Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Botany Candidate: Gabriela Tkáčová Supervisor: RNDr. Jitka Vytlačilová, Ph.D Title of diploma thesis: The occurence of pharmaceuticals in the environment I. Drugs are biologically active substances used for treatment and prophylaxis of human and animal illnesses. Some drugs, however, remain biologically active even after they are excreted from the organism. By various means these substances can appear in the environment and can be detected in wastewater, surface water, seawater, groundwater, drinking water, sediments and soil. Chronic presence of low concentrations of drugs in the environment can negatively affect non-target organisms. Aim of this diploma thesis is to study presence of SSRI, statins and hypoglycemic drugs in the environment. Drugs from these farmacodynamic groups were detected in the environment in concentrations ranging from ng/l to μg/l. Selected drugs from SSRI group were fluoxetine, citalopram, fluvoxamine, sertraline, paroxetine and escitalopram. In water samples they were detected in concentration ranging from tens to hundreds ng/l, they were also detected in soils and sediments. Toxicity for water biota was also proven. Fluoxetine caused changes in secondary sexual characteristics of fish...

Made available in DSpace on 2014-06-11T19:29:12Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-10-01Bitstream added on 2014-06-13T19:59:00Z : No. of bitstreams: 1 americo_jhp_me_ilha.pdf: 1150853 bytes, checksum: 22eb0045ed6531c06a06108c015b424b (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A contaminação dos ecossistemas aquáticos por compostos farmacológicos intensificou-se nos últimos anos devido ao aumento da produção e ao consumo desenfreado destas substâncias pela população. Estes compostos são encontrados em águas naturais e em efluentes de Estações de Tratamento de Esgoto (ETE), comprovando que sua presença em águas naturais é um indicativo de contaminação por águas residuárias de ETE. A presente pesquisa avaliou a ocorrência de compostos farmacológicos no Córrego da Onça, município de Três Lagoas (MS), bem como as relações específicas entre os pontos de monitoramento do corpo d’água. Assim, foram coletadas mensalmente, em um período de 12 meses amostras de água (1L) em seis pontos distintos representando diferentes seções do córrego. As amostras foram submetidas ao processo de extração em fase sólida e analisadas por cromatografia líquida de alta eficiência. Fármacos como atenolol, diclofenaco, ibuprofeno, naproxeno, paracetamol e piroxicam foram detectados nos pontos de coleta do corpo d’água. Com auxílio de uma ferramenta estatística, os pontos amostrais foram reunidos em duas classes, observando-se maior similaridade entre P1(Lagoa do Meio) e P2 (Lagoa Maior), e entre P4 (Jusante da ETE) e P5 (Novas Nascentes). Os resultados evidenciam a contaminação no córrego por compostos farmacológicos, possivelmente devido aos indícios de ligações clandestinas de esgoto sanitário e/ou não eficiência do sistema utilizado pela ETE do município de Três Lagoas. / The contamination of aquatic ecosystems by pharmacological compounds has intensified in recent years due to increased production and consumption of these substances by population. These compounds are found in natural waters and effluents from sewage treatment plants (WTP), confirming that their presence in natural waters is indicative of contamination by wastewater from WTP. This study investigated the occurrence of pharmacological compounds in the Stream of Onça at TrêsLagoas (MS), and the specific relationships between the monitoring points of the waterbody. Water samples were collected monthly, over a period of 12 months (water samples 1L) at six different points representing different sections of the stream. The samples were subjected to the process of solid phase extraction and analyzed by high performance liquid chromatography. Drugs such as atenolol, diclofenac, ibuprofen, naproxen, paracetamol and piroxicam were detected in the sampling points of the waterbody. A statistical tool aided to divide the sites into two classes, with a greater similarity between P1 (Middle Pond) and P2 (Major Pond), and between P4 (Downstream of WTP) and P5 (New springs). The results show that the stream contamination by pharmacological compoundsis an indication of illegal connections of sanitary sewer and/or inefficiency of the system used by WTP of Três Lagoas (MS).

