Dissertations / Theses on the topic 'Psychotropic drugs – adverse effects'

Les psychotropes et les médicaments à propriétés anticholinergiques (anti-muscariniques) ont été associés aux risques de chute et de troubles cognitifs chez les séniors. Nos travaux avaient pour but de mieux comprendre le rôle de ces médicaments dans les phénomènes de troubles de la mobilité et de troubles cognitifs. Dans un premier temps, nous avons montré que la consommation de 2 psychotropes ou plus par jour et/ou d’1 seul médicament à propriétés anticholinergiques par jour, dès la charge anticholinergique minimale, est associée à un déficit lors de tests d’évaluation de la marche et de la cognition chez une population de séniors dès l’âge de 55 ans. En ce qui concerne les médicaments à propriétés anticholinergiques, ces effets néfastes sur la marche et sur la cognition étaient plus prononcés chez les personnes âgées de 75 ans ou plus. Les fonctions exécutives étaient sévèrement affectées par ces deux types de médicaments qui semblaient d’ailleurs affecter la mobilité via ce dysfonctionnement exécutif. Nous avons par ailleurs montré que, parmi les médicaments à propriétés anticholinergiques les plus prescrits dans notre population de séniors, la consommation de tramadol, un antalgique de palier 2, était le plus associé à des effets néfastes sur la marche et la cognition. Il est toutefois difficile d’affirmer que ces effets observés sont dus exclusivement à la consommation du tramadol en raison de la polymédication présente chez les sujets. Pour identifier les médicaments les plus à risque, les études chez l’animal, dans lesquelles l’administration de médicaments peut être contrôlée, peuvent être d’un grand intérêt. C’est ainsi que, dans un second temps, nous avons montré que l’administration chronique de tramadol altère les fonctions exécutives telles que mesurées par un test de flexibilité cognitive chez la souris jeune adulte. L’ensemble de ces résultats devraient alerter les médecins sur le fait qu’il est crucial de réduire la polymédication de psychotropes d’une part, et la prescription de tout type de médicaments à propriétés anticholinergiques d’autre part, chez les séniors, dès l’âge de 55 ans. Il faudrait également prendre des mesures qui visent à prescrire des traitements alternatifs chaque fois que cela est possible. En ce qui concerne le tramadol, ces résultats suggèrent la nécessité de renforcer toutes les mesures qui ont été prises récemment pour lutter contre le mésusage de cet antalgique<br>Psychotropic drugs and drugs with anticholinergic properties (anti-muscarinics) have been associated with risks of falls and cognitive impairment in the elderly. Our work aimed at improving knowledge about the role of these drugs in gait and cognitive impairment. We first showed that daily consumption of 2 or more psychotropic drugs per day and / or only 1 drug with anticholinergic properties, regardless of its anticholinergic burden, is associated with impaired scores on gait and cognitive test in a population of seniors from the age of 55 years. With regard to drugs with anticholinergic properties, these adverse effects were more pronounced in people aged 75 years or older. Executive functions were the severely affected by these drugs consumption. We have also shown that among the most prescribed drugs with anticholinergic properties, the consumption of tramadol, a level 2 analgesic, was the most associated with harmful effects on gait and cognition. However, it is difficult to ascertain that these observed adverse effects are solely driven by the consumption of tramadol due to the polypharmacy in this population. To identify the drugs most at risk, animal studies, in which the administration of drugs can be controlled, may be of great interest. Hence, as a second step, we showed that the chronic administration of tramadol impairs executive functions as measured by cognitive flexibility in young adult mice. Altogether these results should alert physicians on the fact that it is crucial to reduce polypharmacy of psychotropic drugs as well as the prescription of all types of drugs with anticholinergic properties. Alternative treatments should be prioritized as soon as possible. With regard to tramadol, these results suggest the need to strengthen the measures taken recently to combat the misuse of this analgesic

Antipsychotic drugs are the mainstay of treatment for psychotic disorders according to the Standard Treatment Guidelines (2012). However, these drugs are associated with multiple severe adverse drug reactions. In order to limit the effect of adverse drug reactions on patient care, documentation is necessary. Documentation of adverse drug reactions entails recording the reaction experienced, as well as supplementary information. Proper documentation can prevent future occurrences of the same or similar adverse drug reactions. The aim of this study was to determine the effects of an educational intervention targeting increasing documentation of the adverse effects of antipsychotic drugs. The objectives of the study were: to determine the pre-intervention extent and frequency of documentation of antipsychotic-related adverse drug reactions in the patient medical record; to implement an intervention aimed at educating the relevant healthcare professionals, focusing on the adverse drug reactions of antipsychotic drugs and how to record or document these reactions; to assess the post-intervention extent and frequency of documentation of antipsychotic-related adverse drug reactions in the patient medical record; and to assess the attitude of healthcare providers towards the documentation of antipsychotic related adverse drug reactions before and after the intervention.

Thesis (M.S.)--University of North Carolina at Chapel Hill, 2009.<br>Title from electronic title page (viewed Sep. 3, 2009). "... in partial fulfillment of the requirements for the degree of Masters of Sciences in the School of Medicine Toxicology." Discipline: Toxicology; Department/School: Medicine.

Zinberg's Interaction Model implies that the content of a drug-induced experience is a function of the pharmacological properties of the drug, the set (the user’s characteristics e.g. motivation and personality), and the setting (the physical and social context). The current research investigated the function of the set and setting and their role in shaping the psychological effects of 3,4-methylenedioxmethamphetamine (MDMA), as well as their role in reducing the risk of drug abuse. An online survey was distributed among adult MDMA polydrug users (n = 158) and MDMA-naïve controls (alcohol, nicotine and cannabis users, n = 138). Participants answered questions regarding their pattern of drug use, their motivation for MDMA use and the setting (e.g. clubbing, home with friends), as well as the subjective effects of MDMA. Participants also completed a range of self-report measures of self-reflection and insight, emotional intelligence, and personality, as well as a drug dependency measure. MDMA users displayed higher levels of self-reflection and insight, openness to new experience and lower levels of neuroticism and conscientiousness, in comparison to the control group. The significant predictors of self-reflection and insight were openness, emotional intelligence, MDMA use, extraversion and neuroticism. When the analysis was rerun only for the MDMA group, the significant predictors of self-reflection and insight were openness, emotional intelligence and self-insight effects of MDMA. High levels of self-reported negative effects of MDMA were predictors of a problematic drug use. These findings suggest that there might be a relationship between MDMA use and higher levels of self-reflection and insight; however, longitudinal studies are required to further investigate the causality of this relationship. The results add to existing evidence that MDMA has potential for altering emotional experiences. Further research utilising a prospective design is warranted.

A postmarketing surveillance survey of sumatriptan use comprised 32 questions including patient demographics, headache history, and sumatriptan experience. One hundred and forty-one questionnaires were sent out, and 109 patients responded; a total of 108 patients were included in the data analysis. When compared with the national migraine population, on a percentage basis, significantly more African-Americans, females, young patients (less 45 years of age), and patients with higher mean incomes (>$45,000) were found in the present study of those taking sumatriptan (p Males (N=8) and females (N=55) had a significantly different percentage of relief from the second dose of 94.7%±7.1 and 83.5%±24.4, respectively (p=0.01). An average percent of pain relief from the first dose in those weighing less or greater than 144 pounds was 76.5%±28.3 and 86.9%±16.4, respectively (p=0.023). The incidence of the adverse effects reported in this study was significantly greater than those reported in the literature (p<0.005).

>Magister Scientiae - MSc<br>Adverse effects are a significant factor that determine how long patients will tolerate a given antiretroviral drug regimen. They also influence treatment options, and play an important role in the much needed adherence to treatment by patients on Highly Active Antiretroviral Therapy (HAART). This study is aimed at understanding adverse effects experienced by patients on the first line antiretroviral therapy at Keetmanshoop Hospital in Namibia. Methods : A retrospective quantitative method was used to review records of patients on first line antiretroviral treatment who started treatment between November 1st 2007 and December 1st, 2008 and followed up until they reached 36 – 48 months on treatment. Records of 94 patients were found eligible to be included in the study. Data was analysed using Stata 12 data analysis software. Results : The most reported adverse effect was musculoskeletal disorders (25%) whereas headache (16%) was the least reported. Low haemoglobin (78%) was the most common recorded hematologic adverse effect whereas low red cell distribution width and low mean platelet volume were the least recorded adverse effects (0%). A Male patient was more likely to experience a low haemoglobin levels compared to a female patient (adjusted OR: 3.29, 95% CI: 1.3 – 8.3). A male patient was found to be 64% times less likely to experience a higher mean cell haemoglobin compared to a female patient (adjusted OR. 0.31, 95% CI: 0.11 – 0.87). A patient on nevirapine was more likely to experience an elevated creatinine level compared to a patient on efavirenz (adjusted OR; 36.0, 95%CI: 2.02 – 62.5). At baseline, a patient who had prior exposure to ART had an 81 times (adjusted OR: 81.4, 95%CI: 5.3 – 119, p-value=0.00) increased odds of experiencing a high mean cell volume (MCV) compared to a patient with no ART exposure. A patient with a higher CD4 count was also less likely to experience a low hemoglobin compared to a patient with low CD4 count (adjusted OR; 0.31, 95% CI: 0.12 – 0.77). The author recommends further studies with higher sample size to confirm whether higher creatinine levels are more prevalent in patients on nevirapine compared to patients on efavirenz; this will have clinical implications especially in patients with impaired renal system. Antiretroviral treatment increases chances of developing macrocytosis anaemia; clinical implication of this condition may need to be investigated.

Thematic Paper (M.C.T.M. (Clinical Tropical Medicine))--Mahidol University, 2007.<br>LICL has E-Thesis 0024 ; please contact computer services. LIRV has E-Thesis 0024 ; please contact circulation services.

Background. Medication-related patient injuries (adverse drug events, ADEs) are an important problem in all hospitalised populations; however, the potential for injury is reported to be greater in children than adults. Many ADEs are due to error and therefore could be prevented. Data regarding the risk factors (or predictors) for these events in paediatric inpatients is limited. It was hypothesised that "identification of risk factors for ADEs and medication errors in the paediatric inpatient setting will inform likely prevention strategies". Aims. To determine the frequency, nature and risk factors for ADEs and potential ADEs occurring in a paediatric inpatient population; to assess the vulnerable processes in the neonatal intensive care unit (NICU) medication use process; and to provide recommendations for the targeting of likely prevention strategies. Setting. A general paediatric ward (PW), postnatal ward (PNW) and NICU of a University- affiliated urban general hospital. Design. There were two study components: the medEVENT study which involved identification of actual ADEs and potential ADEs over a twelve week period, through prospective review of medical records, medication charts and administration records along with voluntary and solicited staff report and parent interview; and the FMEA study which used a proactive risk assessment technique, Failure Mode and Effect Analysis (FMEA), to rank all potential failures in the NICU medication use process according to risk. Results. In the MedEVENT study 3160 prescription episodes were reviewed (which represented 520 admissions, 3037 patient-days) and revealed a total of 67 ADEs and 77 potential ADEs. The greatest number of events occurred in NICU with very few events in the PNW. However, paediatric surgical admissions experienced the highest rate of ADEs per 1000 patient-days (80) as compared to medical (65) then NICU admissions (19). Over half of the ADEs were deemed preventable, 38 (57%), with the �more serious� ADEs more likely to be preventable than �not serious� ADEs. The impact on hospital resources was considerable with the cost attributed to extra bed days due to ADEs to be $NZD 50,000. Dosing errors were the most common type of error, particularly when prescribing and administering medications. Antibacterial and narcotic analgesics were commonly implicated, as was the intravenous route of administration. Few events were related to unlicensed use of medications. For ADEs, the major risk factors when analysed by admission, were greater medication exposure and increasing age; by prescription, were increasing age, oral route and narcotics and antibacterial agents; for paediatric ward admission, were increasing age and increased length of stay; and for NICU admission, no major risk factors emerged. For potential ADEs, the major risk factors when analysed by admission were greater medication exposure; by prescription, were junior prescriber, intravenous route, narcotics and antibacterials; for paediatric ward admission, were junior prescriber and narcotics; and for NICU admission were antibacterials, electrolytes and umbilical venous catheter administration. Neither ADEs nor potential ADEs were associated with unlicensed use of medicines or high alert status drugs. The FMEA study identified 72 potential failures in the NICU medication use process with 193 associated causes and effects. Multiple failures were possible in the process of �prescribing medication� and in the process of �preparation of medication for administration�. The highest ranking issues were found to occur at the administration stage. Common potential failures related to errors in the dose, timing of administration, infusion pump settings and route of administration. Conclusions. Analysis of the risk factors of ADEs and potential ADEs found that the most vulnerable processes were when prescribing and when preparing a medicine for administration; especially when involving narcotic and antibacterial agents and for children with greater medication exposure Strategies that selectively target these high risk areas are therefore likely to have the greatest impact on preventing drug-related injuries in hospitalised children.

Post-marketing surveillance refers to any non-experimental or observational study, method, or monitoring strategy that is applied to obtain information on drug experience (primarily adverse) after a drug has been approved for clinical use. One of the major problems in post-marketing surveillance studies is the lack or under-reporting of drug experiences by health care professionals. This study was developed to describe the impact of three different prescription event monitoring programmes on the reporting of adverse drug reactions (ADR's) in the hospital situation. The intensive ADR monitoring programme and two voluntary ADR monitoring programmes which followed were conducted in the medical wards of an urban teaching and referral hospital. All patients admitted to the designated wards were monitored by a dedicated pharmacist in the intensive programme, ward pharmacists in the first voluntary programme and by medical and nursing staff in the second voluntary programme. The pharmacist monitored a cohort of patients prospectively in two medical wards for a period of three months. The patient's record was linked with any suspected ADR. All details, i.e. patient drug orders, characteristics and ADR description, were recorded and then reported. From 228 patients monitored, 25 cases have been reported. The impact of the intensive ADR monitoring programme was a reporting rate of 11 percent. Reports were received on ADR's of a particularly mild, common and pharmacologically predictable (type A) nature. The first voluntary ADR monitoring programme comprised the reporting of suspected AD R's and the recording of drug orders for the patients and the patient characteristics. The ward pharmacists monitored for suspected AD R's in all patients during their regular ward rounds. Six cases were reported in a population of 1506 patients monitored during the three months. The reports were mainly on moderate to severe suspected AD R's of pharmacologically unpredictable (type B) nature. The rate of reports received by the surveillance unit in this study was 4 reports per ward pharmacist per annum. The second voluntary ADR monitoring programme comprised the prospective monitoring of 1555 patients by medical and nursing staff during their stay at the designated medical wards during the three month period. Patients were monitored for any ADR and when an ADR was suspected, the patient characteristics and drug orders were recorded and reported to the surveillance unit. Ten cases were reported represented by six reports from doctors and four by sisters. The reporting rate was 2 reports per doctor in four years and 3 reports for each member of the nursing team in 5 years. Reports were mainly received on moderate to severe suspected ADR's of a pharmacologically unpredictable (type B) nature.

Binge drinking is characterised by cycles of ethanol intoxication and withdrawal and is thought to be highly deleterious for the normal functioning of the nervous system. The behavioural and neurophysiological consequences of rapid escalation of blood alcohol concentration and subsequent withdrawal, and their effects on learning and memory and underlying neural circuitry can be studied in suitable animal models. Here, spatial and instrumental learning as well as hippocampal LTP were assessed in C57BL/6J mice for the effects of adolescent intermittent ethanol (AIE) and other ethanol treatments. AIE treatment did not impair spatial or non-spatial memory when tested in adulthood. However, if mice were trained whilst intoxicated during AIE treatment, spatial memory was impaired. Post-training injections of ethanol impaired performance in operant conditioning. A rapid rise and fall in ethanol concentration, prior to stimulation, blocked LTP induction in drug naïve hippocampal slices; an effect that was not seen if the ethanol concentration was gradually increased and decreased. Moreover, AIE treatment caused an NMDA receptor-dependent transient increase in hippocampal LTP. The second part of this study used a novel molluscan model Lymnaea stagnalis and demonstrated that high concentrations of ethanol blocked acquisition and retrieval of an associative memory. However, if acquisition occurred in the presence of ethanol then memory could also be retrieved under ethanol, demonstrating ethanol state dependency. By utilising the cerebral giant cells, a modulatory neuron type with known involvement in memory formation, it was found that ethanol reduced the tonic firing frequency as well as the peak-to-trough and half-width parameters of individual action potentials. The development of in vivo and in vitro ethanol treatment and test protocols, and the findings based on their use, open up new avenues for future systematic investigations on ethanol's effects on behaviour and underlying neural circuitry in both vertebrate and invertebrate model systems.

