With little research documenting elderly medication users’ beliefs and attitudes towards medication, the purpose of this study is to document how seniors experience medication use within the context of their daily lives. The study population was comprised of female and male seniors aged 65 and over who were recruited from the Parksville – Qualicum Beach and Nanaimo communities of eastern Vancouver Island, British Columbia. The findings of this research suggest that for seniors, medication use is a complex and emotionally charged experience. It is an experience filled with contradictions, in which seniors are forced to negotiate between diverse realms of information concerning medications, from the directives they receive from health care professionals, to the signals they receive from their bodies. It is an experience in which powerful conceptions of medications as prolongers of life often trump an individual’s overwhelming desire to stop taking those medications. This research is intended to expand our understandings of the perceptions, attitudes, and beliefs that inform Canadian seniors’ medication use practices. Furthermore, findings from this thesis will contribute to a collaborative investigation of seniors’ experiences with medication designed to address the increasing number of adverse drug reactions experienced by the elderly. / Graduate

Adverse drug reactions (ADRs) are a pervasive complication in the realm of pharmacotherapy. At the root of ADRs lies interindividual variability in drug response, which can range from allergic reactions, to genetic variability, to any factors that influence the pharmacokinetics of a drug. Nonalcoholic steatohepatitis (NASH) is the late-stage of non-alcoholic fatty liver disease (NAFLD), characterized by fat deposition, oxidative stress, inflammation, and fibrosis. Over the last several years, alterations in drug metabolizing enzymes and transporters have been broadly characterized through NAFLD progression. Multidrug resistance-associated protein 2 (MRP2) is a canalicular efflux transporter that directs the biliary elimination of a wide variety of xenobiotics and metabolites. In NASH, MRP2 is mislocalized away from the canalicular membrane in a post-translational event. The mechanism and extent of this mislocalization has yet to be elucidated. While transporter misregulation has been shown to influence the disposition of a variety of substrates, the direct impact of MRP2 mislocalization on its overall transport capacity, and pharmacologic consequence of this change, is unknown. The purpose of this study was to elucidate the mechanism behind, and functional consequence of, MRP2/Mrp2 mislocalization in NASH, predominantly using the rodent methionine-and-choline-deficient (MCD) dietary model.To identify the mechanism of MRP2/Mrp2 mislocalization, a comparison of the activation status of various mediators of MRP2/Mrp2 retrieval was conducted between healthy and NASH livers. Results in rat samples and human NASH samples indicate that activation changes of these mediators, including radixin, PKCα, PKCδ, and PKA, are consistent with a shift toward active retrieval of MRP2/Mrp2 from the membrane, and some evidence of impaired membrane insertion is also present. Measurement of Mrp2 transport capacity was completed using pemetrexed, a novel Mrp2 probe substrate. Comparison of biliary excretion of pemetrexed between wild-type and Mrp2^(-/-) rats shows a 100% decrease, confirming that it relies upon Mrp2 for biliary excretion. NASH rats exhibited a 60% decrease in pemetrexed levels in the bile compared to their control counterparts, indicating that Mrp2 transport capacity is severely impaired in NASH rats. Finally, to ascertain the pharmacologic consequence of impaired Mrp2 transport, a study was conducted measuring the effects of the active morphine glucuronide on control and NASH rats. NASH rats exhibited a decreased biliary excretion, and increased systemic retention, of M3G. While they did also exhibit increased antinociception of M6G, the definitive impact of altered disposition on pharmacologic response was masked due to the interference of an MCD dietary effect on antinociception. Overall, the data reported herein identify active membrane retrieval as a mechanism of MRP2/Mrp2 mislocalization in NASH, and that mislocalization results in a 60% decrease in overall Mrp2 transport capacity. This decrease significantly hinders biliary excretion of Mrp2 substrates, and may result in ADRs by contributing to interindividual variability in drug response.