Orientador: Sandra Helena Pulcinelli / Banca: Raul Cesar Evangelista / Banca: Agnieszka Joanna Pawlicka Maule / Resumo: As condições de preparação de matrizes híbridas siloxano0polióxido de etileno (POE) e siloxano0polióxido de propileno (POP) contendo fármacos foram estabelecidas nessa dissertação. A capacidade de liberação do diclofenaco de sódio por essas matrizes foi estudada a partir de curvas de liberação obtidas em meio aquoso. A caracterização das amostras foi realizada utilizando0se as técnicas de DSC, TG0DTA, DMA, DRX, SAXS, RMN do 13 C, 29 Si e do 23 Na e espectroscopia Raman. O estudo de liberação revelou que é possível controlar a velocidade de saída do fármaco a partir da variação da massa molecular da cadeia polimérica e da concentração do diclofenaco de sódio ou da combinação de precursores híbridos de diferentes classes. As medidas de SAXS "in situ" mostraram que o intumescimento é acompanhado por um relaxamento da matriz polimérica, conduzindo a um afastamento dos grupos siloxano constituintes da molécula. Esse relaxamento também é observado quando se acrescenta fármaco à matriz híbrida polimérica. As medidas de DSC indicaram a existência de interações entre as matrizes híbridas POE e o diclofenaco, mudanças de cristalinidade da fase polimérica e, quando associadas a medidas de TG0DTA e DMA, mostraram que as matrizes híbridas apresentam elevada estabilidade térmica e mecânica. Os espectros de RMN revelaram que a matriz híbrida possui elevado grau de policondensação, que o fármaco se apresenta de forma dissociada dentro da matriz, e que as amostras contendo alta concentração de fármaco apresentam aumento na rigidez da parte polimérica da matriz. Além disso, foi possível definir as regiões de interação das moléculas de diclofenaco de sódio com a matriz polimérica com associação da espectroscopia Raman / Abstract: The preparation conditions of siloxane poly(ethylene oxide) PEO and siloxane poly(propylene oxide) PPO hybrid matrixes containing drugs have been established in this work. The ability of these matrixes to release sodium diclefenac (SDF) was studied from release profiles in aqueous medium. The samples characterization was performed from DSC, TG0DTA, DMA, XRD, SAXS, ¹³C, ² 9 Si and ²³Na NMM and Raman meassurements. The release study revealed that the drugs flux release can be controlled by the polymer molecular weight, the SDF concentration or by combining hybrid precursors of different class. In situ SAXS measurements have shown that swelling is followed by matrix relaxation, giving rise to more separated siloxane groups in the polymeric moities. This relaxation is also observed as drug is loaded in the hybrid matrix. DSC measurements have indicated both the presence of interactions between POE hybrid matrix and SDF, and change in the polymer phase crystallinity. Moreover when these measurements were, associated to TG0DTA and DMA results, they have shown that hybrid matrix presents both high thermal and mechanical stability. The NMR study revealed that matrix shows high polycondensation degree, the drug is loaded insideis in its dissociated form and samples containing the highest tested SDF concentration present more rigid polymer moities. Moreover, the regions responsible for matrix and SDF molecules interaction were determined by associating the Raman results. / Mestre

A dispensação é um serviço farmacêutico importante para a promoção do uso correto dos medicamentos, prevenção de agravos à saúde e alcance de resultados satisfatórios da farmacoterapia. Entretanto, para que essa prática seja realizada adequadamente, é necessário que o farmacêutico esteja devidamente capacitado e possua conhecimento sobre fisiopatologia, terapêutica e legislação sanitária para subsidiar a relação com o paciente e com outros profissionais da saúde. Apesar disso, uma pesquisa revelou que 78,6% dos farmacêuticos não possuem conhecimento satisfatório para a realização da dispensação e mais da metade dos profissionais apontam a falta de tempo e recursos como obstáculo para a participação em cursos de capacitação presenciais. Buscando, então, intervir sobre os resultados da pesquisa citada, o presente estudo teve como objetivo avaliar a efetividade de um curso à distância na capacitação de farmacêuticos para a