and other healthcare providers to report suspected ADRs. The purpose of this system is to operate as a guide in identification of new ADRs and predisposing risk factors to known ADRs. The objective of this study was to assess the prevalence and documentation of adverse drug reactions (ADR) in the private and public antiretroviral clinics in Maseru district, with special reference to zidovudine (AZT) and tenofovir (TDF) - based regimens. The empirical investigation was divided into two phases. The first phase was a cross-sectional quantitative retrospective drug utilisation review study which focused on the occurrence of adverse drug reactions in patients taking zidovudine (AZT) and tenofovir (TDF). The second phase, a survey in a form of questionnaires for the health professionals. Drug utilisation review: The sample size of patients was 300. Of the 44 patients who experience ADRs, 72.73% (n = 32) were female and 27.27% (n = 12) were male. A greater number of patients who experienced ADRs were females with 43.18% (n = 19) presenting with skin rash, 27.27% (n = 12) with nausea/vomiting, and 2.27% (n = 1) with diarrhoea. In male patients, 2.27% (n = 1) had peripheral neuropathy, 18.18% (n = 8) skin rash, 2.27% (n = 1) Fanconi syndrome, 2.27% (n = 1) nausea/vomiting, and 2.27% (n = 1) diarrhoea. Patients whose ART regimen changed due to ADRs were five. 60% (n = 3) of the patients were females and 40% (n = 2) were males. There was an estimated increase of 0.0025 cell/mm³, 0.0026 cell/mm³, 0.0024 cell/mm³, 0.0025 cell/mm³, and of 0.0019 cell/mm³ in CD4 cell count per day according to sex, age group, weight group, initial ART regimen, and ADRs, respectively. An estimated increase of 0.00021 g/dL, 0.00022 g/dL, 0.00018 g/dL, 0.00022 g/dL, and of 0.00020 g/dL in Hb profile per day occurred according to sex, age group, weight group, initial ART regimen, and ADRs, respectively. There was an estimated increase of 0.000062%, 0.000046%, 0.000068%, 0.000062%, and of 0.00017% in neutrophil count according to sex, age group, weight group, initial ART regimen, and ADRs per day, respectively. There was an estimated increase of 0.000044 IU/L, 0.000043 IU/L, 0.000046 IU/L, and of 0.000028 IU/L in ALT according to sex, age group, weight group, and initial ART regimen per day, respectively. An estimated decrease of 0.000013 IU/L in ALT according to ADRs per day also occurred. There was an estimated decrease of 0.00038 μmol/L, 0.00039 μmol/L, 0.00040 μmol/L, 0.00040 μmol/L, and of 0.00028 μmol/L in serum creatinine per day according to sex, age group, weight group, initial ART regimen, and ADRs, respectively. There was an estimated decline of 0.00023 mmol/L, 0.00022 mmol/L, 0.00023 mmol/L, 0.00024 mmol/L, and of 0.00015 mmol/L per day in urea according to sex, age group, weight group, initial ART regimen, and ADRs, respectively. Health professional’s questionnaire: 49 health professionals responded to the questionnaire. 100% (n= 49) of the participants showed that they did not use the yellow card scheme to report ADRs. 34.65% (n = 17) use the individual case safety reports. 57.14% (n = 28) used the structured databases to report ADRs. 85.71% (n = 42) documented in the patient bukana, and 6.12% (n = 3) used the HIV/AIDS ART card to document ADRs occurrence. 91.84% (n = 45) of the health professionals never filled the ADR reporting form in their working environment. In conclusion, adverse drug reactions occurring in a hospital or healthcare facility should be recorded and reported by the medical practitioners, nurses, pharmacists, and the pharmacy technicians. Therefore, it is important to assess the continuous evaluation of the benefits and harm of medicines which will help in achieving the ultimate goal of making safer and more effective treatment available for patients. As well as to help the health professionals to participate in the very important process of continuous surveillance of safety and efficacy of pharmaceutical products used in clinical practice. / MPham (Pharmacy Practice), North-West University, Potchefstroom Campus, 2014