nÃo hà / A farmacovigilÃncia à a ciÃncia relativa à detecÃÃo, avaliaÃÃo, compreensÃo e prevenÃÃo de reaÃÃes adversas ou quaisquer outros possÃveis problemas relacionados a medicamentos. No Brasil, a farmacovigilÃncia encontra-se em desenvolvimento. Ainda nÃo està completamente disseminada a cultura da notificaÃÃo espontÃnea, principalmente na oncologia, onde a ocorrÃncia de reaÃÃo adversa passa muitas vezes despercebida por ser considerada como um evento esperado, e, portanto, sem importÃncia significativa. Este estudo avaliou as aÃÃes de farmacovigilÃncia desenvolvidas numa instituiÃÃo hospitalar da cidade de Teresina-PI, atravÃs da monitorizaÃÃo de pacientes portadores de cÃncer de mama submetidos à terapia antineoplÃsica com o regime de combinaÃÃo FEC. Para isso, foi realizada uma investigaÃÃo baseada em uma revisÃo dos prontuÃrios desses pacientes para detectar o registro: de reaÃÃes adversas decorrentes da quimioterapia antineoplÃsica vigente e da distinÃÃo das mesmas, segundo os graus de severidade estabelecidos pelo National Cancer Institute (NCI); de intercorrÃncias clÃnicas devido à RAM ocorridas durante a terapia e de possÃveis alteraÃÃes no plano do tratamento protocolado (atrasos na realizaÃÃo dos ciclos de quimioterapia ou suspensÃo temporÃria da terapia, reduÃÃes das doses preconizadas) relacionadas com reaÃÃes adversas. De todas as reaÃÃes adversas observadas durante a investigaÃÃo, 2,07% foram registradas em nÃo conformidade com a terminologia qualitativa adotada pelo NCI e 15,06% nÃo foram graduadas quanto à severidade; alÃm disso, 100% das RAMs nÃo foram notificadas à autoridade sanitÃria competente (ANVISA) e nÃo existe um banco de dados institucional com essas reaÃÃes adversas. Foram ainda identificadas 17 (70,83%) intervenÃÃes clÃnicas devido à RAM realizadas em nÃvel ambulatorial e 7 (29,17%) intervenÃÃes clÃnicas devido à RAM que exigiram a hospitalizaÃÃo do paciente; atrasos ou suspensÃo temporÃria da realizaÃÃo dos ciclos de quimioterapia, com 8,70% decorrentes de causas clÃnicas, entre estas reaÃÃes adversas; e 8 (5,84%) casos de reduÃÃo das doses protocoladas devido à presenÃa e severidade de reaÃÃes adversas. Conclui-se que as aÃÃes de farmacovigilÃncia da instituiÃÃo hospitalar ainda sÃo incipientes, com falhas organizacionais que diminuem a confiabilidade das informaÃÃes registradas; alÃm disso, houve a comprovaÃÃo da importÃncia da farmacovigilÃncia em oncologia, onde a toxicidade dos fÃrmacos utilizados pode ser considerada fator limitante primÃrio para uma prÃtica terapÃutica ideal. / Pharmacovigilance is the science concerning the detection, assessment, understanding and prevention of adverse reactions or any other possible drug-related problems. In Brazil, pharmacovigilance is in the developmental stage. The culture of spontaneous reporting not yet fully spread, especially in oncology, where the occurrence of adverse reaction is often unnoticed because it is considered as an expected event, and therefore immaterial. This study evaluated the pharmacovigilance actions carried out at a hospital in the city of Teresina, PI, through the monitoring of patients with breast cancer undergoing anticancer therapy with the FEC protocol. An investigation was undertaken based on a review of the medical records of these patients to detect the registry: of adverse reactions resulting from cancer chemotherapy and the distinction of them according to the degrees of severity established by the National Cancer Institute (NCI); of clinical interventions due to ADR that occurred during therapy and possible changes in the plan of treatment protocol (delays in the achievement of cycles of chemotherapy or temporary suspension of therapy, reductions in the recommended doses) related with adverse reactions. Of all the adverse reactions observed during the investigation, 2,07% were not registered in accordance with the terminology adopted by NCI qualitative and 15,06% were not graded as to severity. In addition, 100% of ADRs were not reported to the recognized health authority (ANVISA) and there is not an institutional database with these adverse reactions. There were also 17 identified (70,83%) clinical interventions due to ADR performed on an outpatient basid and 7 (29,17%) clinical interventions due to ADR that required hospitalization of the patient; delays or temporary suspension of achievement of cycles of chemotherapy with 8,70% due to clinical causes among these adverse reactions; and 8 (5,84%) cases of dose reduction due to the presence and severity of adverse reactions. It is concluded that the pharmacovigilance actions of the hospital are still preliminary, with organizational flaws that reduce the reliability of the information recorded. In addition, there was evidence of the importance of pharmacovigilance in oncology, where the toxicity of drugs used may be considered a limiting factor necessary for an ideal therapeutic practice.