Injury and illness associated with drugs are major problems in Australia and around the world, despite significant developments in the area of adverse drug reaction (ADR) decision support technology. The aims of this thesis are: to investigate the ADR decision domain; to determine factors that may assist in the prevention, detection and management of ADRs; and, to inform the pre-requirements analysis phase of the development of decision support systems. An approach has been taken that permits open and grounded study of the decision environment. This approach can then be used to frame and inform the design of an ADR decision support system. Fifteen case studies that comprise self selected consumers, the treating medical practitioner/s and expert perspectives of a single instance of an ADR (fifteen in-depth consumer interviews, eight in-depth medical practitioner interviews and 30 expert written questionnaires), have been collected and analysed using a grounded theory approach, a symbolic interactionist theoretical framework and a social constructionist epistemology. The analysis was performed from three perspectives: individual case study analysis (all interviews for an instance of an ADR); group analysis (consumer, medical practitioner and expert views) and analysis combining the individual case studies and groups of data. Concepts, themes and theory have emerged from these data in the following areas: • the contribution of the differences in understanding of the core concepts within this domain, to misunderstandings between decision-makers; • the consumer as a diagnostic decision-maker in the ADR decision domain; • differential diagnostic strategies used by the consumers and medical practitioners; • complexities in the ADR decision domain that make diagnosis difficult; • the role of ADR information in consumer and medical practitioner decision-making; • decision types used by consumers and medical practitioners in the ADR decision domain; • resources used by consumers, medical practitioners and experts to inform their ADR decisions; • decision-making with partial knowledge of the consumer case history, drug behaviour and diseases; • the impact of suspected ADRs on consumers and on future decision-making; • medical practitioner/consumer decision-making models; and, • reasons for low ADR reporting and the impact on the development of new ADR knowledge. The results above suggest the following: • The ADR decision domain is more complex than the current ADR decision support focus and that broadening this focus may assist in providing a more complete and useful decision support solution. • Improving the prevention, detection and management of ADRs requires more than providing prescribers with up to date ADR information. Other important factors are sharing of information, awareness of the role of the consumer, a collaborative approach between the consumers and medical practitioners, and generation of new ADR knowledge. • A grounded theory analysis of case study data using the theoretical perspectives of social constructionism and symbolic interactionism provided insight into this domain from the perspectives of multiple decision-makers. This may be an approach that can be used by systems analysts to inform the requirements analysis phases of decision support within other domains. The results of this qualitative work are preliminary. Future work is required to confirm and expand these results.<br>Doctor of Philosophy

Injury and illness associated with drugs are major problems in Australia and around the world, despite significant developments in the area of adverse drug reaction (ADR) decision support technology. The aims of this thesis are: to investigate the ADR decision domain; to determine factors that may assist in the prevention, detection and management of ADRs; and, to inform the pre-requirements analysis phase of the development of decision support systems. An approach has been taken that permits open and grounded study of the decision environment. This approach can then be used to frame and inform the design of an ADR decision support system. Fifteen case studies that comprise self selected consumers, the treating medical practitioner/s and expert perspectives of a single instance of an ADR (fifteen in-depth consumer interviews, eight in-depth medical practitioner interviews and 30 expert written questionnaires), have been collected and analysed using a grounded theory approach, a symbolic interactionist theoretical framework and a social constructionist epistemology. The analysis was performed from three perspectives: individual case study analysis (all interviews for an instance of an ADR); group analysis (consumer, medical practitioner and expert views) and analysis combining the individual case studies and groups of data. Concepts, themes and theory have emerged from these data in the following areas: • the contribution of the differences in understanding of the core concepts within this domain, to misunderstandings between decision-makers; • the consumer as a diagnostic decision-maker in the ADR decision domain; • differential diagnostic strategies used by the consumers and medical practitioners; • complexities in the ADR decision domain that make diagnosis difficult; • the role of ADR information in consumer and medical practitioner decision-making; • decision types used by consumers and medical practitioners in the ADR decision domain; • resources used by consumers, medical practitioners and experts to inform their ADR decisions; • decision-making with partial knowledge of the consumer case history, drug behaviour and diseases; • the impact of suspected ADRs on consumers and on future decision-making; • medical practitioner/consumer decision-making models; and, • reasons for low ADR reporting and the impact on the development of new ADR knowledge. The results above suggest the following: • The ADR decision domain is more complex than the current ADR decision support focus and that broadening this focus may assist in providing a more complete and useful decision support solution. • Improving the prevention, detection and management of ADRs requires more than providing prescribers with up to date ADR information. Other important factors are sharing of information, awareness of the role of the consumer, a collaborative approach between the consumers and medical practitioners, and generation of new ADR knowledge. • A grounded theory analysis of case study data using the theoretical perspectives of social constructionism and symbolic interactionism provided insight into this domain from the perspectives of multiple decision-makers. This may be an approach that can be used by systems analysts to inform the requirements analysis phases of decision support within other domains. The results of this qualitative work are preliminary. Future work is required to confirm and expand these results.<br>Doctor of Philosophy

Injury and illness associated with drugs are major problems in Australia and around the world, despite significant developments in the area of adverse drug reaction (ADR) decision support technology. The aims of this thesis are: to investigate the ADR decision domain; to determine factors that may assist in the prevention, detection and management of ADRs; and, to inform the pre-requirements analysis phase of the development of decision support systems. An approach has been taken that permits open and grounded study of the decision environment. This approach can then be used to frame and inform the design of an ADR decision support system. Fifteen case studies that comprise self selected consumers, the treating medical practitioner/s and expert perspectives of a single instance of an ADR (fifteen in-depth consumer interviews, eight in-depth medical practitioner interviews and 30 expert written questionnaires), have been collected and analysed using a grounded theory approach, a symbolic interactionist theoretical framework and a social constructionist epistemology. The analysis was performed from three perspectives: individual case study analysis (all interviews for an instance of an ADR); group analysis (consumer, medical practitioner and expert views) and analysis combining the individual case studies and groups of data. Concepts, themes and theory have emerged from these data in the following areas: • the contribution of the differences in understanding of the core concepts within this domain, to misunderstandings between decision-makers; • the consumer as a diagnostic decision-maker in the ADR decision domain; • differential diagnostic strategies used by the consumers and medical practitioners; • complexities in the ADR decision domain that make diagnosis difficult; • the role of ADR information in consumer and medical practitioner decision-making; • decision types used by consumers and medical practitioners in the ADR decision domain; • resources used by consumers, medical practitioners and experts to inform their ADR decisions; • decision-making with partial knowledge of the consumer case history, drug behaviour and diseases; • the impact of suspected ADRs on consumers and on future decision-making; • medical practitioner/consumer decision-making models; and, • reasons for low ADR reporting and the impact on the development of new ADR knowledge. The results above suggest the following: • The ADR decision domain is more complex than the current ADR decision support focus and that broadening this focus may assist in providing a more complete and useful decision support solution. • Improving the prevention, detection and management of ADRs requires more than providing prescribers with up to date ADR information. Other important factors are sharing of information, awareness of the role of the consumer, a collaborative approach between the consumers and medical practitioners, and generation of new ADR knowledge. • A grounded theory analysis of case study data using the theoretical perspectives of social constructionism and symbolic interactionism provided insight into this domain from the perspectives of multiple decision-makers. This may be an approach that can be used by systems analysts to inform the requirements analysis phases of decision support within other domains. The results of this qualitative work are preliminary. Future work is required to confirm and expand these results.<br>Doctor of Philosophy

Master of Science<br>Department of Clinical Sciences<br>Gregory F. Grauer<br>Prostaglandins play many important roles in the kidney including regulation of renal blood flow, glomerular filtration, renin release, and sodium excretion. Upon activation of the renin angiotensin aldosterone system (RAAS), prostaglandin upregulation becomes critical to offset the vasoconstrictive effects of norephinephrine, angiotensin II, and vasopressin. Nonsteroidal anti-inflammatory drugs (NSAIDs) produce both their beneficial and detrimental effects through inhibition of the cyclooxygenase enzyme and subsequent interference with prostaglandin production. Healthy canine kidneys express both COX-1 and COX-2, although basal COX-2 expression in dogs is significantly higher than in other species. Nonsteroidal anti-inflammatory drugs that spare COX-1 have exhibited less gastrointestinal toxicity, but no NSAID has been proven safe for the kidney. The kidney is the organ with the second highest reports of adverse drug events, which is usually manifested as functional changes. However, structural changes including renal papillary necrosis, can occasionally be observed. Dogs with chronic kidney disease could be expected to be at increased risk for NSAID-related adverse drug effects. As nephrons and renal reserve are lost in chronic kidney disease, the canine kidney becomes more dependent on COX-2 for production of prostaglandins. Inasmuch as the prevalence of both CKD and OA increases with age, it is expected that many dogs being treated with NSAIDs for OA will have loss of renal reserve and/or early stage CKD. If administration of an NSAID is required for long term treatment of osteoarthritis, frequent monitoring of blood pressure and renal parameters, as well as hepatic enzymes are recommended.

The metabotropic glutamate receptor, mGluR5, is densely expressed in brain regions involved in incentive learning processes. There is considerable evidence to suggest that following exposure to addictive drugs such as cocaine, adaptations in these brain areas may underlie the development and maintenance of behavioural responses related to addictive processes. The present thesis examines the role of mGluR5 in both incentive learning processes and some behavioural and neurobiological effects of cocaine. First, using a novel mutant mouse line in which mGluR5 is selectively knocked down in cells that express dopamine D1 receptors (D1R), I argue that this mGluR5 population is critically important for specific incentive learning processes. By blocking mGluR5 in wild-type mice with a selective antagonist, I then propose mGluR5 as necessary for the acquisition, but not the expression of an incentive association. Next, I present data showing that mGluR5 on dopaminoceptive neurons are not necessary for the „conditioned rewarding‟ properties of cocaine, measured in the conditioned place preference model, but do contribute to the psychomotor activating effects of cocaine. Finally, I present an immunohistochemistry study that examines cocaine-induced activation of the extracellular-signal related kinase (ERK) pathway. In the mGluR5 knock-down mice, activation of the ERK pathway in the striatum is disrupted following an acute injection of cocaine. Given the importance of the ERK pathway in establishing and maintaining long term memories, I propose that disruption of this pathway could contribute, in part, to some findings reported in the present thesis. Taken together, this thesis will argue that signalling through mGluR5 on D1R expressing neurons is important for the formation of incentive associations, and may contribute to neural adaptations necessary for the development and maintenance of behavioural responses related to addictive processes.

Many epidemiological studies assess the effects of time-dependent exposures, where both the exposure status and its intensity vary over time. The analysis of such studies poses the challenge of modelling the association between complex time-dependent drug exposure and the risk, especially given the uncertainty about the etiological relevance of doses taken in different time periods.<br>To address this challenge, I developed a flexible method for modelling cumulative effects of time-varying exposures, weighted by recency, represented by time-dependent covariates in the Cox proportional hazards model. The function that assigns weights to doses taken in the past is estimated using cubic regression splines. Models with different number of knots and constraints are estimated. Bootstrap techniques are used to obtain pointwise confidence bands around the weight functions, accounting for both the sampling variation of the regression coefficients, and the uncertainty at the model selection stage, i.e. the additional variance due to a posteriori selection of the number of knots.<br>To assess the method in simulations, I had to develop and validate a novel algorithm to generate event times conditional on time-dependent covariates and compared it with the algorithms available in the literature. The proposed algorithm extends a previously proposed permutational algorithm to include a rejection sampler. While all the algorithms generated data sets that, once analyzed, provided virtually unbiased estimates with comparable variances, the algorithm that I proposed reduced the computational time by more than 50 per cent relative to alternative methods. I used simulations to systematically investigate the properties of the weighted cumulative dose method. Six different weight functions were considered. Simulations showed that in most situations, the proposed method was able to capture the shape of the true weight functions and to produce estimates of the magnitude of the exposure effect on the risk that were close to those used to generate the data. I finally illustrated the use of the weighted cumulative dose modelling by reassessing the association between the use of selected benzodiazepines and fall-related injuries, using administrative data on a cohort of elderly who initiated their use of benzodiazepines between 1990 and 2004.

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.

Dissertação de Mestrado Integrado em Medicina Veterinária<br>A quimioterapia é uma modalidade terapêutica usada em oncologia, cujo objetivo passa pela total erradicação das células tumorais ou pela cura, através da administração de fármacos quimioterápicos ou anti-neoplásicos. Estes atuam, na sua grande maioria, em células com elevado índice mitótico, atingindo não apenas as células neoplásicas como também as células normais, o que conduz aos chamados efeitos secundários. Este estudo teve como objetivo a avaliação e caracterização dos efeitos secundários dos fármacos quimioterápicos, na prática clínica de animais de companhia consistindo num estudo retrospetivo de casos. O desenho experimental incluiu todos os cães e gatos, machos e fêmeas, submetidos a pelo menos uma sessão de tratamento com fármacos quimioterápicos, independentemente do tipo de neoplasia, no Hospital Veterinário do Baixo Vouga e Policlínica Veterinária de Aveiro (desde 1 de Março de 2008 e de 2010, respetivamente, até dia 31 de Janeiro de 2014). Os efeitos secundários em análise foram a toxicidade hematopoiética, gastrointestinal, dermatológica e pulmonar, reações alérgicas/anafiláticas, cistite hemorrágica estéril, necrose perivascular/extravasamento, cardiotoxicidade, nefrotoxicidade, hepatotoxicidade, neurotoxicidade e síndrome de lise tumoral aguda. A análise estatística foi realizada com recurso ao programa Microsoft Excel 2010® e software R®. Foram avaliadas 266 sessões de quimioterapia realizadas em 42 animais, verificando-se que 71,43% destes exibiram toxicidade. Verificou-se uma clara predominância da toxicidade gastrointestinal e hematopoiética na amostra e nas sessões quimioterápicas avaliadas. Também a toxicidade dermatológica, reações anafiláticas/alérgicas, cistite hemorrágica estéril, necrose perivascular/extravasamento e cardiotoxicidade, foram identificados durante o estudo. Pela análise estatística foi possível identificar uma associação entre a toxicidade gastrointestinal e os fármacos em geral, e a epirrubicina em particular; as reações alérgicas/anafiláticas e a cardiotoxicidade com a doxorrubicina; e a cistite hemorrágica estéril com a ciclofosfamida e com a quimioterapia metronómica (ciclofosfamida e meloxicam).<br>ABSTRACT - EVALUATION OF ADVERSE EFFECTS OF CHEMOTHERAPEUTIC DRUGS IN COMPANION ANIMALS- RETROSPECTIVE STUDY - Chemotherapy is a therapy used in oncology with the objective of elimination of all the tumor cells or the cure, through the administration of chemotherapeutic or antineoplastic drugs. These drugs act mainly in cells with high mitotic rate, affecting not only neoplastic cells but also normal cells, leading to the so-called adverse effects. The purpose of this study was the evaluation and characterization of the adverse effects of chemotherapeutic drugs in small animal clinical practice, and it was a retrospective study. The experimental design included all cats and dogs, males and females, subjected to at least one treatment session with chemotherapeutic drugs, regardless of the type of neoplasia, in the Hospital Veterinário do Baixo Vouga and Policlinica Veterinária de Aveiro (since March 1st, 2008 and 2010, respectively, until day 31th January 2014). The adverse effects under analysis were: hematologic, gastrointestinal, dermatologic and pulmonary toxicity, anaphylactic/allergic reactions, sterile hemorrhagic cystitis, perivascular necrosis/extravasation, cardiotoxicity, nephrotoxicity, hepatotoxicity, neurotoxicity and acute tumor lysis syndrome. The statistical analysis was performed using Microsoft Excel 2010® and software R®. 266 chemotherapy sessions were evaluated in 42 animals, with 71.43% of the animals exhibiting toxicity. A clear predomination of gastrointestinal and hematologic toxicity was detected, in the evaluated sample and therapy sessions. Dermatologic toxicity, anaphylactic/allergic reactions, sterile hemorrhagic cystitis, perivascular necrosis/extravasation and cardiac toxicity were also identified during the study. Through statistical analysis it was possible to identify an association between gastrointestinal toxicity and drugs in general and epirrubicin in particular; allergic/anaphylactic reactions and cardiotoxicity with doxorubicin; and sterile hemorrhagic cystitis with cyclophosphamide and with metronomic chemotherapy (cyclophosphamide and meloxicam).