prática da dispensação de medicamentos. O estudo do tipo experimental teve como população farmacêuticos comunitários de todo o país. Desenvolveu-se um curso de capacitação na plataforma Moodle, no qual foi abordada a dispensação de medicamentos no tratamento das doenças crônicas não transmissíveis mais prevalentes no Brasil (hipertensão arterial sistêmica, diabetes mellitus, dislipidemias e asma). Um questionário foi elaborado e validado para mensurar o conhecimento dos participantes em dois momentos distintos: antes (baseline) e após (endpoint) o curso. Além disso, foram avaliados: i) a satisfação dos participantes em relação ao modelo de capacitação proposto, por meio de um questionário específico; ii) a prática da dispensação pelos farmacêuticos de Ribeirão Preto - SP selecionados para participar do curso, por meio da técnica do paciente simulado. Os resultados indicam que o curso foi efetivo na capacitação dos profissionais (p < 0,05), embora não tenha sido percebido no endpoint um melhor desempenho em relação à prática da dispensação entre os farmacêuticos que participaram da avaliação pelo paciente simulado. Apesar disso, os profissionais se mostraram satisfeitos com relação ao curso. Como conclusão, verificou-se que um curso à distância é efetivo para capacitar farmacêuticos em relação à dispensação de medicamentos, mas também permitiu atestar que essa estratégia não é suficiente para tornar satisfatória a realização do serviço. Atividades práticas que desenvolvam a performance e as condutas dos profissionais devem ser exploradas ao longo da capacitação. Todavia, o farmacêutico precisa também assumir posturas mais adequadas durante a dispensação, não permitindo que as pressões de mercado interfiram sobre a qualidade do seu serviço. / The dispensing drugs is an important pharmaceutical service to promote the rational use of drugs and so it is possible to prevent health problems and achieve satisfactory results of pharmacotherapy. However, for this practice to be properly carried out, it is necessary that the pharmacist is properly trained and have knowledge about pathophysiology, treatments and health legislation to support the relationship with the patient and other health professionals. Nevertheless, a survey revealed that 78.6% of pharmacists do not have adequate knowledge to perform the dispensing drugs and more than half of these professionals point that the lack of time and resources as a barrier to participation in classroom training courses. So we seek to intervene on the results of the cited survey by this study that aimed to evaluate the effectiveness of a distance learning course in the training of pharmacists to the practice of dispensing drugs. This is a clinical trial and the study population wer community pharmacists across the country. A training course was developed in Moodle, which was addressed to dispensing drugs in the treatment of the most prevalent chronic noncommunicable in Brazil (hypertension, diabetes mellitus, dyslipidemia and asthma). A questionnaire was developed and validated to measure the knowledge of the participants at two different times: before (baseline) and after (endpoint) the course. In addition, we also evaluated: i) the satisfaction of participants in relation to the proposed training model through a specific questionnaire; ii) the practice of dispensing drugs by pharmacists of Ribeirão Preto - SP selected to attend the course, through mistery shopper technique. The results indicate that the course was effective in professional training (p <0.05), although it was not realized in endpoint better performance in the practice of dispensing pharmacists who participated in the evaluation by the mistery shopper. Nevertheless, the professionals were satisfied with the course. In conclusion, it was found that a distance course is effective to enable pharmacists in relation to the dispensing drugs, but also allowed certify that this strategy is not sufficient to render satisfactory service realization. Practical activities to develop the performance and behavior of professionals should be explored along the training. However, the pharmacist must also take more appropriate positions during the dispensation and not allow market pressures to interfere on the quality of their service.