Background: There are approximately 12 million statin users in the United Kingdom. Reports of statin intolerance occurs between 7 and 29% of users, manifesting as muscle ache, fatigue or more seriously, muscle breakdown leading to myopathy. Creatine phosphokinase (CK) levels are used as a biomarker of statin-induced muscle damage. Non-adherence or discontinuation of therapy is a common result of intolerance and can result in negative cardiovascular disease-related outcomes. Aim: This thesis attempts to identify trends in record-linked medical data in a Scottish Caucasian cohort (GoDARTS) that best represent statin intolerance in order to study associated genetic factors. Methods: Prescribing trends such as switching or discontinuation of statin therapy were examined, and thresholds created to select true cases of intolerance. Information on CK levels was gathered from medical records and appropriate test results were utilized. Genotypic data was gathered for the variants and genetic regions of interest using a variety of methods including chip-based genotyping followed by imputation, TAQMAN genotyping, and exome sequencing. Subsequently hypothesis-based association analyses were conducted, including linear and logistic regressions, followed by meta-analyses, regional GWAS followed by a regional meta –analysis. Results: The phenotypes of statin intolerance were validated both internally and externally. Previously reported missense variants in LILRB5 (Asp247Gly) and CKM (Glu83Gly) were replicated and shown to be associated with CK levels irrespective of statin usage in the GoDARTS cohort and the clinical trial setting (JUPITER). Further, the CKM variant was also associated with inducibility of CK at times of tissue injury. The Asp247 genotype in LILRB5 was associated with increased risk of statin intolerance, and was replicated in associations with non-compliance to statin therapy and the development of myalgia in the JUPITER trial. The association with myalgia showed a stratified effect based on therapy (statin or placebo), with those on placebo showing the genotype effect. Further, the variant was also associated with increased risk of statin-induced myositis, cases of which had been clinically adjudicated and exome sequenced for the PREDICTION-ADR consortium. Further exploration of the LILR gene region showed an association with variants in LILRB2 (His20Arg and Val235Met) which were in strong LD with each other but were not in linkage with the variant in LILRB5. Stratified analysis revealed that the risk for carriers of the LILRB2 variants was increased depending on the genotype carried at the LILRB5 variant. Conclusions: This study characterises novel genetic factors associated with statin intolerance impacting adherence. The findings point to the immunomodulatory effects of statins. The results suggest that true statin-induced myalgia and non-specific myalgia are distinct, with a possible role for the immune system in their development. The findings encourage further investigation into the immune-physiology of statin-induced muscle damage and identifies genetically susceptible groups who are more likely to be statin intolerant.

Clinical characteristics of idiosyncratic drug reactions (IDRs) suggest that they are immune mediated. Penicillamine-induced autoimmunity in Brown Norway rats was used as a tool for mechanistic studies of this type of IDR. It has been shown that T helper 17 (Th17) cells play a central role in many types of autoimmune diseases. This study was designed to test whether Th17 cells are involved in the pathogenesis of penicillamine-induced autoimmunity. In sick animals, interleukin (IL) 6 and transforming growth factor-β1, known to be driving forces of Th17 differentiation, were consistently increased following penicillamine treatment. IL-17 and IL-22, characteristic cytokines produced by Th17 cells, were increased in sick animals. Furthermore, the percentage of IL-17-producing CD4 T cells was significantly increased, but only in sick animals. Retinoic acid, which has been reported to inhibit Th17 cell development, made the autoimmunity worse, increased IL-6 production, and did not decrease the number of Th17 cells. An infiltration of CD8 cytotoxic T cells in the liver suggests that they may be the key player in causing liver toxicity induced by D-penicillamine. Drug-induced liver injury (DILI) is one of the major causes of morbidity, mortality, and drug candidate failure. Recently, it has been suggested that Th17 cells may play an active role in inflammatory human liver diseases. In a study of patients being treated with isoniazid, some patients developed mild liver injury. The percentage of Th17 cells in the blood of these patients significantly increased when the ALT increased, and this suggests that they play a role in the mechanism of this liver injury. Furthermore, IL-10-producing T cells also increased and this may have prevented the development of severe liver injury. In another study, two hours after treatment of mice with acetaminophen there was a significant increase in Th17 cells in the liver. This rapid response suggests that Th17 cells can be part of the innate immune response to liver injury. Our data provided evidence that Th17 cells are involved in both “toxic” and idiosyncratic liver toxicity. This pathway could be a new target for the therapeutic interventions to treat DILI.

An animal model of nevirapine (NVP)-induced skin rash was used to test the hypothesis that sulfonation of 12-OH NVP, a metabolite of NVP proven essential for rash development, is the link between 12-OH NVP and the skin rash. Female Brown Norway (BN) rats were co-treated with NVP or 12-OH NVP and sulfation inhibitors dehydroepiandrosterone (DHEA) and salicylamide. Co-treatment with salicylamide markedly decreased formation of the sulfate conjugate but did not prevent development of the rash suggesting that the sulfate is not involved. However, it is not known whether the sulfate formation in the skin was affected. Co-treatments with DHEA decreased the sulfate formation and prevented the rash but also had other effects on NVP metabolism. This implies that the sulfate metabolite is responsible for the rash. Additional studies will be required to resolve these conflicting results.