Objectives: The purpose of this study was to determine the prevalence and patterns of use of cognitive enhancing substances (such as caffeine containing products and beverages and prescription stimulant drugs) amongst students at Curtin University. Further, to determine the potential for adverse effects from their use.Method: A cross-sectional study was conducted involving students attending the Curtin University. A sample of students was randomly selected and students were presented with an information sheet explaining the purpose and design of the study as well as their role in the study. Once they gave verbal consent to participate, they were requested to complete a questionnaire. All the completed questionnaires were entered into a dataset on a computer using the SPSS software, and analysis of the data was performed using the SPSS version 17 and SAS statistical software packages for Microsoft Windows. Statistical analysis included descriptive statistics such as frequencies and percentages or means and standard deviations. The cross-tabulation, chi-square statistic and ANOVA were used to assess the statistical significance of difference.The survey included questions regarding demographics, caffeine (consumption, reasons for use, side effects following its consumption) and prescription stimulants (use, reason for use and side effects following consumption). Further, data was collected on the perceived effectiveness of the cognitive enhancing substances by students and their level of caffeine consumption.Results: The final dataset included 526 students out of which 94.5% of surveyed students reported that they drank caffeine containing beverages. Tea and coffee were found to be the most common sources of caffeine followed by soft drinks and energy drinks. The average daily caffeine intake was estimated to be 3.0mg/Kg/day on normal days and 3.8mg/Kg/day on exam days. Females were found to consume slightly more caffeine than males. Also, there was higher caffeine intake by smokers than non-smokers.Regarding energy drinks, a greater percentage of males than females were found to consume energy drinks. The students studying health related courses were less likely than those from other faculties to consume energy drinks. Similarly, there was significant association between the smoking status and energy drinks consumption.The most frequent adverse effects experienced by students were jolt and crash followed by insomnia, and headache following caffeine intake. Moreover, more students experienced side effects following high doses of caffeine as compared to moderate and low doses. The most common self-reported reasons for consuming caffeine containing products were: to boost their energy and while studying for exams or completing major projects, and to counteract lack of sleep.Of all the respondents only 4% (n=21) reported that they used prescription stimulants (other than caffeine). Approximately 3% used stimulants together with caffeine on both normal and exam days. The prevalence of taking prescription stimulants was higher in students consuming higher doses of caffeine. The most common reported reasons for use were to improve concentration and to get high (equal percentage of 66.7% students). Most of the students stated that they experienced insomnia after the prescription stimulants intake. They also reported experiencing jolt and crash. Most of the students perceived that cognitive enhancing substances are effective in improving their energy levels.Conclusion: A substantial proportion of students in this sample were found to consume caffeine containing products. The study demonstrated that cognitive enhancing substance use was increased around times of academic stress. The students taking high doses were at higher risk to side effects. As a greater proportion of students consumed high doses of caffeine during exam period, more were at risk of adverse effects. Only a small percentage of students reported use of other stimulants, but importantly, this was more common amongst high consumers of caffeine. Further studies at other universities are required to confirm the findings of this study.

O Tacrolimus é uma potente droga imunossupressora introduzida no transplante cardíaco no início da década de 90. Pacientes com rejeição refratária ou intolerância à ciclosporina podem responder à terapia de resgate com o tacrolimus. Os objetivos deste estudo foram: avaliar a evolução clínica das crianças submetidas ao transplante cardíaco que necessitaram da conversão de ciclosporina para tacrolimus por rejeição refratária, tardia ou efeitos adversos de difícil controle; avaliar a incidência de rejeição após a conversão para o tacrolimus e comparar a sobrevida dos pacientes em uso de tacrolimus e ciclosporina. Realizou-se estudo coorte, observacional, prospectivo, em 28 crianças submetidas ao transplante cardíaco no Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo e que foram submetidas à conversão da ciclosporina ao tacrolimus, no período de julho de 1999 a dezembro de 2009. Avaliou-se a incidência de episódios de rejeição e a sobrevida após a conversão. Realizou-se, também, a comparação entre os pacientes em uso de tacrolimus e os pacientes que permaneceram em uso de ciclosporina submetidos ao transplante cardíaco no mesmo período. A idade média no momento do transplante foi de 5,3 anos, e no momento da conversão de 8,2 anos. As causas de conversão foram efeitos adversos em 50% dos pacientes, rejeição tardia em 32% e rejeição refratária em 18%. O tempo médio de conversão e seguimento foram 36 meses e 74 meses, respectivamente. Observou-se resolução completa dos episódios de rejeição refratária e melhora dos efeitos adversos em todos os pacientes. A taxa de incidência (x100) de episódios de rejeição antes da conversão foi de 7,98 e após a conversão foi de 2,11 (p=0,0001). A taxa de episódios de infecção antes da conversão foi de 5,89 e após a conversão 4,18 (p=0,023). Pela análise das complicações pré e pós-conversão ao tacrolimus, não se evidenciou diferença estatisticamente significativa em relação a incidência de tumor, insuficiência renal, hipertensão arterial sistêmica, dislipidemia, litíase biliar, diabetes melito, anemia, alterações neurológicas, hirsutismo e hiperplasia gengival. Houve maior prevalência da doença vascular do enxerto após conversão para tacrolimus (p=0,004). Ao se comparar os pacientes com tacrolimus e os com ciclosporina, identificou-se diminuição significativa na taxa de incidência de episódios de rejeição (p=0,001), e na taxa de incidência de episódios de infecção (p=0,002), nos pacientes em uso de tacrolimus. Os pacientes convertidos ao tacrolimus apresentaram menor incidência de complicações neurológicas, hirsutismo e hiperplasia gengival, porém maior prevalência de anemia. Em relação à sobrevida, observou-se uma mortalidade de 25% nos pacientes em uso de tacrolimus, após um período médio de conversão de sessenta meses. Três óbitos foram secundários à rejeição, dos quais apenas um, no primeiro ano de transplante. Evidenciou-se menor sobrevida nos pacientes em uso de ciclosporina. O estudo clínico das crianças submetidas ao transplante cardíaco e que necessitaram de conversão do esquema de imunossupressão permitiu concluir que o tacrolimus foi eficaz como terapia de resgate para rejeição refratária e constitui opção terapêutica como droga imunossupressora de manutenção na faixa etária pediátrica<br>Tacrolimus is a potent calcineurin inhibitor that was introduced in heart transplantation therapy in the early 1990s. Organ transplant recipients with refractory rejection or intolerance to conventional immunosuppressant may respond to rescue therapy with tacrolimus. The aim of this study was to evaluate the clinical outcome of children undergoing heart transplantation who required conversion from a cyclosporine to a tacrolimus-based immunosuppressive regimen due to refractory rejection, late rejection or cyclosporine intolerance. We performed a prospective observational cohort study in 28 children who underwent cardiac transplantation at the Heart Institute (InCor) University of São Paulo Medical School and who required conversion from July 1999 to December 2009. The clinical outcome of the patients was evaluated after tacrolimus conversion. We also compared the patients on tacrolimus to the patients who remained on cyclosporine, and who had undergone heart transplantation during the same period. The mean age at the time of transplantation was 5.3 years and 8.2 years at the time of conversion. The causes of conversion were adverse side effects in 50% of patients, late rejection in 32% and refractory rejection in 18%. The mean time from heart transplant to conversion was 36 months and the mean follow-up period was 74 months. We observed complete resolution of refractory rejection episodes and adverse side effects in all patients. The incidence rate (x100) of rejection episodes before and after conversion was 7.98 and 2.11, respectively (p = <0.0001). The rate of infectious episodes before conversion was 5.89 and after conversion was 4.18 (p = 0.023). There was no statistically significant difference in relation to tumor, renal failure requiring dialysis, systemic arterial hypertension, dyslipidemia, gallstones, diabetes mellitus, anemia, neurological complications, hirsutism and gingival hyperplasia after conversion. A significant incidence of cardiac allograft vasculopathy after conversion to tacrolimus was found (p = 0.004). When comparing patients on tacrolimus to patients on cyclosporine, there was a significant decrease in the incidence of rejection (p = 0.001), and infectious episodes (p = 0.002) in patients using tacrolimus. Patients converted to tacrolimus when compared to patients on cyclosporine had lower neurological complications, hirsutism and gingival hyperplasia, but higher prevalence of anemia. There was a 25% mortality rate in patients using tacrolimus after a mean period of 60 months after conversion. Three deaths were secondary to rejection, and only one in the first year after transplant. Patients using tacrolimus showed greater survival rate when compared to patients taking cyclosporine. The clinical outcome of children undergoing heart transplantation and who required conversion of immunosuppressive regimen allowed us to conclude that tacrolimus is effective as rescue therapy for refractory rejection and is a therapeutic option in pediatric patients

Dissertação de Mestrado Integrado em Medicina Veterinária<br>O aumento da esperança de vida dos animais de companhia favorece um crescimento no número de casos de doença oncológica, havendo, desta forma, cada vez mais donos que optam pelo tratamento quimioterápico, visando o prolongamento da vida dos seus animais. No entanto, a utilização destes compostos está, inevitavelmente, associada a toxicidade em diversos sistemas do organismo, levantando dúvidas relacionadas com a manutenção da qualidade de vida dos animais. Neste contexto, pretendeu-se, com este trabalho, quantificar os efeitos adversos da quimioterapia, assim como caracterizar a qualidade de vida dos animais submetidos a esta terapêutica farmacológica. Nos animais incluídos no estudo identificou-se uma frequência de 87,1% de efeitos adversos, dos quais 45,64% ocorreram a nível hematopoiético, com a manifestação de anemia, neutropénia e trombocitopénia, e 30,87% foram do foro gastrointestinal. Destes, na espécie canina, a diarreia surgiu em 42,5% das ocasiões e o vómito em 37,5%, e nos felídeos, a frequência de vómito foi de 50% e a de anorexia de 33,33%. A maioria das manifestações de efeitos deletérios surgiram em animais de idade avançada, estiveram associadas à administração de doxorrubicina e de vincristina e foram, maioritariamente, de grau I e II. Relativamente ao questionário de qualidade de vida aplicado no estudo, nas questões sobre alterações da higiene, gastrointestinais, urinárias, cardiorrespiratórias, da mobilidade e comportamentais, a maioria dos titulares respondeu que estas nunca ocorreram e, naqueles que responderam ter ocorrido, foram apenas em algumas a raras ocasiões. Também a presença de desconforto não foi significativa para a maioria dos donos e a disposição do animal manteve-se particamente inalterada. Quando questionados sobre se o bem-estar dos seus animais piorou durante a quimioterapia, 51,67% dos donos discordou fortemente. Destes, 45,83% dos titulares de cães e 50% dos titulares de gatos responderam que discordavam fortemente quando questionados se a qualidade de vida dos seus animais diminuiu durante o tratamento. Concluiu-se, assim, que embora tenha sido observada a indução de efeitos adversos pelo tratamento quimioterápico, estes não alteraram de forma considerável os parâmetros de bem-estar e não afetou a qualidade de vida dos pacientes.<br>ABSTRACT - Anticancer chemotherapy and its impact in the quality of life of companion animals - The increase in life expectancy of companion animals favors an increase in the number of cases of oncological disease, with, therefore, more and more owners opting for chemotherapy treatment, aiming to prolong the life of their animals. However, the use of these drugs is inevitably associated with the induction of toxicity in various systems of the body, raising doubts related to the sustenance of the animal’s quality of life. In this context, it was intended with this work to quantify the adverse effects of chemotherapy, as well as to characterize the quality of life of the animals submitted to this treatment. In the animals of the study it was identified a frequency of 87,1% of adverse effects, of which 45,64% were hematopoietic, with the manifestation of anemia, neutropenia and thrombocytopenia, and 30,87% were gastrointestinal. Of these, in the canine species, diarrhea appeared in 42,5% of the occasions and vomiting in 37,5%, and in felids, the frequency of vomiting was 50% and that of anorexia 33,33%. Most manifestations of toxicity appeared in elder animals, were associated with the administration of doxorubicin and vincristine and were mostly grade I and II. Regarding the quality-of-life questionnaire applied in the study, in questions about hygiene and gastrointestinal, urinary, cardiorespiratory, mobility and behavioral changes, most owners replied that these never occurred and, of those who replied that they arose, were only in few to rare occasions. Also, the presence of discomfort was not significant for most owners and the disposition of their animals remained almost unchanged. When asked whether their animals' welfare has worsened during chemotherapy, 51,67% of the owners strongly disagreed. Of these, 45,83% of dog owners and 50% of cat owners responded that they strongly disagreed when asked if their animals' quality of life decreased during treatment. Therefore, it was concluded that although it was observed chemotherapy induced-side effects, these did not considerably alter the parameters of well-being and did not affect the patients’ quality of life.<br>N/A

Introdução: A formação de atelectasia durante a indução anestésica pode ser um dos fatores responsáveis pela ocorrência de complicações pulmonares pós-operatórias (CPP). A aplicação de pressão positiva expiratória ao final da expiração (PEEP), uso criterioso de altas frações inspiradas de oxigênio e a utilização de manobras de recrutamento alveolar no período intra-operatório são recursos utilizados para a prevenção de atelectasia em procedimentos anestésicos. O objetivo deste estudo foi avaliar o modelo de ventilação mecânica adotado em procedimentos anestésicos de longa duração e suas correlações com as complicações pulmonares pós-operatórias. Métodos: Foram avaliadas em estudo observacional as cirurgias com mais de cinco horas de duração. No início do procedimento anestésico, na sala de cirurgia e após o seu término, na unidade de terapia intensiva, os parâmetros ventilatórios utilizados foram anotados e correlacionados com os achados das radiografias torácicas e saturação periférica de oxigênio (SpO2) em ar ambiente. Resultados: Cento e vinte e um pacientes foram observados. O tempo total de anestesia 499,4 ± 159,8 minutos. O volume corrente (VC) determinado no período intraoperatório foi 8,09 ± 2,15 mL/kg e a PEEP utilizada de 3,05 ± 2,31 cmH2O. Houve diferença para a mediana da SpO2 em ar ambiente (96% [95-97] vs 95% [92-96], p <0,001) comparando os períodos pré e pós-operatório. A freqüência de pacientes que apresentaram atelectasia nas radiografias de tórax do período pós-operatório (38,8%) foi significantemente maior que a do período pré-operatório (0%), x2=32,259. Não foi encontrado correlação entre os achados e o tempo de anestesia (p=0,708); a PEEP intra-operatória (p=0,296); tempo de permanência com suporte ventilatório mecânico no pósoperatório (p = 0,146) e tabagismo (p = 0,563). Conclusões: No período intra-operatório o PEEP utilizado em procedimentos de longa duração é baixo. Ocorre queda na SpO2 e aumento na incidência de atelectasia no período pós-operatório em comparação com o pré-operatório. São necessários outros estudos para melhor avaliação dos fatores responsáveis<br>Introduction: The formation of the atelectasis during the induction of the anesthesia can be one of the factors involved in the occurrence of postoperative pulmonary complications (PPCs). The application of the positive end-expiratory pressure (PEEP), low inpiratory concentrations of oxygen and the alveolar recruitment maneuvers perform in the intraoperative period are approaches used in the prevention of atelectasis in the anesthesia procedures. The objective of this study was to evaluate, in prospective observational study, the pattern of mechanical ventilatory assistence during longer anesthesia procedures and its correlations with the PPCs. Methods: The surgeries procedures longer than five hours have been evaluated in observational study. At the beginning of the anesthesia procedure, in the operatory room and after its terminus, in the intensive care unit, the mechanical ventilation parameters were determined and correlated with the findings in the chest x-rays and peripheral oxygen saturation (SpO2) in room air. Results: One hundred twenty one patients have been observed. The total time of anesthesia was 499,4 ± 159,8 minutes. The tidal volume (VT) in the intraoperative period was 8,09 ± 2,15 mL/kg and the PEEP used was 3,05 ± 2,31 cmH2O. There was a difference for the median of the SpO2 in room air (96% [95-97] vs 95% [92-96], p <0,001) comparing the pre and postoperative periods. The frequency of patients who had presented atelectasis in the chest x-rays of the postoperative period (38,8%) was significantly higher than the preoperative period (0%), x2=32,259. No correlation was found among these findings and the anesthesia time (p=0,708); the intraoperative PEEP used (p=0,296); time with mechanical ventilatory support in the postoperative period (p = 0,146) and smoking habits (p = 0,563). Conclusions: In the intraoperative period, the PEEP is low in longer procedures. The SpO2 decreases and the incidence of the atelectasis increases in the postoperative period, when compared with the preoperative one. Other researches are required for better evaluation of the factors related for the development of the PPCs

