En tredjedel av alla bypass-operationer leder till att kärlimplantaten slutar fungerar inom ettårs tid. En anledning till detta är bildandet av ogynnsam vävnad som sker i form av ärrbildning efter implantationen. Ärrvävnaden orsakar nya förträngningar vilket leder till ett försämrat blodflöde. Kärlimplantatet Y-graft har genom sin design som följer Murray´s lag, en naturlig blodflödesfördelning. Designen i form av ett Y har kunnat bekräftas vara fördelaktig då geometrin vid utflödet minskar risken för ärrbildning. Vad som saknas för att Y-graft ska kunna komma ut på marknaden är ett lämpligt material. Med detta som bakgrund uppkom syftet med litteraturstudien att undersöka vilka material meddokumenterad klinisk historik som är möjliga att använda vid textil tillverkning av Y-graft. Genom en gedigen litteratursökning med hjälp av sökverktyg som U.S. Food and Drug Administration (FDA) tillsammans med andra databaser inom de medicinska och materialtekniska områdena, har en förståelse skapats kring vilka material som används i medicintekniska produkter och som är möjliga kandidater till Y-graft. Litteraturstudien resulterade i att materialen polyetentereftalat, polybutentereftalat, polybutester polytetrafluoreten, polyester-, polyeter- och polykarbonatbaserade polyuretaner samt polypropen, polyeten, alfatisk polyamid och silke finns i godkända medicintekniska produkter på den amerikanska marknaden. De presenterade materialen har på så visdokumenterad klinisk historik och är lämpliga kandidater att använda vid textil tillverkning av Y-graft. De godkända materialkandidaterna som presenteras kan även beläggas medbiologiska polymerer för förbättrad biokompatibilitet. Materialkandidaterna har godkänts i medicintekniska produkter av U.S. Food and Drug Administration (FDA). Genom godkännandet har alla de presenterade materialen dokumenterad klinisk historik och är där med lämpliga kandidater att använda vid textiltillverkning av Y-graft. / One third of all bypass surgeries causes vascular implants to stop working within a year. A reason for this is the formation of unfavorable tissue that occurs in the form of scarring after implantation. The scar tissue causes new constrictions, which leads to impaired blood flow. The vascular implant Y-graft, by design follows Murray's law and therefore has a natural blood flow distribution. The design in the form of a Y has been confirmed to be advantageous. The Y geometry at the outflow reduces the risk of scarring. What is missing for Y-graft to be able to enter the market is a suitable material. With this as a background, the purpose of the literature study was to investigate which materials with documented clinical history can be used in textile production of Y-graft. Through a thorough literature search, using search tools like the U.S. Food and Drug Administration (FDA) together with other databases in the medical and material engineering fields, an understanding has been created about which materials are used in medical technology products and which are potential candidates for Y-graft. The literature study concluded that the materials polyethylene terephthalate, polybutheneterephthalate, polybutester polytetrafluoroethylene are found in approved medical technology products in the United States. Polyester, polyether and polycarbonate based polyurethanes and polypropylene, polyethylene, alphatic polyamide and silk are also found in the United States medical market. These presented materials thus have documented clinical history and are suitable candidates for use in textile manufacturing of Y-graft. The approved material candidates presented can also be coated with biological polymers for improved biocompatibility. The material candidates have been approved in medical technology products by the U.S. Food and Drug Administration (FDA). With this approval, all the presented materials have documented clinical history and are therefore suitable candidates to use when manufacturing Y-graft.