Introdução: As reações adversas a medicamentos (RAM) seguem constituindo um problema importante dentro do âmbito hospitalar. Na clínica médica, as reações adversas apresentam-se com alta frequência, pois os pacientes recebem maior número de medicamentos e apresentam maior número de comorbidades. Portanto, são necessárias abordagens que permitam a detecção precoce dos eventos, de maneira que possam ser propostas intervenções que minimizem o dano ao paciente. A busca ativa de rastreadores, sendo estes, resultados alterados de exames laboratoriais, administração de medicamentos específicos e certos acontecimentos, tem se mostrado aplicável e efetiva para o monitoramento das reações adversas a medicamentos. Objetivo: Identificar reações adversas a medicamentos na enfermaria da Clínica Médica de um hospital de nível secundário a partir de rastreadores. Métodos: Desenvolveu-se um estudo de coorte prospectiva na clínica médica do Hospital Universitário da Universidade de São Paulo, sendo utilizada uma lista de 34 rastreadores. Pacientes maiores de 15 anos que permaneceram no mínimo 24 horas na enfermaria foram aleatorizados para compor a amostra. Em cada caso, foram coletadas, de forma cronológica, informações relacionadas aos medicamentos administrados, resultados de exames laboratoriais e a evolução médica. Todos os prontuários foram discutidos por profissionais de saúde, sendo avaliada a causalidade e a gravidade. Realizou-se uma análise univariada comparando pacientes com e sem RAM. Adicionalmente estudou-se o desempenho dos rastreadores usados. Resultados: No período de agosto de 2015 até abril de 2016 foram monitorados 116 pacientes. Identificaram-se reações adversas a medicamentos em 37,9 por cento dos pacientes, sendo achadas 47 suspeitas de RAM em cada 1000 paciente-dia. Pacientes que apresentaram RAMs foram internados mais vezes em leitos classificados como alta-dependência, apresentaram maior duração da internação, maior número de medicamentos usados e menor grau de escolaridade. Em relação ao nível de gravidade, a maioria das suspeitas de RAM (49 eventos, 89,1 por cento ) foram classificadas como moderadas e afetaram o sistema gastrointestinal. Foram identificados 429 rastreadores. Os rastreadores que apresentaram melhor desempenho foram menção da hipotensão, diminuição de plaquetas maior que 50 por cento , administração de glicose hipertônica em 25 ou 50 por cento e suspensão abrupta da medicação. Conclusão: A aplicação prospectiva do método de rastreadores a uma coorte aberta de pacientes da clínica médica permitiu a identificação de suspeitas de reações adversas, a caracterização dos pacientes, as suspeitas, os medicamentos envolvidos e o desempenho dos rastreadores. / Introduction: Adverse drug reactions (ADRs) continues to represent a major problem at hospitals. In internal medicine wards, adverse drug reactions present high frequencies, as patients receive more medicines and have higher number of comorbidities. Therefore, approaches are needed that allow early detection of events, so, interventions could be proposed to minimize harm to patients. The active surveillance using triggers, which are, abnormal laboratory values, administration of specific drugs and certain events, has been proven applicable and effective for monitoring adverse drug reactions. Objective: To identify adverse drug reactions in the internal medicine ward of a secondary university hospital using triggers. Methods: a prospective cohort study was developed in the teaching hospital of the University of São Paulo, using a list of 34 sentinel words. Patients aged 15 years or more, who were hospitalized at least 24 hours, were randomized for the sample. For each case, information related to administered drugs, laboratory results and progress notes were collected chronologically. All charts were discussed by health professionals, assessing causality and severity. A univariate analysis was developed comparing patients with and without ADRs. Additionally, the performance of each trigger was studied. Results: In the period from August 2015 to April 2016, 116 patients were monitored. Adverse drug reactions were identified in 37.9 per cent of patients, presenting a rate of 47 suspected ADRs per 1,000 patient-days. Patients who experience ADRs were frequently classified as nursing high dependency, had longer length of stay, lower education level and used larger number of medicines. Regarding to severity, most of the suspected ADRs (49 cases, 89.1 per cent ) was classified as mild and affected the gastrointestinal system. 429 triggers were identified. Triggers with high performances were \"mention of hypotension\", \"platelets decrease greater than 50 per cent ,\" \"administration of dextrose 25 or 50 per cent \" and \"abrupt medication stop\". Conclusion: The prospective surveillance using triggers in an open cohort of internal medicine inpatients allowed the identification of adverse drug reactions and the characterization of patients, drugs involved and triggers.