A avaliação do risco é um processo sistemático pelo qual a possibilidade de dano, a exposição e o próprio risco são identificados e quantificados. A consideração, de que a participação em um estudo é de risco, fundamenta-se no princípio da precaução, que é a garantia da existência de medidas de proteção contra riscos potenciais. De acordo com a gravidade dos eventos adversos, e de sua probabilidade de ocorrência, determina-se se o risco previsto é negligenciável, tolerável ou intolerável. Portanto, a caracterização do risco representa um importante elo entre os dados científicos obtidos nos diferentes estudos e as tomadas de decisões, ao monitoramento e à comunicação do risco. O objetivo deste estudo é avaliar os riscos previstos de eventos adversos gastrintestinais em projetos de pesquisa em seres humanos na área farmacológica, realizados no Hospital de Clínicas de Porto Alegre (HCPA), através da análise do Termo de Consentimento Livre e Esclarecido (TCLE), do manual do pesquisador e do projeto. Realizou-se um estudo transversal, com unidade de observação nos eventos adversos (EAs) gastrintestinais, através do levantamento de risco de projetos de pesquisa farmacológica, com patrocínio privado, submetidos e aprovados pelo Comitê de Ética em Pesquisa (CEP) do HCPA, no ano de 2004. De 58 projetos analisados, identificou-se 9734 referências de riscos de EAs gerais, sendo que 1463 (15,0%) eram gastrintestinais. Destas, 181 (12,4%) aparecem somente no TCLE, desprovida de embasamento teórico; já 1047 (71,6%) estão descritas nos documentos não disponibilizados ao participante, informação não compartilhada, tendo embasamento teórico; e apenas 235 referências de riscos, que representam 16,0% dos riscos gastrintestinais totais, como informação compartilhada e documentada, para o participante e pesquisador, com embasamento teórico. Essas 1463 referências de riscos de EAs gastrintestinais foram padronizadas, fazendo-se uso do Código Internacional de Doenças, décima revisão (CID 10), obtendo-se 170 tipos diferentes de riscos. Os riscos com maior repetição de referência nos projetos foram: náusea e vômitos 14,1%; alteração do hábito intestinal 6,5%; aumento dos níveis de transaminases e da desidrogenase lática 5,7%; outras dores abdominais e as não especificadas 4,9%. Quanto à gravidade, dos 170 tipos de riscos, obteve-se 65 (38,2%) graves, 52 (30,6%) moderados, 30 (17,6%) leves e 23 (13,5%) múltipla classificação. Todos os documentos relativos ao projeto de pesquisa deveriam conter a descrição e quantificação dos riscos importantes, seja pela alta gravidade ou freqüência associada. No TCLE, parte dos riscos estavam descritos, porém desprovidos de uma quantificação e caracterização adequadas. O manual apresentava as informações sobre os riscos, mas de forma dispersa ao longo do documento, levando a uma dificuldade de utilização desses dados nas intervenções propostas. Nos projetos analisados, observa-se a falta de homogeneidade e padronização para se expressar adequadamente os riscos já ocorridos em estudos prévios. Isso demonstra a importância da leitura atenta de toda documentação encaminhada para avaliação pelo CEP, visando a proteção ativa dos sujeitos da pesquisa.<br>Risk evaluation is a systematic process whereby damage possibility, exposure and the risk itself are identified and quantified. The consideration that the participation in a study is risky is founded on the precaution principle, i.e., the warranty of existing protection measures against potential risks. According to the severity of the adverse events and of its occurrence probability, one determines if the foreseen risk is negligible, tolerable or intolerable. Therefore, risk characterization represents an important link between the scientific data obtained from the different studies and the decision-makings, to monitoring and to risk communication. The objective of this study is evaluating the foreseen risks of gastrointestinal adverse events (AEs) in research projects with human beings in the pharmacological field carried out at Hospital de Clínicas de Porto Alegre – HCPA by means of the Informed Consent Form – ICF, of the researcher brochure and of the Research Protocol. A transversal study was carried out with an observation unit in the gastrointestinal AEs, through the survey of risk of projects of clinical trial with private sponsorship submitted to and approved by the Research Ethics Committee – REC of the HCPA in 2004. Out of 58 analyzed protocols were identified 9734 risk references of general AEs, being 1463 (15.0%) gastrointestinal. Out of these, 181 (12.4%) appear on the ICF only, deprived of theoretical basis; while 1047 (71.6%) are described in documents non available for the participant, non-shared information, with theoretical basis; only 235 risk references that represent 16.0% of the total gastrointestinal risk, as shared and documented information for the participant and the researcher, having theoretical basis. These 1463 risk references of gastrointestinal AEs were standardized by making use of the International Code of Diseases – 10th Revision –, and 170 different risk types were obtained. The risks with more reference repetition in the protocols were: nausea and vomit 14.1%; alteration of intestinal habit 6.5%; increase of the levels of transaminases and of lactic dehydrogenase 5.7%; abdominal pain 4.9%. As to the severity, out of the 170 risk types, 65 (38.2%) are severe, 52 (30.6%) moderate, 30 (17.6%) soft and 23 (13.5%) of multiple classification. All of the documents regarding the research protocol should contain the description and quantification of the important risks either due to high severity or to frequency. In the ICF, some of the risks were described however deprived of an adequate quantification and characterization. The brochure presented the information about the risks, however in a disperse way over the document leading to a difficult utilization of these data in the proposed interventions. In the analyzed protocols was observed lack of homogeneity and standardization to adequately express the risks that had already occured in previous studies. This observation demonstrates the importance of careful reading of all of the documentation addressed for evaluation by the REC aiming at the active protection of the research subjects.

A nifedipina atua como bloqueador de canais de cálcio inibindo o fluxo transmembrânico de ions Ca2+ no interior das células do músculo cardíaco e células do músculo liso vascular, o qual induz ao relaxamento do músculo liso e diminuição da resistência vascular periférica. É utilizado no Brasil no tratamento de hipertensão arterial sistêmica (HAS), faz parte da Relação Nacional de Medicamentos Essenciais do Ministério da Saúde e vem sendo distribuída pela Secretaria da Saúde do Estado de São Paulo. Uma vez que a determinação plasmática do fármaco contribui para maior segurança de seu uso, o objetivo deste trabalho se prendeu em padronizar e validar um método analítico em cromatografia em fase gasosa com detecção por captura de elétrons, sensível, específico e reprodutível para a quantificação das concentrações plasmáticas com a finalidade de avaliar a relação entre a dose diária de 60mg e a concentração plasmática versus a resposta da pressão arterial sistêmica, observando a ocorrência de possíveis reações adversas, alterações bioquímicas e hematológicas, em pacientes portadores de HAS, submetidos à farmacoterapia. O método apresentou linearidade na faixa de 10 a 200 ng.mL-1 , com coeficiente de correlação (r) igual a 0,9977. Coeficientes de variação de precisão intra e interensaio menor que 10% e recuperação absoluta da nifedipina de 74,47 a 75,97%. Os limites de detecção e quantificação do método foram de 1,0 e 2,0 ng.mL-1, respectivamente e o fármaco demonstrou ser estável por 90 dias quando armazenado a -70°C ao abrigo da luz. Os dados observados no presente estudo permitiram evidenciar que os pacientes apresentaram concentrações plasmáticas no intervalo terapêutico preconizado, as quais foram efetivas na redução da pressão arterial sistólica e diastólica. Estas concentrações não acarretaram efeitos adversos em nível do sistema hematológico e bioquímico estatisticamente significativos e em relação às reações adversas relacionadas ao medicamento, tais como: cefaléia, edema periférico vascular, tontura, hipotensão arterial, rubor, tosse e cãibras, apesar de relatadas de forma significativa pelos pacientes no inicio do tratamento, foram ao longo do mesmo minimizadas e pouco relatadas.<br>Nifedipine, a compound of dihydropyridine class, is a calcium-channel antagonists drug that inhibits the transmembrane influx of Ca+2 into cardiac muscle cells and vasculas smooth muscle cells throught specific ion channels. It induces smooth muscle relaxation and decreases peripheral vascular resistance. It is widely used for the treatment of high blood pressure, and is considered as a essencial medicine by the Brazilian government. In Sao Paulo state, this drug has been distributed to hypertensive patients in treatment. Since the drug quantification in plasma contributes for a drug safety use, the objective of the present study was to develop and validate a accurate, specific and reproducible method for the determination of nifedipine in plasma by gas chromatography with eletron capture detection. The validated method was applied in samples of hipertensive patients on 60 mg daily dose of nifedipine with the purpose to evaluate the relation between drug plasma concentration and it\'s daily dose versus the hemodymamic effects, possible side effects and biochemical and hematologic alterations. The method was linear over a concentration range of 10 -200 ng.mL-1 (r2>0,99). The coefficient of variation of intra- and inter-assay precision less than 10% and the recovery was higher than 74%. The limit of detection and quantification were 1,0 and 2,0 ng.mL-1, respectively. Nifedipine was found to be stable in samples stored at -70ºC for 90 days and protect from light. The result showed that patients with drug plasma concentration within therapeutics levels also showed systolic and diastolic blood pressure succesfully controled. Therefore, these patients do not manifested any adverse effects specially in biochemical and hematologic systems. Other adverse efects of nifedipine such as headache, peripheral edema, hypotension, redness, cramp and cough reported by the patients at the beggining of thetreatment, were gradually diminishing and rarely related.

Older people admitted to hospital are at high risk of rehospitalization and medication errors. We have demonstrated, in a randomized controlled trial, that a clinical pharmacist intervention reduces the incidence of revisits to hospital for patients aged 80 years or older admitted to an acute internal medicine ward. The aims of this thesis were to further study the effects of the intervention and to investigate possibilities of targeting the intervention by identifying predictors of treatment response or adverse health outcomes. The effect of the pharmacist intervention on the appropriateness of prescribing was assessed, by using three validated tools. This study showed that the quality of prescribing was improved for the patients in the intervention group but not for those in the control group. However, no association between the appropriateness of prescribing at discharge and revisits to hospital was observed. Subgroup analyses explored whether the clinical pharmacist intervention was equally effective in preventing emergency department visits in patients with few or many prescribed drugs and in those with different levels of inappropriate prescribing on admission. The intervention appeared to be most effective in patients taking fewer drugs, but the treatment effect was not altered by appropriateness of prescribing. The most relevant risk factors for rehospitalization and mortality were identified for the same study population, and a score for risk-estimation was constructed and internally validated (the 80+ score). Seven variables were selected. Impaired renal function, pulmonary disease, malignant disease, living in a nursing home, being prescribed an opioid and being prescribed a drug for peptic ulcer or gastroesophageal reflux disease were associated with an increased risk, while being prescribed an antidepressant drug (tricyclic antidepressants not included) was linked with a lower risk. These variables made up the components of the 80+ score. Pending external validation, this score has potential to aid identification of high-risk patients. The last study investigated the occurrence of prescription errors when patients with multi-dose dispensed (MDD) drugs were discharged from hospital. Twenty-five percent of the MDD orders contained at least one medication prescription error. Almost half of the errors were of moderate or major severity, with potential to cause increased health-care utilization.

Esteróides anabólicos androgênicos (EAA) são usados por atletas profissionais e amadores, com o objetivo de melhorar a capacidade atlética, aparência e massa muscular. Muitos efeitos adversos têm sido associados com o abuso de EAA, incluindo doenças do trato urogenital. Este estudo teve como objetivo avaliar as alterações morfológicas no lobo ventral da próstata de ratos púberes e adultos cronicamente tratados com doses suprafisiológicas de EAA, usando métodos morfométricos. Foram estudados 39 ratos Wistar machos pesando entre 400 e 550 g. Os ratos foram divididos em quatro grupos: (a) ratos controle, com 105 dias de idade (C105) (n = 7); (b) ratos controle com 65 dias de idade (C 65) (n = 9), injectados com o veículo (óleo de amendoim); (c) ratos tratados com 105 dias de idade (T105) (n = 10) e (d) Os ratos tratados com 65 dias de idade (C 65) (n = 13). Os ratos tratados foram injectados com decanoato de nandrolona, numa dose de 10 mg.Kg-1 de peso corporal. O hormônio esteróide e o veículo foram administrados por via intramuscular, uma vez por semana, durante oito semanas. Os ratos foram sacrificados aos 161 dias de idade (C105 e T105) e 121 dias de idade (C65 e T65) e do lóbulo ventral da próstata foi dissecada e processada para histologia. A altura do epitélio acinar foi medida em micrômetros em fotomicrografias com ampliação de 400x. As densidades de superfície do lúmen do epitélio e estroma foram calculadas pelo método de contagem de pontos, com uma grade de 100 pontos sobrepostos sobre imagens ampliadas em 200x. Todas as análises foram realizadas com o software ImageJ. O teste t de Student e ANOVA foram utilizados para a comparação de médias. Foi considerado significativo quando p<0,05. O peso e volume do lobo ventral da próstata mostraram diferenças entre os grupos C65, T65, C105 e T105. A altura do epitélio não mostrou nenhuma diferença entre os grupos C65 e T65 (p = 0,8509), mas o grupo T105 mostrou um aumento de 32% em relação ao C105 (p = 0,0089). No que diz respeito à densidade de superfície do lúmen não houve diferença entre C65 e T65 (p = 0,9031) mas uma diminuição de 19% em relação a T105 em comparação com C105 (p = 0,0061). Não houve diferença na densidade de superfície do epitélio entre C65 e T65 (p = 0,7375), mas o grupo T105 apresentou 51% de aumento (p = 0,0065) em comparação com o C105. Em relação à densidade superficial do estroma, não foram observadas diferenças entre C65 e T65 e entre C105 e T105. Finalmente, não houve diferença no padrão de colágeno entre C105 e T105, mas o grupo T65 mostrou uma predominância de fibras de colágeno tipo I em relação ao C65. A utilização de esteróides androgênicos anabólicos em ratos promove mudanças estruturais na próstata. Observamos mudanças estruturais na altura, volume e epitélio do lobo da ventral da próstata e uma predominância de fibras de colágeno.

INTRODUÇÃO: A rigidez arterial é fator de risco cardiovascular pouco estudado e importante determinante de sobrecarga cardiovascular, estando associada ao envelhecimento. Analisou-se a ação das terapêuticas com estrogênios eqüinos conjugados (EEC) ou raloxifeno sobre os índices de rigidez, com o intuito de se observar a influência destas medicações na rigidez arterial, bem como se as mesmas são capazes de influenciar o envelhecimento vascular bem sucedido. MÉTODOS: Realizou-se estudo duplo cego, randomizado, placebo-controlado, que envolveu sessenta e sete mulheres saudáveis, normotensas e com 1 a 10 anos de menopausa, divididas em três grupos de 24, 25 e 18 mulheres. Estas receberam placebo, 0,625 mg EEC ou 60 mg de raloxifeno, respectivamente, 1 comprimido por dia, por 4 meses consecutivos. Analisou-se a rigidez arterial, através da avaliação das velocidades de onda de pulso carótida-femoral (VOP CF), fêmoro-pediosa (VOP FP), e do índice de amplificação (IA) da pressão sistólica na artéria carótida. RESULTADOS: Não se observou qualquer alteração dos índices de rigidez arterial associada às intervenções farmacológicas no grupo placebo (VOP CF pré x pós: 644 x 626 cm/s, p= 0,09; VOP FP pré x pós: 1006 x 1012 cm/s, p= 0,77; IA pré x pós = 30 x 29%, p= 0,55), no grupo EEC (VOP CF pré x pós: 642 x 600 cm/s, p= 0,11; VOP FP pré x pós: 952 x 971 cm/s, p= 0,66; IA pré x pós: 25 x 32%, p= 0,82) e no grupo raloxifeno (VOP CF pré x pós: 636 x 601 cm/s, p= 0,12; VOP FP pré x pós: 964 x 941 cm/s, p= 0,62; IA pré x pós:25 x 25%, p= 0,65). Apesar da ausência de ação das drogas sobre a rigidez arterial, houve uma correlação significativa entre o grau de rigidez arterial basal e a resposta à intervenção farmacológica, particularmente no grupo EEC, de tal maneira que a redução dos índices de rigidez neste grupo foi proporcional ao nível de rigidez basal, apresentando as seguintes relações: VOP CF (r= -0,602, p= 0,001); VOP FP (r= -0,455, p= 0,022); IA (r= -0,410, p= 0,042). CONCLUSÃO: EEC e raloxifeno não parecem afetar a rigidez arterial de mulheres sadias e normotensas com menos de 10 anos de menopausa<br>INTRODUCTION: Arterial stiffness has been recognized as a cardiovascular risk factor, an important determinant of the left ventricular overload and a marker of cardiovascular aging. However, the clinical impact of arterial stiffness and how it is affected by hormone therapy has not been fully investigated. This study analyzed the influence of conjugated equine estrogens (CEE) or raloxifene on arterial stiffness and how the may influence successful cardiovascular aging. METHODS: Sixty-seven healthy and normotensive women with 1 to 10 years of menopause were randomly assigned to one of three groups, with 24, 25, and 18 participants. They were given oral placebo, 0,625 mg of conjugated equine estrogen, or 60 mg of raloxifene, respectively, for 4 consecutive months. Arterial stiffness was evaluated by measurement of the carotid-femoral pulse wave velocity (PWV CF) and femoral-dorsalis pedis pulse wave velocity (PWV FP), and the systolic pressure augmentation index (AI) at the carotid artery obtained by applanation tonometry. RESULTS: None of the treatment regimens affected arterial stiffness: placebo (PWV CF before x after: 644 x 626 cm/s, p= 0.09; PWV FP before x after : 1006 x 1012 cm/s, p= 0.77; AI before x after = 30 x 29%, p= 0.55), CEE (PWV CF before x after: 642 x 600 cm/s, p= 0.11; PWV FP before x after: 952 x 971 cm/s, p= 0.66; AI before x after: 25 x 32%, p= 0.82) and raloxifene (PWV CF before x after: 636 x 601 cm/s, p= 0.12; PWV FP before x after: 964 x 941 cm/s, p= 0.62; AI before x afer:25 x 25%, p= 0.65). Despite the absence of statistically significant reduction in arterial stiffness with treatment, there was a significant correlation between basal stiffness and the degree of reduction in the indexes measured, indicating that the higher the basal stiffness, the greater the degree of reduction, particularly in the CEE group: PWV CF (r= -0.602, p= 0.001); PWV FP (r= -0.455, p= 0.022); AI (r= -0.410, p= 0.042). CONCLUSIONS: Conjugated equine estrogen and raloxifene do not seem to affect arterial stiffness of healthy normotensive women with less than 10 years of menopause