Signal detection from Adverse Event Reports (AERs) is important for identifying and analysing drug safety concern after a drug has been released into the market. A safety signal is defined as a possible causal relation between an adverse event and a drug. There are a number of safety signal detection algorithms available for detecting drug safety concern. They compare the ratio of observed count to expected count to find instances of disproportionate reportings of an event for a drug or combination of events for a drug. In this thesis, we present an algorithm to mine the AERs to identify drugs which show sudden and large changes in patterns of reporting of adverse events. Unlike other algorithms, the proposed algorithm creates time series for each drug and use it to identify start of a potential safety problem. A novel vectorized timeseries utilizing multiple attributes has been proposed here. First a time series with a small time period was created; then to remove local variations of the number of reports in a time period, a time-window based averaging was done. This method helped to keep a relatively long time-series, but eliminated local variations. The steps in the algorithm include partitioning the counts on attribute values, creating a vector out of the partitioned counts for each time period, use of a sliding time window, normalizing the vectors and computing vector differences to find the changes in reporting over time. Weights have been assigned to attributes to highlight changes in the more significant attributes. The algorithm was tested with Adverse Event Reporting System (AERS) datasets from Food and Drug Administation (FDA). From AERS datasets the proposed algorithm identified five drugs that may have safety concern. After searching literature and the Internet it was found that the five drugs the algorithm identified, two were recalled, one was suspended, one had to undergo label change and the other one has a lawsuit pending against it.

Phased array based systems have extending applications in electronic warfare, radio astronomy, civilian applications with technological advancements. The main virtue offered by these systems is the creation of agile beams with utilization of phase shifting or delay elements. In fact, the desire for flexible steering comes with a cost. Frequency Diverse Array (FDA) concept is another approach to beam steering problem. In this context, the subsequent antenna elements are fed with stepped discrete frequencies causing continuous scanning of space in time. So a range-angle dependent scanning is made possible. Also the diversity of waveforms between the antennas is another area of research especially in Moving Target Indicator (MTI) applications. Although several implementation schemes were proposed, the costs and the non-ideal behavior of building blocks make the schemes hard to implement. During this study, a new implementation scheme is proposed where a Linear Frequency Modulated Continuous Wave (LFMCW, Linear FMCW) source is used for feeding a special beam forming network, where the subsequent outputs of the beam forming network have uniform delays. The dynamic behavior of the source and the uniform (or non-uniform) delay provided by the beam forming network create the required frequency steps between antenna elements as described in conventional FDA. So, the implementation of FDA concept requires just the design of the source, beam forming network and the antenna array. Throughout the study, mathematical analysis of both conventional FDA and the LFMCW based FDA is made and various implementations are realized. Justification of the mathematical derivations is made by the results of the measurements with the implemented structures. Besides, analysis and simulation of the array in a radar environment with various scenarios are performed. The drawbacks and the proposals for overcoming these drawbacks are also reported during the analysis, which will be useful for future studies on the subject.

Throughout the 20th century, American farmlands, agricultural policy, and diets have seen dramatic transformations. The number of farms in America has decreased, but the average size of farms has increased. These larger farms are increasingly more industrialized and produce a short list of profitable, subsidized commodity crops. Similarly, changes in the American diet throughout the 20th and 21st centuries have reflected these shifts in the landscape of American farmland. Simultaneous to the evolution of American farms was an increase in federal involvement in American agriculture through policy that seems to encourage these trends. Although separating out the causes from the effects can be difficult, this paper attempts to understand the role that policy has played in a changing American farmland, the players behind American food and agricultural policy, and the implications these changes have had on the American diet.