Polimorfismos nos genes da n-acetiltransferase 2 (NAT2), CYP2E1 e glutationa S-transferase (GST) têm sido associados a diferenças na resposta ao tratamento da tuberculose. O papel de variantes dos genes NAT2, CYP2E1 e GSTM1/GSTT1, no perfil de segurança do tratamento da tuberculose, foi avaliado em 99 pacientes com tuberculose, sem co-infecção por HIV ou vírus da hepatite, tratados por 6 meses. Amostras de sangue foram colhidas antes e durante o tratamento para avaliação de marcadores de lesão hepatocelular (ASLT e AST), colestase (ALP, GGT e bilirrubinas) e função renal (creatinina). O DNA genômico foi extraído de sangue colhido em EDTA pelo método precipitação salina. Os polimorfismos NAT2 foram analisados por PCR-RFLP e seqüenciamento de DNA. Os polimorfismos da região promotora do CYP2E1 foram detectados por PCR-RFLP e para a análise dos genótipos nulos de GSTM1 (GSTM1*0) e GSTT1 (GSTT1*0) foi utilizada a PCR multiplex. Durante o tratamento, 59,6% dos pacientes apresentaram reações adversas aos medicamentos (RAM) e alterações nos marcadores de lesão hepatocelular e colestase, com aumento de 1 a 4 vezes o limite superior de referência. Foi observada forte relação entre RAM e alterações nos marcadores séricos (p< 0,05) e também com o uso de medicação concomitante (p< 0,001). As freqüências dos alelos NAT2*4 e NAT2*6 foram maiores e menores, respectivamente, quando comparadas com outros estudos na população brasileira. O perfil de acetilador lento (alelos NAT2*5, NAT2*6 e NAT2*7) foi associado com manifestação de RAM e hepatotoxicidade. Os portadores dos genótipos NAT2*4/*5 e NAT2*5/*5 apresentaram, respectivamente, risco 2,4 e 5,0 vezes maior de RAM que os portadores dos demais genótipos NAT2 (p< 0,05). O genótipo funcional GSTM1*1/GSTT1*1 foi associado com alterações acentuadas de ALT, AST e ALP (p< 0,05). Enquanto que as variantes da CYP2E1 não foram associadas a alterações no perfil bioquímico ou com risco de RAM ou hepatotoxicidade. Em conclusão, o perfil de acetilação lenta de NAT2 e o genótipo funcional de GSTM1/GSTT1 aumentam a susceptibilidade de lesão hepatocelular e outras RAM induzidas pelos antimicobacterianos utilizados no tratamento da tuberculose. / Polymorphisms in N-acetiltransferase 2 (NAT2), CYP2E1 and glutatione S-transferase (GST) have been associated with differences in response to antituberculosis drugs. The role of the NAT2, CYP2E1 and GSTM1/GSTT1 variants on safety profile of the anti-tuberculosis therapy was evaluated in 99 tuberculosis patients, without co-infection by HIV or hepatitis virus, treated during 6 months. Blood samples were collected before and after the therapy to evaluate serum markers for hepatocelullar damage (ASLT and AST), cholestasis (ALP, GGT and bilirrubin) and kidney function (creatinine). Genomic DNA was extracted from EDTA-blood samples by salting-out method. NAT2 polymorphisms were analyzed by PCR-RFLP and DNA sequencing. CYP2E1 promoter region polymorphisms were detected by PCR-RFLP and for analysis of the null genotypes GSTM1 (GSTM1*0) e GSTT1 (GSTT1*0) PCR multiplex technique was used. During the therapy, 59.6% of the patients had adverse drug reactions (ADR) and alterations on hepatocellular damage and cholestasis serum markers, with increase of 1 to 4 times the upper limit reference level. There was a significant relationship between ADR and serum markers alterations (p< 0,05), as well as, the concomitant medicine (p< 0,001). The frequencies of the NAT2*4 and NAT2*6 alleles were higher and lower, respectively, when compared to other studies in the Brazilian population. The slow acetilator profile (NAT2*5, NAT2*6 and NAT2*7 alleles) was associated with ADR and hepatotoxicity manifestations. The NAT2*4/*5 and NAT2*5/*5 genotypes carriers had, respectively, 2.4 and 5.0 times higher risk for ADR than those carrying the other NAT2 genotypes (p< 0,05). The functional genotype GSTM1*1/GSTT1*1 was associated with enhanced variations on ALT, AST and ALP (p< 0.05). No relationship was found between CYP2E1 variants and variations on biochemical profile or risk for ADR or hepatotoxicity. In conclusion, the NAT2 slow acetilator profile and the GSTM1/GSTT1 functional genotype increase the susceptibility to hepatocellular damage and other ADR induced by antibiotics used in tuberculosis therapy.