Introdução: Os antiinflamatórios não esteróides (AINEs), incluindo a aspirina, são drogas largamente utilizadas para tratamento das doenças inflamatórias e da dor, e que podem causar efeitos colaterais sérios, causando considerável morbidade e mortalidade, relacionadas á doença ulcerosa, duodenal e gástrica, particularmente ao sangramento gastrointestinal. O risco relativo global de complicações gastroduodenais é de três a dez vezes, maior nos usuários de AINEs, quando comparado com indivíduos sadios. Cerca de 25% dos usuários crônicos dos antiinflamatórios não esteroides (AINEs) deverão desenvolver doença ulcerosa, e de 2 a 4% deverão apresentar sangramento ou perfuração. Mais de 17.000.000 de norte americanos utilizam vários tipos de drogas antiinflamatórios não esteróides (AINEs) diariamente e que provocam mais de 100.000 hospitalizações e cerca de 7000 a 10.000 mortes por ano nos Estados Unidos da América do Norte, fazendo desta família de drogas uma das mais comumente usadas em todo planeta. Cerca de 50% das lesões observadas em endoscopias de controle, ocorrem sem que o paciente tenha qualquer tipo de sintoma. Acredita-se que houve recrudescimento da prevalência de lesões digestivas pela substituição dos antiinflamatórios COX-2 pelos antiinflamatórios tradicionais, principalmente pela ausência de cuidados na prevenção deste tipo de ocorrência, em populações consideradas de risco. Objetivos: a) avaliar a prevalência de lesões e complicações digestivas secundárias ao uso de AINEs; b) qual é o perfil clínico deste paciente atendido em razão de queixas digestivas e a relação destas com os achados endoscópicos. Materiais e métodos: estudo aberto, prospectivo, multicêntrico avaliando consecutivamente 1.231 pacientes submetidos a exame de endoscopia digestiva alta em virtude de queixas digestivas, única ou associadas, como: 1) pirose; 2) dor epigástrica; 3) dor abdominal; 4) náusea; 5) vômito. Antes da realização do exame de endoscopia digestiva alta, os pacientes respondiam a questionário cujo objetivo era avaliar o início e o tipo de queixa clínica, o uso de medicamentos e possíveis complicações associadas como sangramento digestivo. Os critérios de inclusão foram: pacientes de ambos os sexos com idade mínima de 18 anos e que tivessem sintomas prévios iniciados, no máximo, há 14 dias antes da realização do exame de endoscopia digestiva alta. Os critérios de exclusão foram os de pacientes que se recusaram a participar do estudo e/ou de assinar o Termo de Consentimento Livre e Esclarecido, os incapazes de responder ao questionário, os com idade inferior aos 18 anos, os pacientes que já haviam realizado cirurgia gástrica e pacientes portadores de insuficiência renal ou hepática. Resultados: Foram avaliados 1.213 pacientes de 18 a 82 anos sendo que 65% destes eram do sexo feminino, 13,1% eram fumantes e 15,6% referiam ingestão de bebidas alcoólicas. A utilização de AINEs foi mais frequente no sexo feminino, porém número de complicações foi maior nos pacientes do sexo masculino (sangramentos foi duas vezes maior; p=0,045 e a ocorrência de úlcera quase 1,5 vezes maior; p=0,041). Os principais sinais e sintomas relatados foram epigastralgia e pirose (67% e 62%, respectivamente). Os 1.213 pacientes foram alocados em dois grupos: Grupo I - AINE composto por 228 (18,8%) e o Grupo II - Não AINEs (NAINEs) por 985 (81,2%) pacientes.. O exame de endoscopia digestiva alta foi normal em 3,9% dos pacientes do grupo I e em 10,7% dos do grupo II (p< 0,001). A probabilidade de um paciente que não utiliza AINE ter endoscopia digestiva alta normal é 2,5 vezes maior quando comparado aos que utilizaram AINEs (p=0,001). As presenças de lesões erosivas ou ulceradas no estômago e duodeno também foram mais frequentes nos pacientes do Grupo I quando comparado aos do Grupo II. Observa-se que é maior a incidência de lesões, tanto erosivas quanto ulceradas no estômago quando comparadas ao duodeno (erosões: 49,12% vs 13,60 respectivamente, p=0,001; úlceras: 14,04% vs 11,84% respectivamente, p= 0,05). O risco de hemorragia digestiva, 12 vezes maior (6,14% vs 0,51%) nos pacientes que fizeram uso de AINEs sendo o estômago o sítio de maior prevalência de sangramento. Não se observou diferença estatística quando analisada a presença de esofagite erosiva nos dois grupos. Conclusões: Evidenciamos frequência maior de úlcera gástrica, úlcera duodenal e sangramento digestivo nos pacientes que utilizaram AINEs. Não foram encontradas relações entre os achados endoscópicos e os sintomas dispépticos. Não observamos influência dos AINEs no aparecimento de esofagite erosiva<br>Introduction: The non steroidal anti-inflammatory drugs (NSAID), including aspirin, are drugs widely used in the treatment of inflammatory diseases and pain. This use may cause serious side-effects, leading to considerable morbidity and mortality related to ulcer, duodenal and gastric disease, especially gastrointestinal bleeding. The overall relative risk of gastroduodenal complications is three to ten times higher in users of NSAID, compared to healthy individuals. Around 25% of the chronic users of non steroidal anti-inflammatory drugs (NSAID) will develop ulcer disease, and 2 to 4% will present bleeding or perforation. More than 17,000,000 North Americans use several kinds of non steroidal anti-inflammatory drugs (NSAID) on a daily basis. This causes more than 100,000 hospitalizations and from 7,000 to 10,000 deaths every year in the USA, which makes this drug one of the most commonly used on the planet. About 50% of the lesions observed in endoscopies occur without any kind of symptom. It is believed that there was an increase in the prevalence of digestive lesions due to the replacement of COX-2 anti-inflammatory drugs with traditional anti-inflammatory drugs, especially because of the lack of preventive care of this kind of occurrence in at-risk populations. Goals: a) Evaluate the prevalence of lesions and digestive complications, secondary to the use of NSAID; b) Evaluate the clinical profile of the patient seen for digestive complaints and the relation of these complaints with the endoscopic findings. Materials and Methods: Prospective, multi-centric, open study, evaluating consecutively 1,231 patients who underwent upper gastrointestinal endoscopy exam due to digestive complaints in isolation or associated, such as: 1) pyrosis; 2) epigastric pain; 3) abdominal pain; 4) nausea; 5) vomiting. Before performing the exam of upper gastrointestinal endoscopy, patients answered a questionnaire whose goal was to evaluate the onset and kind of clinical complaint, the use of medication and possible complications associated to digestive bleeding. The inclusion criteria were: Patients of both sexes with the minimum age of 18 and whose symptoms had begun up to 14 days before undergoing the upper gastrointestinal endoscopy. Exclusion criteria: patients who refused to participate in the study and/ or who refused to sign the Informed Consent Term, the ones who were unable to respond to the questionnaire, the ones who were under 18 years old, patients who had undergone a previous gastric surgery and patients with kidney or hepatic failure. Results: 1,213 patients with ages ranging from 18-82 were evaluated, 65% of which were female and 13,1% were smokers, 15,6% mentioned they ingested alcoholic beverages. The use of NSAID was more frequent among females. However, the number of complications was higher among males (bleeding occurred twice as much; p=0,045 and the occurrence of ulcer was almost 1,5 times higher; p=0,041). The main signs and symptoms reported were epigastralgia and pyrosis (67% and 62%). The 1,213 patients were divided into two groups: Group I- NSAID, made up by 228 (18,8%) and Group II- Non NSAID, made up by 985 patients (81,2%). The upper gastrointestinal endoscopy was normal in 3,9% of the patients in Group I and in 10,7% of the patients in Group II (p<0,001). A patient who does not use NSAID will be 2,5 times more likely to have normal upper gastrointestinal endoscopy than the one who used NSAID (p=0,001). The presence of erosive or ulcer lesions in the stomach and duodenum was more frequent in Group I patients when compared to those of Group II. It is observed that the incidence of lesions in the stomach, both erosive and ulcer is higher when compared to the duodenum (erosions: 49,12% vs. 13,60, p=0,001; ulcers: 14,04% vs. 11,84, p= 0,05). The risk of digestive bleeding is 12 times higher (6,14% vs. 0,51%) in patients who used NSAID, and the stomach is the site with higher prevalence of bleeding. No statistic difference was observed when the presence of erosive esophagitis in both groups was analyzed. Conclusions: We observed that the frequency of gastric ulcer, duodenal ulcer and digestive bleeding was higher in patients who used NSAID. Relations between the endoscopic findings and the dyspeptic symptoms were not found. The influence of NSAIDs on the appearance of erosive esophagitis was not observed

Várias condições podem estar associadas com a atrofia muscular, tais como inatividade, envelhecimento, septicemia, diabetes, câncer e uso de glicocorticoides. Todas estas condições levam a atrofia muscular através de mecanismos que incluem aumento da degradação proteica e/ou redução na síntese proteica, envolvendo pelo menos cinco sistemas: lisossomal, da calpaína, das caspases, metaloproteinases e o sistema ubiquitina-proteasoma (SUP). Glicocorticoides, tais como a dexametasona, acarretam atrofia muscular atuando em quase todos esses sistemas, com significante ativação do SUP e lisossomal, afetando uma importante via de trofismo muscular, a via do IGF-1/PI-3K/Akt/mTOR. Ácidos graxos poli-insaturados, como o Ômega-3 (ômega-3), têm sido utilizados de forma benéfica na atenuação da atrofia muscular que ocorre na septicemia e na caquexia associada ao câncer, no entanto, sua atuação sobre a atrofia muscular induzida por glicocorticoides ainda não foi avaliada. Objetivo: Avaliar se a suplementação do ácido graxo ômega-3 influenciaria o desenvolvimento da atrofia muscular induzida pela dexametasona em ratos. Metodologia: Vinte e quatro ratos Wistar suplementados e não suplementados com ômega-3 (40 dias) foram submetidos à administração de dexametasona subcutânea (5mg/Kg/dia) nos últimos 10 dias, formando assim quatro grupos: Controle (CT), dexametasona (DX), ômega3 e dexametasona+ômega3 (DX+ômega3). Através de estudo de comportamento motor, histológico, PCR em tempo real e Western Blotting foram avaliados respectivamente, o número de grandes e pequenos movimentos em campo aberto; a área de secção transversa das fibras musculares (fibras I, IIA e IIB); a expressão dos genes MyoD, Miogenina, MuRF-1, Atrogina-1 e Miostatina; e a expressão de proteínas relacionadas com a via do IGF-1/PI-3K/Akt/mTOR: Akt, GSK3beta, FOXO3a e mTOR, totais e fosforiladas. Resultados: A dexametasona produziu diminuição na quantidade de pequenos movimentos, atrofia muscular em fibras do tipo IIB e diminuição na expressão de P-Akt, P-GSK3ômega e P-FOXO3a/FOXO3a total. A suplementação com Ômega-3 não se mostrou eficaz na atenuação de tais alterações. Por outro lado, o Ômega-3 associado à dexametasona (grupo DX+3) induziu a maior expressão de atrogenes (MuRF-1 e atrogina-1) causando, adicionalmente, maior atrofia muscular em fibras do tipo I e IIA, além de menor expressão gênica de Miogenina. O Ômega-3 de forma isolada conduziu de forma significativa a maior expressão de Miostatina e MyoD, e de forma não significante elevou a expressão proteica de mTOR total e induziu menor ganho de peso corporal dos animais ao fim do estudo. Conclusão: A suplementação de Ômega-3 não foi capaz de atenuar as alterações comportamentais, atrofia muscular e perda de peso corporal causadas pela administração de dexametasona, levando por outro lado a maior atrofia das fibras musculares e aumento na expressão de atrogenes. Desta forma, este estudo sugere que suplementos alimentares usualmente considerados benéficos para saúde, tal como o ácido graxo Ômega-3, podem agir em interação com alguns medicamentos, como os glicocorticoides, potencializando seus efeitos colaterais<br>Many conditions can be related to muscle atrophy, such as inactivity, aging, sepsis, diabetes, cancer, as well as, glucocorticoid treatment. All these conditions lead to muscle atrophy through mechanisms that include increase of protein degradation and/or decrease of protein synthesis involving at least five systems: lysossomal, calpain, caspases, metaloproteinases and ubiquitin proteasome system (UPS). Glucocorticoids, such as dexamethasone cause muscle atrophy acting in almost all of these systems, with a significant UPS activation and affecting an important pathway related to muscular trophism, IGF-1/PI-3k/Akt/mTOR pathway. Poly-unsaturated fatty acids, such as Omega-3 (omega-3), have been used beneficially to attenuation of muscle atrophy that occur in sepsis and cachexia related to cancer, however, its action in the glucocorticoid-induced muscle atrophy, has never been evaluated. Objective: Assess whether the omega-3 supplementation would influence the development of dexamethasone-induced muscle atrophy in rats. Methods: Twenty four Wistar rats supplemented and non-supplemented with omega-3 (40 days) were submitted to dexamethasone administration (5mg/kg/day) during the last 10 days, thus establishing 4 groups: control (CT), dexamethasone (DX), omega-3 and dexamethasone+omega-3 (DX+ omega-3). The amount of large and small movements in open field; muscle fiber cross sectional areas (I, IIA and IIB); MyoD, Myogenin, MuRF-1, Atrogin-1 and Myostatin gene expression; and protein expression of Akt, GSK3omega, FOXO3a and mTOR, total and phosphorylated forms were assessed, respectively, by: motor behavior testing, histological reactions, Real-time PCR and Western Blotting analysis. Results: Dexamethasone administration induced significant decrease of small motor movements, atrophy in type IIB muscle fibers and decrease of P-Akt, P-GSK3omega and P-FOXO3a/total FOXO3a expression. Omega-3 supplementation was not able to attenuate these changes. Instead, omega-3 associated to dexamethasone (DX+ omega-3 group) additionally induced higher muscle atrophy in type I, IIA muscle fibers, and reduced expression of Myogenin. The isolated use of Omega-3 led to a significant higher expression of Myostatin and MyoD, and a non-significant increase of total mTOR protein expression and less body weight gain at end of study. Conclusion: Supplementation of omega-3 was not able to attenuate motor behavioral changes, muscle atrophy and loss of body weight caused by dexamethasone administration, leading on the other hand to higher muscle fibers atrophy and increase in atrogenes expression. Therefore, this study suggests that food supplements, usually considered benefic to the health, such as Omega-3 fatty acid, may interact with some medications, such as glucocorticoids, potentiating its side effects

The elderly population is growing in nursing homes (NHs), with an estimated 3 million seniors to be residing in NH facilities by year 2030. Many of these seniors are potentially at risk for falls or infections. NH residents with Alzheimer’s disease or other forms of dementia are also increasing, and they are vulnerable to the adverse effects of medications. Psychotropics are overused in NHs, with approximately half to two thirds of residents receiving one or more psychotropics. Many negative health outcomes, e.g. falls and infections, have been associated with their use. The usage of psychotropic medications among NH residents has been a concern and topic of scrutiny for nearly three decades. In 1986, the Institute of Medicine published a landmark report that identified the overuse of psychotropic medications in NHs. The following year, the federal government passed the Omnibus Budget Reconciliation Act that included reform legislation to address psychotropic drug overuse. Since then, additional policies and initiatives have endeavored to rectify the problem, and scientists have conducted research regarding psychotropics and negative health outcomes. However, newer research within the last decade and at a national level is lacking. Therefore, this dissertation explores the association of psychotropic medications with falls and infections among NH residents using a national dataset, and this document is organized into five chapters. The first chapter discusses the background, significance, and current challenges surrounding psychotropic medication use in NHs. The second chapter delineates the search of the literature and relevant findings. The third chapter describes the methodology upon which this analytics of this dissertation was conducted. The fourth chapter outlines the results from the analyses. Lastly, the fifth chapter provides a synthesis and discussion of the findings and recommendations for health policy, practice, and future research.