An animal model of nevirapine (NVP)-induced skin rash was used to test the hypothesis that sulfonation of 12-OH NVP, a metabolite of NVP proven essential for rash development, is the link between 12-OH NVP and the skin rash. Female Brown Norway (BN) rats were co-treated with NVP or 12-OH NVP and sulfation inhibitors dehydroepiandrosterone (DHEA) and salicylamide. Co-treatment with salicylamide markedly decreased formation of the sulfate conjugate but did not prevent development of the rash suggesting that the sulfate is not involved. However, it is not known whether the sulfate formation in the skin was affected. Co-treatments with DHEA decreased the sulfate formation and prevented the rash but also had other effects on NVP metabolism. This implies that the sulfate metabolite is responsible for the rash. Additional studies will be required to resolve these conflicting results.

Darbo tikslas: ištirti hospitalizacijų dėl vaistų sukeltų nepageidaujamų reakcijų ypatybes bei dėsningumus. Uždaviniai: 1) nustatyti hospitalizacijų dėl NRV dažnumą, sunkumą bei įvertinti pasekmes; 2) identifikuoti vaistų grupes, dėl kurių sukeltų NRV ligonius dažniausiai reikia hospitalizuoti; 3) nustatyti priežastis, kurios galėjo padidinti hospitalizacijų dėl NRV dažnį; 4) nustatyti rizikos veiksnius, kurie gali didinti hospitalizacijų dėl NRV dažnį; 5) paruošti praktines rekomendacijas, kaip sumažinti hospitalizacijų dėl NRV dažnį. Metodika: buvo peržiūrimos pacientų, kurie per 5 mėnesius gydėsi Vidaus ligų diagnostikos skyriuje, ligos istorijos. Įtarus, kad pacientas galėjo būti hospitalizuotas dėl NRV, atvejis būdavo nagrinėjamas. NRV tikėtinumas buvo vertinamas pagal Naranjo tikėtinumo metodą. NRV išvengiamumas buvo nustatynėjamas analizuojant ligos istorijų anamnezes ir kitus paciento duomenis ir vertinamas panaudojant specifinį 10 klausimų klausimyną. Visi duomenys buvo renkami ir apdorojami su statistinės duomenų analizės programos SPSS 20.0 versija. Rezultatai: nustatyta 41 NRV sukelta hospitalizacija (4,4 proc.). 53,7 proc. hospitalizacijų dėl NRV buvo vidutinio intensyvumo (p < 0,05). Nustatyti 3 mirties atvejai (7,3 proc.) dėl NRV hospitalizuotų moterų grupėje. Išgyvenusiems pacientams po NRV sukeltų hospitalizacijų buvo reikalingas papildomas ambulatorinis gydymas (92,8 proc., p < 0,05). 73,2 proc. pasireiškė gretutinių ligų pablogėjimas (p < 0,05), 70,7 proc... [toliau žr. visą tekstą] / Objective: To examine characteristics and patterns of hospitalizations caused by adverse drug reactions. Methods: During 5 month period, medical records of Internal Diagnostic section patients were evaluated to determine hospitalizations caused by adverse drug reactions. In case of suspicion that the patient could be hospitalized due to adverse drug reaction, the case was examining. Probability was evaluated according to Naranjo Adverse Drug Reaction Probability Scale. Preventability was determined while using specific questioniere from 10 questions. Statistical data was collected and evaluated with SPSS version 20.0. Results: 41 hospitalizations occured due to ADR (4,4%). 53,7% of them were evaluated as mild severity (p < 0,05). 3 deaths (7,3%) occured in hospitalized women group because of ADR. Patients who outlived after ADR hospitalizations were in need of additional out-patient treatment (92,8%, p < 0,05). 73,2% experienced worsening of the underlying diseases (p < 0,05), 70,7% were hospitalized for more than 7 days (p < 0,05). Approximate cost of one hospitalization was 3 617,70 Lt, while others, not related to ADE - 2 729,05 Lt. Most of ADR hospitalzitions were caused by anticoagulants (53,7%, p < 0,05): warfarin (41,5%), acetylsalicylic acid (9,8%). Major reasons which might have enhanced hospitalizations due to ADR risks were evaluated as drug interactions (24,4 proc.), overdose (22,0%), drug use to the discretion of the patient's (17,1%), drug prescribing regardless... [to full text]