The Cytochrome P450 family of enzymes is responsible for the majority of Phase I metabolism, and has been identified as an important source of pharmacokinetic variation in therapeutic responses. CYP2C19 and CYP2D6, metabolising >35% of commonly prescribed medications, are two of the most important pharmacogenetic markers that have been studied with the aim of improving treatment response and reducing adverse drug reactions. The Food and Drug Administration (FDA) approved AmpliChip CYP450 Test (AmpliChip) was compared to a previously developed PCR-RFLP platform and a newly developed XLPCR+ Sequencing platform for the ability to identifying genotype and predicting phenotype for CYP2C19 and CYP2D6 respectively. The AmpliChip was found not to be genotypically comprehensive enough for evaluating CYP2C19 genotype, not robust enough for determining CYP2D6 genotype and inaccurate in predicting phenotype for both. The XLPCR+ Sequencing method identified three novel alleles and one sub-variant. Advances in online column-switching solid phase extraction generated a rapid and robust LCMS/ MS method for simultaneously quantifying the probe drugs omeprazole (CYP2C19 substrate), dextromethorphan (CYP2D6 substrate) and their metabolites. Antimodes were identified for phenotypic cut-offs which offered measured phenotype for comparison to predicted phenotype. Omeprazole metabolism by CYP2C19 correlated well with predicted phenotype in a demographically representative South African cohort. There are concerns regarding the use of omeprazole as a probe drug as participants predicted to be ultrarapid metabolisers for CYP2C19 had similar rates to extensive metabolisers. Regardless of this concern, decreased metabolism was assigned to the CYP2C19*15 for the first time. CYP2D6 predicted phenotype correlated very well with measured phenotype, validating the suitability of dextromethorphan use for measuring CYP2D6 metabolism. Substrate modified activity score using 0.5 to predict intermediate metabolisers fine-tuned the XLPCR+ Sequencing platform for phenotype prediction. This finding, along with observations in CYP2C19 metabolism of omeprazole, highlights the importance of substrate specific phenotype prediction strategies. Controversially, attempts to associate CYP2D6 phenotype prediction with risperidone-related adverse drug reactions has yielded conflicting results. The XL-PCR+Sequencing platform was able to discount this association by predicting a variety of metabolisers in a pilot cohort selected to be experiencing risperidone-related adverse drug reactions. The comprehensive capability of the XL-PCR+Sequencing allowed for the identification of an additional novel allele in this cohort. The data presented in thisthesis has provided insight into the relationship between predicted and measured phenotype for CYP2C19 and CYP2D6 in the South African population. The XL-PCR+Sequencing platform can be used for future research or can be applied to improve treatment outcome. The LC-MS/MS method developed could be used for future evaluations of predicted and measured phenotype with the ability to be adjusted for therapeutic drug monitoring. This thesis advances pharmacogenetics of CYP2C19 and CYP2D6 for use in the South African population. / Thesis (PhD)--University of Pretoria, 2013. / gm2014 / Pharmacology / unrestricted

The U.S. Food and Drug Administration (FDA) uses the FDA Adverse Event Reporting System (FAERS) to monitor adverse events resulting from pharmaceutical drug use. However, this system has limitations such as not allowing real-time data collection. To address these limitations, the FDA launched the Sentinel Initiative in 2008. This comparative case study was conducted to describe perceptions of investigating the efficacy of the Sentinel Initiative compared with the FAERS. The study was based on the theory of preemption as it emphasized the need for efficient means for providing unquestionable proof that consumers suffered adverse drug effects. The sample included interivews of 20 individuals, who worked closely with the FAERS program and were familiar with the Sentinel Initiative. In-depth key-informant interviews had been conducted to determine the perceptions of the participants regarding the challenges and benefits of the Sentinel Initiative compared with FAERS. To analyze data, content analysis was used. The study concluded that the FAERS and Sentinel Initiative provided a systematic database, which included health data, that could be used to improve public health. Due to the FAERS and Sentinel Initiative, adverse effects of drugs will be recognized and the safety of the patients and the public will be prioritized. The findings of this study have potential social impact for positive change at the societal level, organizational level, and individual level in terms of overall safety of the drugs. Sentinel initiative at its present state complements the existing FAERS and leverage its benefits by connecting at a grass roots level patients to an organization level as well as stakeholders to make an impact in providing safer drugs on the market.

There is no known cure for the family of diseases known as Transmissible Spongiform Encephalopathies. These include the infamous Mad Cow disease-technically known as Bovine Spongiform Encephalopathy (BSE)--as well as its human form, variant Creutzfeldt-Jakob disease. Although BSE was initially diagnosed in Britain in 1986, the first U.S. regulation to prevent BSE was not enacted until three years later. This delayed reaction proved to be a trend amongst the regulatory agencies responsible for keeping the U.S. food supply safe and BSE-free. The focus of this study is to delineate the degree of U.S. government liability in the event of a BSE outbreak. This study takes into account the various aspects of administrative law as it relates to liability, along with the numerous medical and scientific documents from domestic as well as international authorities, to determine governmental liability. There is sufficient evidence to suggest that the U.S. regulatory agencies concerned with food safety have created legislation consistently favoring industry concerns over those of public health. The legal system of a truly civilized society should be derived from ethical principles, which are then applied to institutions like the economy. When the process is reversed, when laws are based on industrial or economic concerns, ethics becomes an after-thought. This thesis sheds light on the government's handling of the threat of BSE: its shortcomings, competence, failures and successes. - ---