The number of drugs currently available at the commercial level is quite large. The therapeutic importance and the benefit of these are indisputable. However, unknown effects of individual drugs and/or the interaction of effects between drugs may have serious consequences for the health of the population.The use of some drugs may prove to be unsafe and risky, since the response and interaction of the population to their use differ substantially. It is known that in practice and despite all measures taken during the premarketing phase they may be insufficient, since factors such as the patients age, clinical history and interaction with other medicinal products may be at the apex of these undesirable effects.This report gives an overview of existing studies of detection and prevention of adverse drug effects and the possible contribution of informatics to the diagnosis of this problem. We go one step further and, propose to study and apply the use of Data Mining techniques to prevent the adverse effects of drugs.

The number of drugs currently available at the commercial level is quite large. The therapeutic importance and the benefit of these are indisputable. However, unknown effects of individual drugs and/or the interaction of effects between drugs may have serious consequences for the health of the population.The use of some drugs may prove to be unsafe and risky, since the response and interaction of the population to their use differ substantially. It is known that in practice and despite all measures taken during the premarketing phase they may be insufficient, since factors such as the patients age, clinical history and interaction with other medicinal products may be at the apex of these undesirable effects.This report gives an overview of existing studies of detection and prevention of adverse drug effects and the possible contribution of informatics to the diagnosis of this problem. We go one step further and, propose to study and apply the use of Data Mining techniques to prevent the adverse effects of drugs.

碩士<br>國立成功大學<br>臨床藥學研究所<br>97<br>Background NSAIDs (Nonsteroidal Anti-Inflammatory Drugs) are among the most widely used medicines in the world. Unfortunately, they are associated with dose-dependent gastrointestinal adverse events ranging from dyspepsia (10–20%) to symptomatic and complicated ulcers (1–4%). Although clinical trial results suggest that coxibs has less gastrointestinal toxicity than most other non-steroidal anti-inflammatory drugs (NSAIDs), but not in meta-analysis. Objective To estimate whether preferential and selective coxibs have been channeled towards high risk patients, and to estimate the risk of hospitalisation for gastrointestinal haemorrhage associated with the use of these drugs, allowing for the effects of channelling. Method This was a retrospective cohort study using National Health Insurance databases. The study included only new episodes of prescribed NSAID or coxib use between 2002 and 2003 and controlled for multiple baseline risk factors for upper gastrointestinal disease. We compared gastrointestinal haemorrhage hospitalization rates among patients taking NS-NSAIDs, preferential and selective coxibs. Result There are total 29,887 people as the object of study of which female accounts for 46.77%. The average age is 48.46 year-old and the percentage of people above 60 is 28.01. Analyses stratified by propensity score with individual covariate adjustments, the adjusted HRs of gastrointestinal haemorrhage for preferential coxibs compared with older non-specific NSAIDs are 0.606 (95% CI: 0.315-1.164). The adjusted HRs of gastrointestinal haemorrhage for selective coxibs compared with older non-specific NSAIDs are 1.473 (95% CI: 0.872-2.488). There was no significant difference in the HRs for preferential and selective coxibs compared with older non-specific NSAIDs. Conclusion Channelling towards high risk gastrointestinal patients occurred in the prescribing of preferential and selective coxibs. After attempting to correct for channelling bias, preferential and selective coxibs exposure was not associated with a significantly lower risk of gastrointestinal haemorrhage than older non-specific NSAID exposure.

Hin-Chung Chu.<br>Thesis submitted in: July 2002.<br>Thesis (M.Phil.)--Chinese University of Hong Kong, 2003.<br>Includes bibliographical references (leaves 281-306).<br>Abstracts in English and Chinese.<br>Cover (English & Chinese version) --- p.I<br>中文封面 --- p.II<br>Abstract (English version) --- p.III-IV<br>中藥不良反應論文摘要 --- p.V<br>Acknowledgements --- p.VI<br>Abbreviations --- p.VII-VIII<br>Publication in press --- p.IX<br>Content --- p.X-XV<br>Lists of Table --- p.XVI<br>Chapter Chapter 1 --- Introduction --- p.1-3<br>Chapter Chapter 2 --- Chinese herbal medicines used in Hong Kong. --- p.4-15<br>Chapter 2.1 --- Overview --- p.4-5<br>Chapter 2.2 --- The Policy In Hong Kong -- Past And Present --- p.5-1<br>Chapter 2.3 --- The Preparatory Committee on Chinese Medicine (PCCM) --- p.7-8<br>Chapter 2.4 --- The Chinese Medicine Council of Hong Kong --- p.8-10<br>Chapter 2.5 --- Development of Standards --- p.10<br>Chapter 2.6 --- Development of Centres of Good Clinical Practice --- p.10-11<br>Chapter 2.7 --- Establishment of a Good System of Education and Training --- p.11<br>Chapter 2.8 --- Investigation of Suspected Herbal Toxicity Cases --- p.12-13<br>Chapter 2.8.1 --- Herbal Safety Surveillance --- p.13-14<br>Chapter 2.9 --- Conclusion --- p.14-15<br>Chapter Chapter 3 --- Herbal medicines used in other countries --- p.16-45<br>Chapter 3.1 --- Overview --- p.16<br>Chapter 3.2 --- China --- p.16-19<br>Chapter 3.3 --- Macau --- p.22-23<br>Chapter 3.4 --- Taiwan --- p.23-26<br>Chapter 3.5 --- Japan --- p.27-30<br>Chapter 3.6 --- Singapore --- p.30-31<br>Chapter 3.7 --- Australia --- p.31-34<br>Chapter 3.8 --- Others Asian countries --- p.35<br>Chapter 3.9 --- USA --- p.35-39<br>Chapter 3.10 --- United Kingdom --- p.39-41<br>Chapter 3.11 --- Europe --- p.41-43<br>Chapter 3.12 --- Germany --- p.43-45<br>Chapter Chapter 4 --- Adverse reaction -- General Aspect --- p.46-63<br>Chapter 4.1 --- Overview --- p.46<br>Chapter 4.2 --- Traditional Chinese medicine --- p.47-49<br>Chapter 4.2.1 --- Compound Prescriptions to Reduce Toxicity --- p.50<br>Chapter 4.2.2 --- Processing Of Chinese Herbs --- p.50-51<br>Chapter 4.2.2.1 --- The Aims of Herbal Drug Processing --- p.51-52<br>Chapter 4.2.2.2 --- The Methods of Herbal Drug Processing --- p.52<br>Chapter 4.2.2.3 --- External processing (simple treatment by trimming) --- p.52-53<br>Chapter 4.2.2.4 --- Water processing --- p.53-54<br>Chapter 4.2.2.5 --- Fire processing --- p.54<br>Chapter 4.2.2.6 --- Water-fire processing --- p.54-55<br>Chapter 4.2.2.7 --- Other methods --- p.55<br>Chapter 4.3 --- Practical Problem in Traditional Chinese Medicine --- p.55-57<br>Chapter 4.4 --- Evaluation of herbal adverse reactions --- p.57<br>Chapter 4.4.1 --- Type A reactions --- p.57<br>Chapter 4.4.2 --- Type B reactions --- p.58<br>Chapter 4.4.3 --- Type C reactions --- p.58<br>Chapter 4.4.4 --- Type D reactions --- p.58<br>Chapter 4.5 --- Chinese Proprietary medicine --- p.58-59<br>Chapter 4.6 --- Potential Risks for Herbal Adverse Reaction --- p.59<br>Chapter 4.6.1 --- Misidentification --- p.59-60<br>Chapter 4.6.2 --- Lack of standardisation --- p.60<br>Chapter 4.6.3 --- Contamination --- p.60<br>Chapter 4.6.4 --- Incorrect preparation / dosage --- p.60<br>Chapter 4.6.5 --- Excessive dosage --- p.60-61<br>Chapter 4.6.6 --- Individual errors --- p.61<br>Chapter 4.6.7 --- Individual response --- p.61<br>Chapter 4.6.8 --- Unqualified Herbal Practitioner with Wrong Prescription --- p.61-62<br>Chapter 4.6.9 --- Interaction with Western medicine --- p.62<br>Chapter 4.6.10 --- Prolonged Usage --- p.62<br>Chapter 4.6.11. --- Coexisting disease --- p.62-63<br>Chapter 4.7 --- Conclusion --- p.63<br>Chapter Chapter 5 --- "Substitution, Adulteration or Misusing with Toxic Herbs" --- p.64-84<br>Chapter 5.1 --- Overview --- p.64-65<br>Chapter 5.2 --- Adulteration by Guijiu --- p.65-68<br>Chapter 5.3 --- Anticholinergic reactions Caused by <Yangjinhua> --- p.69-74<br>Chapter 5.4 --- Overdosage --- p.74<br>Chapter 5.4.1 --- Overdose of Aconitine --- p.74-78<br>Chapter 5.4.2 --- Overdose of Liquorice ('Gancao') --- p.78-80<br>Chapter 5.4.3 --- Overdose of <Chansu> --- p.80<br>Chapter 5.5 --- Misusing - Personal abuse --- p.80<br>Chapter 5.5.1 --- <Banmao> --- p.80-81<br>Chapter 5.6 --- Discussion --- p.81-84<br>Chapter 5.7 --- Conclusion --- p.84<br>Chapter Chapter 6 --- Chinese Patent Medicine - General Aspect --- p.85-112<br>Chapter 6.1 --- Chinese Patent Medicine --- p.85<br>Chapter 6.1.1 --- Introduction --- p.85-87<br>Chapter 6.1.2 --- Herbal Injection and Infusion --- p.87-88<br>Chapter 6.1.2.1 --- Variety & Processing --- p.88<br>Chapter 6.1.2.2 --- Stabilization --- p.88-89<br>Chapter 6.1.2.3 --- The Molecular Size --- p.89-90<br>Chapter 6.1.3 --- Adverse Reactions Caused by Chinese Proprietary Medicines --- p.90<br>Chapter 6.1.3.1 --- Aconitine poisoning --- p.90<br>Chapter 6.1.3.2 --- Nan Lien Chui Fong Toukuwan' --- p.90-91<br>Chapter 6.1.3.3 --- Jin Bu Huan' --- p.91<br>Chapter 6.1.3.4 --- Baoyingdan' --- p.91<br>Chapter 6.1.4 --- Heavy metals in CPM --- p.91<br>Chapter 6.1.5 --- The Necessarity to Develop Randomise Herbal Clinical Trial. --- p.91-92<br>Chapter 6.1.6 --- Recommendation --- p.92-93<br>Chapter 6.1.7 --- Conclusion --- p.93-94<br>Chapter 6.2 --- Adulteration by synthetic therapeutic substances --- p.95-104<br>Chapter 6.2.1 --- The Experiences in China --- p.91-99<br>Chapter 6.2.2 --- The Experiences in Hong Kong --- p.99-101<br>Chapter 6.2.3 --- The Experience in Taiwan --- p.101-102<br>Chapter 6.2.4 --- Discussion --- p.102-104<br>Chapter 6.3 --- Oil of Wintergreen (Methyl salicylate) --- p.104-112<br>Chapter 6.3.1 --- Overview --- p.104-111<br>Chapter 6.3.2 --- Prevention --- p.111-112<br>Chapter Chapter 7 --- Adverse effects of Ginseng. --- p.113-123<br>Chapter 7.1 --- Overview --- p.113<br>Chapter 7.2 --- Botany --- p.113-114<br>Chapter 7.3 --- Pharmacological Effects --- p.114-115<br>Chapter 7.4 --- Adverse reaction of Ginseng --- p.115<br>Chapter 7.4.1 --- Overdosage --- p.115-116<br>Chapter 7.4.2 --- Substitution with cheaper and more toxic herbs --- p.116-121<br>Chapter 7.5 --- Drug - herb Interaction --- p.121-122<br>Chapter 7.6 --- Conclusion --- p.123<br>Chapter Chapter 8 --- Herbal Medicines With Cardiovascular Adverse Reactions --- p.124-123<br>Chapter 8.1 --- Overview --- p.124<br>Chapter 8.2 --- Hypertension --- p.124<br>Chapter 8.3 --- Atherosclerosis --- p.124-125<br>Chapter 8.4 --- Arrhythmias --- p.125-126<br>Chapter 8.5 --- Cardic Failure --- p.126<br>Chapter 8.6 --- Angia Pectoris --- p.126<br>Chapter 8.7 --- Thromboembolic Disorders --- p.126-127<br>Chapter 8.8 --- Discussion --- p.127-128<br>Chapter 8.8.1 --- Herbal Medicine Used in Cardiovascular System --- p.131<br>Chapter 8.8.1.1 --- Ginseng --- p.131-133<br>Chapter 8.8.1.2 --- Ma huang (Ephedra sinica) --- p.133-136<br>Chapter 8.8.1.3 --- Yellow oleander (Thevetia neriifolia) --- p.136-137<br>Chapter 8.8.1.4 --- Stephania tetrandra --- p.137-138<br>Chapter 8.8.1.5 --- Danshen (Salvia miltiorrhiza) --- p.138<br>Chapter 8.8.1.8 --- Ginkgo biloba --- p.138-140<br>Chapter 8.8.1.9 --- Dong Quai (Angelicae Sinensis) --- p.140-141<br>Chapter 8.8.1.10 --- Licorice (Glycyrrhiza Glabra) --- p.141-143<br>Chapter 8.8.1.11 --- Berberine --- p.143<br>Chapter 8.8.2 --- Potential Problem Caused by Chinese Proprietary Medicine --- p.143-144<br>Chapter 8.9 --- Other Herbal Adverse Effects And Drug Interaction --- p.144-145<br>Chapter 8.10 --- Conclusion --- p.145<br>Chapter Chapter 9 --- Review of the Adverse Reactions to herbal treatments of Obesity --- p.146-150<br>Chapter 9.1 --- Overview --- p.146<br>Chapter 9.2 --- Combined With Unknown medication --- p.146-147<br>Chapter 9.3 --- Dietary Supplements and Herbal Preparations --- p.147-149<br>Chapter 9.4 --- Conclusion --- p.149-150<br>Chapter Chapter 10 --- Adverse Effects of CHM used for Diabetes --- p.151-159<br>Chapter 10.1 --- Introduction --- p.151<br>Chapter 10.2 --- Traditional Chinese medicine used in Diabetes --- p.151<br>Chapter 10.3 --- Adverse Reaction of Alternative Diabetic Treatment --- p.152-158<br>Chapter 10.4 --- Conclusion --- p.159<br>Chapter Chapter 11 --- Review of Herbal Hepatotoxicity --- p.160-194<br>Chapter 11.1 --- Introduction --- p.160-161<br>Chapter 11.2 --- Drug-induced hepatic injury --- p.161-163<br>Chapter 11.3 --- Types of Liver Injury --- p.163<br>Chapter 11.3.1 --- Pyrrolizidine alkaloid (PA) --- p.163<br>Chapter 11.4 --- Hepatotoxicity Herbs --- p.163<br>Chapter 11.4.1 --- Tripterygium wilfordii --- p.163-164<br>Chapter 11.4.2 --- Rhizoma Discoreae Bulbiferae --- p.164-165<br>Chapter 11.5 --- Consumption of Insect herbs --- p.165<br>Chapter 11.6 --- Hepatotoxicity Cause by Chinese Proprietary Medicine --- p.165-166<br>Chapter 11.6.1 --- Jin Bu Huan --- p.166-168<br>Chapter 11.6.2 --- Chi R Yun (Breynia officinalis) --- p.168<br>Chapter 11.6.3 --- Sho-saiko-to --- p.168-169<br>Chapter 11.6.4 --- Shou-Wu-Pian --- p.169-171<br>Chapter 11.7 --- Importance of Drug-Herb and Herb-Herb Interactions --- p.171-172<br>Chapter 11.8 --- Diagnosis of Herbal Hepatotoxicity --- p.172-173<br>Chapter 11.9 --- Recomandation --- p.173-174<br>Chapter 11.10 --- Conclusion --- p.175<br>Table --- p.176-180<br>Chapter Chapter 12 --- Review of Herbal Nephropathy --- p.181-194<br>Chapter 12.1 --- Introduction --- p.181<br>Chapter 12.2 --- Aristolochia acids (AA) --- p.181-183<br>Chapter 12.2.1 --- Intoxication of Aristolochia in Worldwide --- p.183-184<br>Chapter 12.2.2 --- Morphological findings --- p.184-185<br>Chapter 12.2.3 --- Carcinogenic --- p.185-187<br>Chapter 12.3 --- MuTong (Aristolochia manshuriensis) --- p.187-188<br>Chapter 12.4 --- Ma-dou-ling (Fructus Aristolochiae) --- p.188<br>Chapter 12.5 --- Tripterygium wilfordii --- p.188-189<br>Chapter 12.6 --- Gastrodia Elata --- p.189<br>Chapter 12.7 --- Licorice (Glycyrrhiza glabra) --- p.190-191<br>Chapter 12.8 --- Hippocampus (Sea Horse) --- p.191<br>Chapter 12.9 --- Milabris Phanalerata --- p.191-192<br>Chapter 12.10 --- Chinese Proprietary Medicine --- p.192-193<br>Chapter 12.11 --- Conclusion --- p.193-194<br>Chapter Chapter 13 --- Adverse Reaction of Herbal Medicine in Dermatology. --- p.195-217<br>Chapter 13.1 --- Overview --- p.195-196<br>Chapter 13.2 --- Chinese Herbal Medicine Used in Psoriasis --- p.196<br>Chapter 13.2.1 --- Tripterygium wilfordii --- p.197<br>Chapter 13.2.2 --- Radix Angelicae pubescentis and Radix Angelicae dahuricae --- p.197-198<br>Chapter 13.2.3 --- Radix macrotomiae seu Lithospermi Injection --- p.198<br>Chapter 13.3 --- Chinese Herbal Decoction For Atopic Dermatitis --- p.198-200<br>Chapter 13.3.1 --- Tea Extracts --- p.200-201<br>Chapter 13.4 --- Potential Adverse Effect with Herbal Medicine --- p.201<br>Chapter 13.4.1 --- Allergic skin reactions --- p.201-202<br>Chapter 13.4.2 --- Stevens-Johnson syndrome --- p.202<br>Chapter 13.4.3 --- Photosensitization --- p.202-204<br>Chapter 13.4.4 --- Pellagra --- p.204<br>Chapter 13.4.5 --- Hepatotoxic Effects --- p.204-205<br>Chapter 13.4.6 --- Others Adverse Reaction --- p.205<br>Chapter 13.4.7 --- Potential Adverse Reaction Caused by Interactions --- p.205<br>Chapter 13.5 --- Potential Adverse Reaction Caused by Contamination of Herbal Product --- p.206<br>Chapter 13.5.1 --- Herbal creams adulterated with corticosteroids --- p.206-207<br>Chapter 13.5.2 --- Arsenic dermatoses --- p.207<br>Chapter 13.5.3 --- Mercury poisoning --- p.207-208<br>Table --- p.208-211<br>Chapter 13.6 --- Dermatological Adverse Reaction Caused by Herbs --- p.211<br>Chapter 13.7 --- Contact Dermatitis Caused by CPM --- p.211-212<br>Chapter 13.7.1 --- Liushenwan' --- p.211-212<br>Chapter 13.7.2 --- Heiguiyou' --- p.212<br>Chapter 13.7.3 --- 101 Hair Regrowth Liniment' --- p.212-213<br>Chapter 13.7.4 --- Zhenggushui' --- p.213<br>Chapter 13.7.5 --- Tiedayaoiing' --- p.213-214<br>Table --- p.214-215<br>Chapter 13.8 --- Non-dermatological adverse effects of systemic herbal treatments used for dermatological conditions --- p.215-216<br>Chapter 13.9 --- Conclusion --- p.216-217<br>Chapter Chapter 14 --- "Chinese Herbal Medicine in Pregnancy, Infants & Children," --- p.218-229<br>Chapter 14.1 --- Overview --- p.218-219<br>Chapter 14.2 --- Asian Cultures for Pregnancy --- p.219-223<br>Chapter 14.3 --- Teratogenic Herbs --- p.224-225<br>Chapter 14.4 --- Chinese proprietary medicines --- p.225<br>Chapter 14.4.1 --- "“Tse Koo Choy""" --- p.225-226<br>Chapter 14.4.2 --- "“Lu Shen Wan""" --- p.226<br>Chapter 14.4.3 --- "“Po Ying Pills""" --- p.226-227<br>Chapter 14.4.4 --- """Jin Bu Huan Toxicity"" in Children" --- p.227<br>Chapter 14.6 --- Topical Preparations --- p.227-228<br>Chapter 14.7 --- Dietary supplement --- p.228-229<br>Chapter 14.8 --- Conclusion --- p.229<br>Chapter Chapter 15 --- Heavy metals poisoning in traditional Chinese medicines. --- p.230-251<br>Chapter 15.1 --- Introduction --- p.230-232<br>Chapter 15.2 --- LEAD --- p.232<br>Chapter 15.2.1 --- Overview --- p.232<br>Chapter 15.2.2 --- Poisoning Cases of Boa Ning Dan --- p.233-235<br>Chapter 15.2.3 --- Lead Poisoning in Worldwide --- p.235-238<br>Chapter 15.3 --- MERCURY --- p.238<br>Chapter 15.3.1 --- Overview --- p.238-239<br>Chapter 15.3.2 --- Cinnabar --- p.239-240<br>Chapter 15.3.3 --- Presentation --- p.240-241<br>Chapter 15.3.4 --- Poisoning Cases --- p.241-242<br>Chapter 15.4 --- ARSENIC --- p.242<br>Chapter 15.4.1 --- Overview --- p.242-243<br>Chapter 15.4.2 --- Arsenic toxicity --- p.243-244<br>Chapter 15.4.3 --- The toxicologic mechanisms of inorganic arsenic --- p.244-246<br>Chapter 15.4.4 --- Poisoning Cases --- p.246<br>Chapter 15.4.5 --- Discussion --- p.247-248<br>Chapter 15.5 --- Conclusion --- p.248<br>Table --- p.249-251<br>Chapter Chapter 16 --- Herb - Drug Interactions --- p.252-269<br>Chapter 16.1 --- Overview --- p.252-254<br>Chapter 16.2 --- Effects of Herb-drug interactions --- p.255<br>Chapter 16.2.1 --- Gastrointestinal system --- p.255-256<br>Chapter 16.2.2 --- Cardiovascular system --- p.256<br>Chapter 16.2.3 --- Central nervous system --- p.257<br>Chapter 16.2.4 --- Endocrine system --- p.257<br>Chapter 16.3 --- Reason regard to herb-drug interactions --- p.257<br>Chapter 16.3.1 --- Lack of Knowledge About Herbs --- p.257<br>Chapter 16.3.2 --- Mislabelling or Adulteration --- p.258<br>Chapter 16.3.3 --- Lack of Patient Communication About Use of Botanicals --- p.258<br>Chapter 16.3.4 --- Lack of Practitioner Knowledge About Potential Interactions --- p.258<br>Chapter 16.4 --- Metabolism of Herb-Drug Interaction --- p.258-259<br>Chapter 16.5 --- Pharmacologic Interactions --- p.259-260<br>Chapter 16.5.1 --- Interaction with Antibiotics --- p.260<br>Chapter 16.5.2 --- Interaction with Nonsteroidal Anti-inflammatory Drugs --- p.260-261<br>Chapter 16.5.3 --- Interaction with Sedatives --- p.261-262<br>Chapter 16.5.4 --- Interaction with Anticoagulants --- p.262-263<br>Chapter 16.5.5 --- Interaction with Anti-hypertensives and Diuretics --- p.263<br>Chapter 16.5.6 --- Interaction with Spironolactone --- p.264<br>Chapter 16.5.7 --- Interaction with Corticosteroids and Cyclosporine --- p.264-265<br>Chapter 16.5.8 --- Interaction with Estrogen Replacement Therapy --- p.265<br>Chapter 16.5.9 --- Interactions Between Natural Product and Drug --- p.265-266<br>Chapter 16.6 --- Herb-to-Herb Interactions --- p.266-267<br>Chapter 16.7 --- Conclusion --- p.268-269<br>Chapter Chapter 17 --- Recommendation --- p.270-264<br>Chapter 17.1 --- Overview --- p.270<br>Chapter 17.2 --- The need to evaluate the clinical effectiveness of traditional Chinese medicine --- p.270-271<br>Chapter 17.3 --- For the Pharmaceutical Industries --- p.211-212<br>Chapter 17.4 --- For the physicians & patient --- p.272-274<br>Conclusion --- p.274<br>Chapter Chapter 18 --- Conclusion --- p.275-280<br>Chapter Chapter 19 --- Reference --- p.281-306