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No. of bitstreams: 2 Dissertação - Ana Carolina Figueiredo Modesto - 2014.pdf: 6541862 bytes, checksum: e3323351d0b19ca89de7c95a670ee23b (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2014-07-09 / Fundação de Amparo à Pesquisa do Estado de Goiás - FAPEG / Background: The use of drugs isn’t harmless, and require greater attention by health professionals to assist in identifying and preventing adverse drug reactions. These, and other problems related to drug use are the subject of study of pharmacovigilance. It becomes necessary knowledge by health professionals to improve patient safety. Objective: To measure the knowledge and attitudes among healthcare professionals in a teaching hospital towards adverse drugs reactions and a pharmacovigilance program. Methodology: Cross-sectional study conducted from October 2013 to January 2014 with 54 health professionals in a medical unit and in the pharmacy of a sentinel hospital. Data were collected through a questionnaire divided into three sessions: the first is the profissiographic and demographic characteristics of health professionals, and the subsequent identification of knowledge on adverse drug reactions and Pharmacovigilance hospital program. Results: There was a predominance of technical professionals in nursing (35.2%), female (79.6%), aged between 26 and 30 years (33.4%). Almost half of the participants (46.2%) had knowledge about adverse drug reactions, likewise 35.8% did towards pharmacovigilance. The probability of having knowledge about adverse drug reactions increases with longer professional training and activities at the institution, and the same does not occur with the knowledge of pharmacovigilance. Regarding the institutional knowledge, only 11.1% of participants stated that they know the site that has operations across the suspected adverse drug reactions and 38.9% reported the knowledge about the inclusion of the institution on a pharmacovigilance program. Conclusion: There was a predominance of female professionals, the technical area in nursing and training time and work at less than or equal to five years institution. It was observed that doctors have more knowledge about the concept of adverse drug reaction, and nurse technician, the lowest. Health professionals had little knowledge about the location of the institution that has operations across the adverse drug reactions and inserting the same in any program pharmacovigilance. / Introdução: A utilização de medicamentos não está isenta de riscos, maior atenção por parte dos profissionais de saúde pode auxiliar na identificação e prevenção das Reações Adversas a Medicamentos (RAM). Estas, e demais problemas relacionados ao seu uso são objeto de estudo da Farmacovigilância (FV). Faz-se necessário seu conhecimento, por parte dos profissionais de saúde, como forma de contribuir para a segurança do paciente. Objetivo: Identificar os conhecimentos e condutas de profissionais de saúde de um hospital de ensino frente às Reações Adversas a Medicamentos e ao programa de Farmacovigilância hospitalar. Metodologia: Estudo transversal, com coleta de dados realizada no período de outubro de 2013 a janeiro de 2014 com 54 profissionais de saúde em uma unidade de clínica médica e no serviço de farmácia de um hospital da rede sentinela. Os dados foram coletados por meio de um questionário dividido em três sessões: a primeira consiste na caracterização demográfica e profissiográfica dos participantes, e as subsequentes, na identificação dos conhecimentos e condutas sobre as Reações Adversas a Medicamentos e ao programa de Farmacovigilância hospitalar. Resultados: Quase metade dos participantes (46,2%) mostraram conhecimentos sobre RAM, destes, os médicos foram os que detém maior conhecimento em relação aos demais profissionais (p=0,00). Em contrapartida, os técnicos em enfermagem mostraram menos conhecimento (p=0,00). Um total de 35,8% dos participantes do estudo mostraram conhecimentos em relação à FV, destes, os farmacêuticos demonstraram maior conhecimento em relação aos demais profissionais (p=0,00), em oposição, os médicos apresentaram menores conhecimentos sobre este conceito (p=0,01). A probabilidade de apresentar conhecimentos sobre as RAM aumenta em profissionais com maior tempo de formação e atuação na instituição, e o mesmo não ocorre com os conhecimentos sobre a farmacovigilância. Somente 11,1% dos participantes declararam conhecer o local que tenha atuação frente às suspeitas de RAM e 38,9% mencionaram o conhecimento acerca da inserção da instituição em um programa de FV. Conclusão: Houve predominância de profissionais do sexo feminino, da área técnica em enfermagem e tempo de formação e de trabalho na instituição inferior ou igual à cinco anos. Observou-se, dentre os profissionais participantes do estudo, que os médicos possuem maior conhecimento sobre o conceito de RAM, e o técnico em enfermagem, o menor. Os profissionais de saúde apresentaram poucos conhecimentos quanto ao local da instituição que tenha atuação frente às RAM, bem como a inserção da mesma em algum programa de FV.