It is the purpose of this thesis to develop a course of study for pharmacy schools on drug regulation by the Food and Drug Administration (FDA). A summarization of the history of the development of the Food and Drug Administration (FDA) and of pharmacy education reveals a lack of interface between the two. The necessity for the interface of pharmacy education and the agency which has significant control over the products forming the basis of the pharmacy profession will be made apparent. A period of residency through which the course of study on drug regulation by the FDA was to be developed, will be described. This description details the responsibilities and functions of the various segments of the FDA involved in the regulation of drugs as acquired through discussion with agency officials during the residency. It is intended to be used as the textual material for the didactic portion of the course of study to be offered at schools of pharmacy. Based upon the experience, recommendations will be made regarding the applicability of the course of study to include possible residencies for pharmacy students at the agency.

Liberação transdérmica de fármacos apresenta várias vantagens na terapêutica quando comparada com administração oral ou parenteral. Não existe até o momento nenhum método previsto na Farmacopéia Brasileira para realizar testes de liberação de fármacos em adesivos transdérmicos, outros compêndios oficiais como Farmacopéia Americana, Britânica e Européia, descrevem o aparato de pás sobre disco, o cilindro rotatório e o suporte recíproco. Atualmente a literatura descreve diversos tipos de células de difusão para liberação transdérmica das quais a célula de difusão de Franz tem sido a mais empregada tanto para adesivos transdérmicos como formas semi-sólidas, utilizada no desenvolvimento farmacotécnico, caracterização biofarmacêutica e controle de qualidade. A proposta deste estudo tem por objetivo estipular critérios para a escolha mais adequada do equipamento e metodologias in vitro na avaliação da liberação transdérmicas de fármacos, utilizando a nicotina como fármaco modelo. Para tal, foram empregados ensaios in vitro de liberação e retenção cutânea utilizando métodos de pás sobre disco e método de célula de difusão de Franz modificada em sistema estático e fluxo contínuo. A validação dos fatores que influenciam a taxa de liberação in vitro da nicotina foram fundamentais para escolha do meio receptor, escolha da velocidade de agitação que promoveu mais semelhança no perfil de liberação em diferentes equipamentos assim como a escolha da membrana biológica mais adequada para o método proposto. Os resultados mais promissores foram selecionados para os ensaios in vitro de liberação, permeação e retenção cutânea. Os dados de liberação, tanto em quantidades de nicotina liberada como seu fluxo, demonstraram semelhança no uso de diferentes equipamentos, indicando possíveis intercambialidades entre os métodos propostos para liberação de nicotina transdérmica. Ensaios in vitro de permeação cutânea em célula de difusão vertical de Franz não demonstraram diferenças significativas em diferentes modelos de membranas biológicas utilizadas, as quais foram pele de orelha de porco, pele de camundongo sem pelo e pele de cobra cascavel hidratada por 24 horas. A quantidade de nicotina permeada em até 8 horas, assim como o fluxo de permeação foram significativamente menor para o método de pás sobre disco (FDA) quando comparado com os resultados obtidos utilizando célula de difusão vertical de Franz tanto em sistema estático com em fluxo contínuo. Estes resultados podem estar relacionados com a estrutura física do equipamento de célula de difusão vertical de Franz, uma vez que oferece um sistema oclusivo, dificultando o contato do adesivo com o meio receptor. Desta forma, os resultados deste projeto podem indicar o uso da célula de difusão vertical de Franz para ensaios in vitro de liberação e permeação cutânea da nicotina em formas farmacêuticas transdérmicas, podendo ser aplicado em pesquisas de desenvolvimento de formulações, controle da qualidade e testes de Equivalência Farmacêutica para produtos genéricos. Os resultados desta pesquisa apresentam-se podem ter importante influência nas discussões em torno dos medicamentos genéricos no Brasil, bem como na elaboração de diretrizes para testes de Equivalência Farmacêutica e Controle de Qualidade de medicamentos transdérmicos. Poderão ainda fornecer dados para indicações de protocolos para Farmacopéia Brasileira e pesquisa científica em torno dos sistemas de liberação transdérmicas de fármacos. / The aim of this work was to compare in vitro release and permeation of nicotine from transdermal patch (TDS) using three different methods such as, FDA paddle method and both Vertical Diffusion Cell (VCD) static and continuous flux. We evaluated different kinds of membrane (hairless mouse, porcine ear skin and snake skin), different composition and pH of acceptor phases (0.01N isotonic phosphate buffer pH 7.4 (± 0.2), water, and HCL 0.025N), agitation of acceptor phase and batches of the transdermal patches. Profiles of release and permeation from all methods evaluated were linked statistically using linear regression and one-way ANOVA nonparametric assay. The 0.01N isotonic phosphate buffer pH 7.4 (± 0.2) improved greater release rate of nicotine than those obtained using HCL and water as acceptor phase. Cumulative released and permeated amounts of nicotine were almost equal for all methods evaluated and there is not significantly different (one-way ANOVA p 0.05) were observed after 8 h. However nicotine permeated fluxes (J) after 8 h were significantly higher using VDC than those obtained using FDA paddle method. Cumulative permeated amounts (reported to the effective surface area of the cells) were overestimated when skin permeation experiments were prolonged to 12 h, indicating that the actual diffusion surface area of NiQuitinTM exceeded the effective diffusion surface area of the cells. Reducing the trimmed TDS surface area led not only to a reduction of the cumulative permeated amounts, but also to a reduction of the flux at 12 h. In order to evaluate the edge effect on drug release flux studies were performed using static VDC. In vitro penetration studies using different membranes showed not significantly difference for ear pig skin, hairless mouse and snake skin at 8 h. However data obtained without membrane were about 1.25 times smaller than those obtained with biological membranes. These results demonstrated that NiQuitinTM TDS had dependent release of membrane at 8 h of permeation. In conclusion there is not significantly different for in vitro release and permeation amounts of nicotine from NiQuitinTM using VDC and FDA method. In term of release efficiency all methods released up to 80% of nicotine after 8 h. The results suggested the use of VDC as potential method to evaluate both in vitro release and skin permeation of nicotine in transdermal patches.