Clinical characteristics of idiosyncratic drug reactions (IDRs) suggest that they are immune mediated. Penicillamine-induced autoimmunity in Brown Norway rats was used as a tool for mechanistic studies of this type of IDR. It has been shown that T helper 17 (Th17) cells play a central role in many types of autoimmune diseases. This study was designed to test whether Th17 cells are involved in the pathogenesis of penicillamine-induced autoimmunity. In sick animals, interleukin (IL) 6 and transforming growth factor-β1, known to be driving forces of Th17 differentiation, were consistently increased following penicillamine treatment. IL-17 and IL-22, characteristic cytokines produced by Th17 cells, were increased in sick animals. Furthermore, the percentage of IL-17-producing CD4 T cells was significantly increased, but only in sick animals. Retinoic acid, which has been reported to inhibit Th17 cell development, made the autoimmunity worse, increased IL-6 production, and did not decrease the number of Th17 cells. An infiltration of CD8 cytotoxic T cells in the liver suggests that they may be the key player in causing liver toxicity induced by D-penicillamine. Drug-induced liver injury (DILI) is one of the major causes of morbidity, mortality, and drug candidate failure. Recently, it has been suggested that Th17 cells may play an active role in inflammatory human liver diseases. In a study of patients being treated with isoniazid, some patients developed mild liver injury. The percentage of Th17 cells in the blood of these patients significantly increased when the ALT increased, and this suggests that they play a role in the mechanism of this liver injury. Furthermore, IL-10-producing T cells also increased and this may have prevented the development of severe liver injury. In another study, two hours after treatment of mice with acetaminophen there was a significant increase in Th17 cells in the liver. This rapid response suggests that Th17 cells can be part of the innate immune response to liver injury. Our data provided evidence that Th17 cells are involved in both “toxic” and idiosyncratic liver toxicity. This pathway could be a new target for the therapeutic interventions to treat DILI.

Magister Pharmaceuticae - MPharm / South Africa faces a huge Human Immunodeficiency Virus (HIV) burden with more than 400,000 children currently on antiretroviral therapy (ART). Studies on lipid and haematological profile changes in paediatrics are of particular interest since these children are exposed to ART in the course of a developmentally significant period and will possibly have longer collective exposure to ART. As such, monitoring for adverse effects, including lipid and haematological abnormalities, is essential for curtailing morbidity and mortality rates of children on ART. There is a dearth of studies assessing lipid and haematological abnormalities in the South African paediatric population on ART where genetic differences, co-morbidities, malnutrition and use of traditional medicines, all influence the safety profile of a drug. The goal of this study was twofold: Firstly to identify a suitable parameter for assessing lipid and haematological abnormalities in paediatrics on Antiretroviral (ARV) treatment using available secondary data and secondly, to assess prescriber adherence to routine monitoring tests in the ART guidelines. This study was a retrospective review of secondary data obtained from 168 patient clinical records at a Community Health Centre in the Cape Metropole, Western Cape and corresponding laboratory data from the National Health Laboratory Service (NHLS) database. Appropriate cholesterol, triglyceride, haemoglobin and neutrophil test results were compared against the standard reference ranges/values. The Chi-Squared test identified associations between total cholesterol (TC) /triglycerides and haemoglobin (Hb)/neutrophil and other independent variables. Evaluation of health care provider adherence to routine monitoring tests was assessed against relevant national ARV management guidelines. There was a paucity of baseline data for all laboratory markers and infrequent follow-up tests were ordered by healthcare providers. This precluded the measurement of changing lipid and haematological levels and an alternative parameter, viz., the highest available laboratory test value for each marker per patient, was assessed against reference values/ranges. Only nine out of the 36 (25%) patients on an AZT regimen had any Hb or neutrophil laboratory tests performed and 23 and two out of 97 (24% and 2%) patients, respectively, on a protease inhibitor (PI) had a TC and triglyceride laboratory test performed. Anaemia was detected in 45.5 % of children below five years of age, in 21.7% between ages of six and 11 and in 65.5 % between 12 and 14 years of age. Neutropenia was detected in 25.6% of children below five years of age and in 50% aged between six and 11. Hypercholesterolemia was found in 13.1% of patients. The only statistically statistical associations were found between the TC and CD4 count in children aged six to 14 years (χ2=5.000; p=0.025) and between neutrophil counts and viral load in children aged six to 14 years (χ2=6.4532; p=0.0240). A significant association was also found between Hb levels and viral load (χ2=7.000; p=0.008). In the absence of baseline test results and routine monitoring of haematological and lipid profiles, this study presents a potential alternative marker for assessing lipid and haematological abnormalities using the highest level of neutrophil, Hb, TC and triglycerides recorded for each patient.