INTRODUCTION: Smoking, alcohol and other drugs use among high school learners has become a major public health problem across the globe. Here in South Africa, it is estimated that a large proportion of learners indulge in smoking and the use of alcohol and illicit drugs. Data from treatment sites across the country indicate that the number of patients who are below 20 years seeking treatment is escalating. These indulgences have been blamed for escalating school violence, rapes, robbery and accidents, all of which contribute to increased morbidity, disability and premature deaths. It is expected that the result of this study may provide additional understanding about learners’ drug and alcohol use. Such additional understanding can be of benefit to those responsible for the planning and implementation of cessation programmes. AIM AND OBJECTIVES: To determine the extent of drug and alcohol use, the relationship between substance use and academic performance, and the factors that may influence cessation of alcohol and drug use among high school learners in Mogalakwena municipality. METHOD: The protocol involved purposeful selection of one school from each of the nine education circuits within the Mogalakwena Municipality, Limpopo Province. The questionnaire was anonymous, requiring no data that can identify any learners. The sample consisted of five hundred and fifty five students aged 15 to 23(53% females and 47% males). The data was coded and analysed with epi-info version 6(Dutch) and this involved descriptive statistics and cross tabulations with specific reference to chi square test and students t-test yielding p-values. RESULTS: The result of this study indicate that among high school learners in the Mogalakwena municipality 28% have smoked cigarette, 65% have drunk alcohol and 16% have used illicit drugs.In addition there was statistically significant difference between urban and rural learners in terms of smoking and alcohol consumption, with higher rates among urban students, but there was no difference in the use of drugs between the two groups. Also, there was statistically significant difference in drug usage and smoking with regard to age but no difference in alcohol consumption. Younger students tended to smoke more and also were more involved in the use of drugs. More males than females were involved in smoking, alcohol consumption and drugs use. The most reported factors that could influence cessation of alcohol and drugs use were bad effect 49%, cost 23% and parents’ influence 15%. Among the parameters examined as proxies for impact of alcohol and other drugs use on academic performance, indications point to negative impact. CONCLUSION: Alcohol and other drugs use is prevalent among high school learners in the Mogalakwena municipality and is reported to have a negative impact on academic performance. “Bad effects”, high costs and significant relationships are reported as the most important factors that could influence alcohol and other drugs use cessation and these may be important considerations in planning risk reduction.

碩士<br>國立成功大學<br>臨床藥學研究所<br>84<br>Nonsteroidal anti-inflammatory drugs (NSAIDs) have been found to be associated with an elevated risk of peptic ulcer and upper gastrointestinal hemorrhage. A retrospective cohort study was performed to estimate the incidence and cumulative incidence of serious ulcer disease among long-term users of NSAIDs, using a computerized prescriprion data base of National Cheng-Kung University Hospital. Twenty-eight thousand seven hundred and seventy four NSAID recipients, who had NSAID prescription record, were included. Three hundred and ten patients became the study cases after medical record review and two hundred and forty-two were interviewed via telephone. Incidence of serious ulcer disease was between 11.7 per 1,000 person-year (95% confidence interval 1.4-22.0) and 15.6 per 1,000 person-year (95% confidence interval 1.9-29.3). Cumulative incidence of serious ulcer disease was between 1.61% (95% confidence interval 0.53-3.72) and 2.07% (95% confidence interval 0.67-4.76). The second objective in this study was to describe the prescribing patterns of NSAIDs users. Osteoarthritis was the most commonly listed indication. Among these NSAIDs, diclofenac SR was prescribed most often in terms of defined daily dose. The department of Orthopaedics prescribed the most of NSAIDs. Within the limits of statistical error, the results of this study was similar to that presented in previous reports. These drugs should be used with caution, and alternatives to NSAIDs should be strongly considered.

碩士<br>長榮大學<br>醫學研究所<br>98<br>Background: The treatment effect of chronic hepatitis C (HCV) is often limited due to the adverse effects of interferon and ribavirin. Hemolytic anemia and hematological adverse effect may influence the treatment program. Previous studies documented Genotype I, hypertension, low baseline hemoglobin, and raised creatinine were factors associated with the development of hematological abnormalities. Aims: The study evaluate if some host factors, included oxidative stress and leukocyte mitochondrial DNA copy number before treatment are associated with severe hematological adverse effect in HCV patients treated with peginterferon plus ribavirin. Methods: 132 patients who age between 40 to 60 years old were treated with peginterferon plus ribavirin for 6 months. We checked hemogram parameters at baseline, first week, second week, and then per month until treatment ended. We defined severe drop in hemoglobin levels as hemoglobin compared with baseline dropped more than 4 g/dL any time during treatment period without other bleeding event. The host factors included leukocyte mitochondrial DNA copy number and delta Ct were evaluated the possible association with severe drop in hemoglobin levels ( drop > 4g/dL) and WBC, ANC,Platelet drop ratio. Results: 72 patients had drop > 4 g/dL in hemoglobin levels, and 60 patients did not. Compared the host factors of two groups, high creatinine levels (0.94 ± 0.18 vs. 0.87 ± 0.19 mg/dL, P= 0.047) were associated with severe drop in hemoglobin levels. In genotype 1 HCV infected patients, high CKD stage(=>2) also were associated with severe drop in hemoglobin levels(P= 0.02). Besides, high CKD stage(=>2) and genotype 1 HCV infection, also associated with the severity of WBC count decline. (48.9± 14.5 v.s. 54.5± 12.6 %, P = 0.019 and 54.4±13.5 v.s. 48.0±13.0 %, P = 0.009) Conclusions: Renal function is a significant host factor of severe drop in hemoglobin and WBC count levels in patients with HCV treated with peginterferon plus ribavirin. Genotype 1 HCV infection also is a factor of severe WBC decline.