In the first 3 years of the Obama Administration, 2009-2011, the number of warning letters issued to pharmaceutical firms for manufacturing and quality issues increased by 81% to 49 letters. Only 9 letters were issued in the last 3 years of the George W. Bush Administration. Shortfalls in compliance and product quality led to medicine shortages that affected patients' treatment and health. This quantitative study sought to learn to what extent, if any, the independent variables, management behaviors and financial indicators at pharmaceutical firms in the United States, correlated with, or predicted, the dependent variable, compliance with the FDA regulations. FDA's enforcement actions on the firms were the treatment event. A shift in the relationship between the variables occurred after the FDA interventions, which highlighted a new level of compliance. Of the 1144 SurveyMonkey invitations sent to the members of the International Society of Pharmaceutical Engineers, only 21 completed the survey's 133 questions. Three research questions were addressed using correlations and linear regressions. The theory of planned behavior was applied to correlate behavioral constructs with the compliance of the firms leading to the rejection of the null hypothesis. By establishing an inverse relation between financial indicators and the firms' level of compliance, the study offers awareness and insight to senior leaders regarding their behaviors and the decision-making process. Enhancing managers' decision-making processes in light of their beliefs, along with their control over financial indicators, could reinforce the presence of effective quality systems among pharmaceutical manufacturers minimizing medicine shortages.