Introdução: As reações adversas a medicamentos (RAM) seguem constituindo um problema importante dentro do âmbito hospitalar. Na clínica médica, as reações adversas apresentam-se com alta frequência, pois os pacientes recebem maior número de medicamentos e apresentam maior número de comorbidades. Portanto, são necessárias abordagens que permitam a detecção precoce dos eventos, de maneira que possam ser propostas intervenções que minimizem o dano ao paciente. A busca ativa de rastreadores, sendo estes, resultados alterados de exames laboratoriais, administração de medicamentos específicos e certos acontecimentos, tem se mostrado aplicável e efetiva para o monitoramento das reações adversas a medicamentos. Objetivo: Identificar reações adversas a medicamentos na enfermaria da Clínica Médica de um hospital de nível secundário a partir de rastreadores. Métodos: Desenvolveu-se um estudo de coorte prospectiva na clínica médica do Hospital Universitário da Universidade de São Paulo, sendo utilizada uma lista de 34 rastreadores. Pacientes maiores de 15 anos que permaneceram no mínimo 24 horas na enfermaria foram aleatorizados para compor a amostra. Em cada caso, foram coletadas, de forma cronológica, informações relacionadas aos medicamentos administrados, resultados de exames laboratoriais e a evolução médica. Todos os prontuários foram discutidos por profissionais de saúde, sendo avaliada a causalidade e a gravidade. Realizou-se uma análise univariada comparando pacientes com e sem RAM. Adicionalmente estudou-se o desempenho dos rastreadores usados. Resultados: No período de agosto de 2015 até abril de 2016 foram monitorados 116 pacientes. Identificaram-se reações adversas a medicamentos em 37,9 por cento dos pacientes, sendo achadas 47 suspeitas de RAM em cada 1000 paciente-dia. Pacientes que apresentaram RAMs foram internados mais vezes em leitos classificados como alta-dependência, apresentaram maior duração da internação, maior número de medicamentos usados e menor grau de escolaridade. Em relação ao nível de gravidade, a maioria das suspeitas de RAM (49 eventos, 89,1 por cento ) foram classificadas como moderadas e afetaram o sistema gastrointestinal. Foram identificados 429 rastreadores. Os rastreadores que apresentaram melhor desempenho foram menção da hipotensão, diminuição de plaquetas maior que 50 por cento , administração de glicose hipertônica em 25 ou 50 por cento e suspensão abrupta da medicação. Conclusão: A aplicação prospectiva do método de rastreadores a uma coorte aberta de pacientes da clínica médica permitiu a identificação de suspeitas de reações adversas, a caracterização dos pacientes, as suspeitas, os medicamentos envolvidos e o desempenho dos rastreadores. / Introduction: Adverse drug reactions (ADRs) continues to represent a major problem at hospitals. In internal medicine wards, adverse drug reactions present high frequencies, as patients receive more medicines and have higher number of comorbidities. Therefore, approaches are needed that allow early detection of events, so, interventions could be proposed to minimize harm to patients. The active surveillance using triggers, which are, abnormal laboratory values, administration of specific drugs and certain events, has been proven applicable and effective for monitoring adverse drug reactions. Objective: To identify adverse drug reactions in the internal medicine ward of a secondary university hospital using triggers. Methods: a prospective cohort study was developed in the teaching hospital of the University of São Paulo, using a list of 34 sentinel words. Patients aged 15 years or more, who were hospitalized at least 24 hours, were randomized for the sample. For each case, information related to administered drugs, laboratory results and progress notes were collected chronologically. All charts were discussed by health professionals, assessing causality and severity. A univariate analysis was developed comparing patients with and without ADRs. Additionally, the performance of each trigger was studied. Results: In the period from August 2015 to April 2016, 116 patients were monitored. Adverse drug reactions were identified in 37.9 per cent of patients, presenting a rate of 47 suspected ADRs per 1,000 patient-days. Patients who experience ADRs were frequently classified as nursing high dependency, had longer length of stay, lower education level and used larger number of medicines. Regarding to severity, most of the suspected ADRs (49 cases, 89.1 per cent ) was classified as mild and affected the gastrointestinal system. 429 triggers were identified. Triggers with high performances were \"mention of hypotension\", \"platelets decrease greater than 50 per cent ,\" \"administration of dextrose 25 or 50 per cent \" and \"abrupt medication stop\". Conclusion: The prospective surveillance using triggers in an open cohort of internal medicine inpatients allowed the identification of adverse drug reactions and the characterization of patients, drugs involved and triggers.