Lee, Hoi Ying.<br>"September 2010."<br>Thesis (M.Phil.)--Chinese University of Hong Kong, 2010.<br>Includes bibliographical references (leaves 171-189).<br>Abstracts in English and Chinese.<br>Abstract (English) --- p.i<br>Abstract (Chinese) --- p.iii<br>Acknowledgement --- p.v<br>Publications --- p.vi<br>Abbreviations --- p.vii<br>Table of Content --- p.x<br>Chapter 1 --- Introduction --- p.1<br>Chapter 1.1 --- Human mast cells and its activation --- p.1<br>Chapter 1.2 --- Role of mast cells in inflammation --- p.2<br>Chapter 1.3 --- Mast cell heterogeneity --- p.5<br>Chapter 1.4 --- Interaction of bone and immune system --- p.1<br>Chapter 1.5 --- Introduction of bone system --- p.8<br>Chapter 1.6 --- Bone remodeling --- p.9<br>Chapter 1.7 --- Regulation of bone remodeling --- p.10<br>Chapter 1.8 --- Introduction of Osteoporosis --- p.12<br>Chapter 1.9 --- Pathophysiology of osteoporosis --- p.13<br>Chapter 1.10 --- Pharmacological interventions in osteoporosis --- p.14<br>Chapter 1.11 --- Involvement of mast cells in bone metabolism --- p.18<br>Chapter 1.12 --- Aim of study --- p.20<br>Chapter 2 --- Materials and Methods --- p.27<br>Chapter 2.1 --- Materials --- p.27<br>Chapter 2.2 --- Methods --- p.34<br>Chapter 2.2.1 --- Human mast cells culture --- p.34<br>Chapter 2.2.2 --- Human mast cells characterization --- p.35<br>Chapter 2.2.3 --- Histamine release assay --- p.36<br>Chapter 2.2.4 --- Immunofluorescence staining of estrogen receptors --- p.37<br>Chapter 2.2.5 --- Reverse Transcriptase Polymerase Chain Reaction --- p.37<br>Chapter 2.2.6 --- TNF measurement --- p.38<br>Chapter 2.2.7 --- Calcium mobilization studies of mast cells --- p.38<br>Chapter 2.2.8 --- Statistical analysis --- p.39<br>Chapter 3 --- Effects of estrogen and selective estrogen receptor modulators (SERMs) on mediators release from human mast cells --- p.41<br>Chapter 3.1 --- Introduction --- p.41<br>Chapter 3.2 --- Materials and methods --- p.50<br>Chapter 3.3 --- Results --- p.51<br>Chapter 3.3.1 --- Characterization of human mast cells --- p.51<br>Chapter 3.3.2 --- Effect of estrogen on mediator release from human mast cells --- p.52<br>Chapter 3.3.2.1 --- Basal histamine release after treatment of estrogen --- p.52<br>Chapter 3.3.2.2 --- Histamine release induced by immunological stimulus --- p.52<br>Chapter 3.3.2.3 --- Histamine release induced by chemical secretagogues --- p.54<br>Chapter 3.3.3 --- Effect of selective estrogen receptor modulators (SERMs) on mast cell activity --- p.54<br>Chapter 3.3.3.1 --- Basal histamine release after SERMs treatment --- p.54<br>Chapter 3.3.3.2 --- Histamine release induced by immunological stimulus --- p.55<br>Chapter 3.3.3.3 --- Histamine release induced by chemical secretagogues --- p.57<br>Chapter 3.3.4 --- Effect of estradiol on TNF-α release from human mast cells --- p.57<br>Chapter 3.3.5 --- Effect of SERMs on TNE-α release from human mast cells --- p.58<br>Chapter 3.3.6 --- Expression of estrogen receptors on human mast cells --- p.59<br>Chapter 3.3.6.1 --- Expression of estrogen receptor after treatment of estradiol --- p.59<br>Chapter 3.3.7 --- Expression of various bone remodeling molecules on human mast cells --- p.60<br>Chapter 3.3.7.1 --- Expression of bone remodeling molecule after treatment of estradiol --- p.61<br>Chapter 3.4 --- Discussion --- p.63<br>Chapter 4 --- Effects of anti-osteoporosis Chinese herbal medicines on activity of human mast cells --- p.98<br>Chapter 4.1 --- Introduction --- p.98<br>Chapter 4.2 --- Materials and methods --- p.103<br>Chapter 4.3 --- Results --- p.104<br>Chapter 4.3.1 --- Effect of the anti-osteoporosis Chinese herbal formulation ELP on histamine release from human mast cells --- p.104<br>Chapter 4.3.1.1 --- Histamine release induced by immunological stimulus --- p.104<br>Chapter 4.3.1.2 --- Histamine release induced by chemical secretagogues --- p.105<br>Chapter 4.3.2 --- Effect of Herba Epimedii (HEP) on histamine release from human mast cells --- p.105<br>Chapter 4.3.2.1 --- Histamine release induced by immunological stimulus --- p.106<br>Chapter 4.3.2.2 --- Histamine release induced by chemical secretagogues --- p.106<br>Chapter 4.3.3 --- Effect of Fructus Ligustri Lucidi (FLL) on histamine release from human mast cells --- p.107<br>Chapter 4.3.3.1 --- Histamine release induced by immunological stimulus --- p.107<br>Chapter 4.3.3.2 --- Histamine release induced by chemical secretagogues --- p.107<br>Chapter 4.3.4 --- Effect of Fructus Psoraleae (FP) on histamine release from human mast cells --- p.108<br>Chapter 4.3.4.1 --- Histamine release induced by immunological stimulus --- p.108<br>Chapter 4.3.4.2 --- Histamine release induced by chemical secretagogues --- p.109<br>Chapter 4.3.5 --- Effect of various partitions from solvent extraction of HEP on histamine release from human mast cells --- p.109<br>Chapter 4.3.5.1 --- Histamine release induced by immunological stimulus --- p.110<br>Chapter 4.3.5.2 --- Histamine release induced by chemical secretagogue --- p.111<br>Chapter 4.3.6 --- Effect of various partitions from solvent extraction of FLL on histamine release from human mast cells --- p.112<br>Chapter 4.3.6.1 --- Histamine release induced by immunological stimulus --- p.113<br>Chapter 4.3.6.2 --- Histamine release induced by chemical secretagogue --- p.114<br>Chapter 4.3.7 --- Effect of ELP and its herbal constituents on the production of cytokine from human mast cells --- p.115<br>Chapter 4.3.8 --- Modulation in calcium mobilization in activated human mast cell by ELP and its herbal constituents --- p.117<br>Chapter 4.4 --- Discussion --- p.119<br>Chapter 5 --- General discussion --- p.163<br>Reference --- p.171

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfillment of the requirements for the degree of Master of Medicine. Johannesburg 2017.<br>Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used analgesics worldwide. NSAIDs are increasingly available as an expanding range of over the counter (OTC) and prescription formulations. Straube et al, in a systematic review, report the mortality rate of individuals with UGIT bleeding/perforation using chronic oral NSAIDs is 1 in 5 due to gastrointestinal complications. The economic implications to a challenged, South African public healthcare system of treating serious, potentially preventable upper gastrointestinal complications attributed to the consumption of OTC NSAIDs does not appear to have been quantified. A prospective observational study was conducted at Chris Hani Baragwanath Academic Hospital and Charlotte Maxeke Johannesburg Academic Hospital over six months. Patients admitted to the surgical service with signs and symptoms of upper gastrointestinal bleeding were asked to complete a questionnaire-based survey. The cost to treat each patient was calculated. Over the study period, 321 patients were admitted with upper gastrointestinal tract (UGIT) bleeding. The cost to treat patients included in the study sample (n=253) was R 10 463 668. Patients using NSAIDs (n=215) consumed 88% (R 9 194 698) of the expenditure, seven times more than the cost of treating patients who did not use NSAIDs (n=38; p = 0.043). Of the patients who used NSAIDS, 183 had purchased over the counter NSAIDs and consume 73% of the total expenditure. The average cost to treat a patient with UGIT complications secondary to OTC vs. Prescription NSAIDs was not statistically significant. Due the higher number of viii patients who used OTC NSAIDs the cost incurred to treat these patients was five fold more than to treat the patients taking prescription only NSAIDs. We recommend strict enforcement of existing regulations governing the sale and marketing of OTC NSAIDs and intensive consumer education of their adverse effects, which may decrease the substantial financial cost to the public health system and morbidity to the South African population at risk.<br>LG2018

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Tereza Klapková Supervisor: Assoc. Prof. PharmDr. František Trejtnar, CSc. Title of diploma thesis: Recent knowledge on drug effect on male fertility Among the various types of side effects presented in clinically used drugs, negative effects on male reproductive functions can be find. This issue seems to be important and current especially due to the general trend of the decrease in fertility in men and the increasing drug use in younger age groups. The aim of this diploma thesis was to create an overview summarizing current expert knowledge on the effect of drugs on male fertility. For this purpose, we selected relevant publications in the PubMed database, perform their analysis and create the text ofthe thesis. The review focuses mainly on groups of drugs that are often clinically used and discussed in relation to male fertility, such as drugs acting on the cardiovascular system, antimicrobial drugs, drugs used in pain therapy, antidepressants, antiepileptics, antipsychotics, immunosuppressants and some other drugs. In addition to standard drugs, the review also includes several important natural substances, which are used as adjunctive therapy of various diseases or are important from a...

Relatório de Estágio do Mestrado Integrado em Ciências Farmacêuticas apresentado à Faculdade de Farmácia<br>O Vírus da Imunodeficiência Humana (HIV) surgiu no final dos anos 70, tornando-se uma das doenças infeciosas mais devastadoras do século XX. Com o surgimento dos primeiros fármacos e com o início da era da Highly Active Antiretroviral Therapy (HAART) foi possível começar a inverter a tendência do número de novas infeções e atrasar a progressão da infeção, tornando, nos dias de hoje, o Síndrome da Imunodeficiência Adquirida (SIDA) uma doença crónica. No entanto, a infeção por HIV continua a ser um problema de saúde pública, uma vez que se estima que 36,7 milhões de indivíduos se encontram infetados por todo o mundo, sendo que 1,8 milhões correspondem a infeções em crianças. A transmissão vertical é uma das formas possíveis de transmissão do vírus, podendo variar de cerca de 15 a 45%, na ausência de qualquer medida preventiva. Esta percentagem pode ser reduzida para valores abaixo de 5% se houver intervenções adequadas em fases em que essa transmissão possa ocorrer (gravidez, parto e aleitamento). A prevenção da transmissão vertical pode, assim, ser alcançada se houver um acompanhamento da grávida por profissionais de saúde qualificados, acesso a terapia antirretroviral durante a gestação, parto e pós-parto, recurso a parto por cesariana e cuidados adequados de alimentação dos recém-nascidos. Em países abundantes em recursos económicos o risco de transmissão vertical consegue, em alguns países, estar abaixo de 1%. O uso de fármacos antirretrovirais constitui a maior arma na prevenção, ainda que o conhecimento sobre a segurança do uso desses fármacos na gravidez seja limitado.Em países em desenvolvimento e subdesenvolvidos, nomeadamente na África Subsariana, a infeção por HIV através da transmissão vertical atinge valores inaceitáveis, havendo uma necessidade urgente de instituir e melhorar sistemas de saúde que promovam um maior acesso a cuidados de saúde especializados e direcionados para a erradicação do vírus.<br>The Human Immunodeficiency Virus (HIV) has emerged in the late seventies, becoming one of the most devastating infectious diseases of the 20th century. With the advent of the first medicines and with the dawn of the Highly Active Antiretroviral Therapy (HAART) era, it was possible to start to reverse the trend of new infections and to delay the infection development. As a result, Acquired Immune Deficiency Syndrome (AIDS) has become a chronic disease. However, HIV infection stills a Public Health issue. It is estimated that 36.7 million of people are infected all over the world, of which 1.8 million are children.Mother-to-child transmission is one of the possible virus transmission pathways, varying between 15 to 45% without any preventive measures. These values can be reduced to values below 5% if the appropriate interventions are performed during the transmission phases (pregnancy, delivery and breast-feeding). The prevention of mother-to-child can thus be achieved with monitoring of the pregnant woman by qualified health professionals, access to antiretroviral therapy during pregnancy, delivery and postpartum, use of cesarean section and adequate nourishment of newborns.In countries with high economic resources, the MTCT risk can be, in some cases, lower than 1%. The use of antiretroviral medicines represent the most powerful weapon on PMTCT, even though there is limited knowledge regarding its safety in pregnancy.On the other hand, in middle and low economic resources countries, particularly in Sub-Saharan Africa, MTCT HIV infection reaches intolerable values, leading to an urgent necessity to improve access to health systems that promote more specialized health care and that are focused on HIV eradication.

Dissertação de Mestrado em Farmacologia Aplicada apresentada à Faculdade de Farmácia<br>IntroduçãoA Hipertensão Arterial é considerada um dos mais importantes fatores de risco da principal causa de mortalidade em Portugal e em todo o mundo: as doenças cérebro-cardiovasculares. Uma das principais variáveis que conduzem a um mau controlo da pressão arterial em doentes hipertensos é a falta de adesão à terapêutica. A adesão à terapêutica é influenciada por múltiplos fatores, que condicionam o seguimento das recomendações médicas relativas à toma da medicação, sendo um deles a presença de efeitos adversos percecionados com a medicação. Existem múltiplos métodos capazes de avaliar a adesão à terapêutica, sendo os questionários os mais utilizados na prática clínica.Objetivo O objetivo principal deste trabalho é analisar de que forma a perceção de efeitos secundários associados à terapêutica anti-hipertensora é avaliada nos questionários de adesão à terapêutica anti-hipertensora já validados na população portuguesa.Material e MétodosFoi realizada uma pesquisa bibliográfica na PubMed para a recolha dos questionários de adesão à terapêutica, através de uma equação de pesquisa que incluiu os seguintes termos: “medication adherence”, “patient adherence”, “instrument”, “scale”, “questionnaire”, “hypertension”, “antihypertensive agents”, “portuguese”, “Portugal”.A seleção dos artigos atendeu a critérios de inclusão previamente estabelecidos. Foram incluídos todos os artigos que utilizassem um questionário de adesão à terapêutica anti-hipertensora, desde que esse questionário estivesse validado em português. Posteriormente, os questionários identificados foram comparados com base nos itens presentes em cada um, agrupando-os de acordo com as temáticas abordadas. Foram analisados e comparados os itens que avaliavam a presença ou perceção de efeitos adversos.ResultadosForam obtidos 66 artigos através da equação de pesquisa selecionada. Outros 2 artigos foram adicionados pela sua identificação em referências bibliográficas. Num total de 68 artigos obtidos, foram excluídos 64, uma vez que apenas 4 cumpriram os critérios de inclusão. No total dos 4 questionários, foram analisados 41 itens, onde apenas 6 estavam possivelmente relacionados com os efeitos adversos da medicação. Outros itens avaliavam, por exemplo, razões económicas (em 3 itens), esquecimento (em 11 itens), conhecimentos acerca da doença (em apenas 1 item), crenças na medicação (em 6 itens) e adesão às medidas não farmacológicas (em 6 itens).ConclusãoExistem poucos questionários validados na população portuguesa capazes de avaliar ou predizer a adesão à medicação em indivíduos hipertensos. A análise revelou que os 4 questionários continham itens capazes de avaliar a perceção de efeitos adversos, contudo alguns deles não eram diretos, podendo originar múltiplas interpretações. Não existem grandes diferenças entre os questionários de adesão validados em português e aqueles que se encontram validados noutros países. São necessários estudos observacionais que avaliem, na prática, a relação entre a perceção de efeitos adversos e a adesão, para uma melhor confirmação do impacto negativo de efeitos adversos percecionados na decisão de toma da medicação.<br>IntroductionArterial hypertension is considered one of the most important risk factors of the primary cause of mortality in Portugal and worldwide: brain-cardiovascular diseases. One of the main variables that lead to a bad control of blood pressure in hypertensive patients is the lack of adherence. Adherence to medication is influenced by multiples factors that conditionate the following of medical recommendations about taking medicines, and the presence of perceived adverse effects with medication is one of them. There are multiple measures available to assess adherence, although questionnaires are preferred in clinical practice.ObjectiveThe principal objective of this work is to analyse in which way the perception of adverse effects associated to antihypertensive medication is evaluated in adherence questionnaires validated in portuguese population.Material and MethodsIt was made a bibliographic research in PubMed to collect adherence questionnaires, through a research equation which included the following terms: “medication adherence”, “patient adherence”, “instrument”, “scale”, “questionnaire”, “hypertension”, “antihypertensive agents”, “portuguese”, “Portugal”.The selection of the articles attended to a previously established inclusion criteria. All the articles that utilized at least one adherence questionnaire to antihypertensive medication, since it was validated in portuguese-portuguese were included. Then, questionnaires were compared based on their items, grouping them according to the topics covered. All the items that evaluated the presence or the perception of adverse effects were analysed and compared.Results66 articles were obtained using the selected research equation. Two other articles were added through their identification in the bibliographic references. In a total of 68 articles, 64 were excluded and only 4 fulfilled all the inclusion criteria.In the total of 4 questionnaires, 41 items were analysed and only 6 were possibly related to adverse effects of medication. Other items evaluated, for example, economic reasons (in 3 items), forgetfulness (in 11 items), knowledge about the disease (in only 1 item), beliefs about medication (in 6 items) and adherence to non-pharmacological interventions (in 6 items).ConclusionsThere are few questionnaires validated in Portuguese population with hypertension that are able to evaluate or predict medication adherence. The analysis revealed that all the 4 questionnaires had items that were capable of evaluate the adverse effects perception. However, some of those items aren’t totally direct to adverse effects and are able to originate multiple interpretations. There isn’t much difference between Portuguese adherence questionnaires and questionnaires validated in other countries. Future observational studies are necessary to evaluate the relationship between adverse effects perception and adherence, to estimate the negative impact of perceived adverse effects with the decision of taking antihypertensive drugs.