Pharmaceutical compounds comprise a wide range of substances that are consumed in large quantities by modern societies and are generally released into local sewer networks through excretion. This research aimed to identify the factors affecting the removal efficiencies of these compounds in biological wastewater treatment plants (WWTPs) under different environmental conditions. Of the pharmaceutical compounds selected for this study, the highest influent concentrations measured in municipal wastewater treatment plants (MWWTPs) were for paracetamol, naproxen and bezafibrate (> 1 μg/L), followed by carbamazepine, atenolol, lidocaine, sulfamethoxazole and NACS (<1 μg/L). In hospital wastewater treatment plants (HWWTPs), the highest concentrations measured were for paracetamol and caffeine (> 10 μg/L), followed by ciprofloxacin and NACS (1–6 μg/L), and finally bezafibrate, carbamazepine, atenolol, lidocaine, clarithromycin and sulfamethoxazole (< 1μg/L). Antibiotic drugs were detected in HWWTPs, but rarely detected in MWWTPs. In general, the hospital wastewaters contained relatively higher levels of pharmaceuticals than municipal wastewaters. The removal efficiencies of the pharmaceutical compounds ranged widely. This was found to be related to characteristics and operational parameters of the individual WWTPs. The MWWTPs that utilized long aeration and biomass retention times (HRT,SRT), as evidenced by the occurrence of complete nitrification, were more efficient at removing paracetamol, naproxen, bezafibrate and atenolol, than the non-nitrifying plants with relatively shorter HRT and SRT. HWWTPs that operated under elevated ambient temperatures (> 26°C) achieved higher removal efficiencies (90%) for several compounds, including paracetamol, caffeine, sulfamethoxazole, ciprofloxacin, clarithromycin, NACS, atenolol, carbamazepine and lidocaine. In addition to the elevated ambient temperatures, elevated HRT and SRT and less dilution can lead to increased active biomass and can result in higher removal rates for the pharmaceutical compounds. Overall, the removal efficiencies of pharmaceuticals in WWTPs have been correlated to the type of treatment plant, the plants’ operational parameters (HRT, SRT), the climatic conditions (temperature and dilution effect of rainfall) and characteristics of the micropollutants (type and concentration). Aerobic and anaerobic batch biodegradation experiments were conducted to observe the removal of paracetamol, naproxen, ibuprofen and sulfamethoxazole at various SRTs. The biodegradation rates varied widely ranging from poor, to moderate, to high, depending on the SRT. Paracetamol was highly biodegradable under both aerobic and anaerobic conditions. Sulfamethoxazole was poorly biodegradable under aerobic conditions but highly biodegradable under anaerobic conditions. Relatively slow biodegradation rates were observed for ibuprofen and naproxen under both conditions; longer microbial adaptation periods for these two compounds were probably required. The most important factor affecting the removal of the compounds was the SRT. Therefore, the conclusion was drawn that combining anaerobic and aerobic systems with longer SRT and HRT could bring about significant reductions in the emissions of these contaminants into the environment via WWTPs; this is also a cost-effective option.

This diploma thesis deals with the selected institutes and specifics of patent law in pharmaceutical industry. The aim is to analyze and critically evaluate these institutes and specifics. Although the topic requires a certain overlap into different scientific fields, the thesis emphasizes on the legal aspects of these institutes. The thesis is based on the Czech legislation; however, many chapters require an insight into the European or/and international legal context. Furthermore, the case law of a foreign court and the European Patent Office is also presented. To begin with, the thesis deals with definitions of the key terms of a patent law and presents a brief overview of the legislation on the national level as well as internationally. In the next chapter the area of pharmaceutical industry is introduced, more specifically its historical background and a specific terminology used in such area. The thesis contains a chapter dealing with the area of biotechnology as well. In the crucial part of this thesis, firstly general requirements for patentability of inventions are defined and the question of patentability of biotechnological inventions is evaluated. The attitude towards patentability of genetic modifications and cloning is evaluated more closely. Furthermore the requirements of the gene's...

Main objective of the diploma thesis was to observe the concentrations of selected types of drugs in the environment around the area of the village Horní Beřkovice. This goal was achieved by monitoring of the drugs concentration in surface and ground waters at Horní Beřkovice site. Monitoring system allowed to detect the passage of pollution from the source of the contamination, through sewage treatment plant, the unsaturated zone and aquifer to a potential user of contaminated groundwater. The diploma thesis is based on the field data from TACR project. I have analyzed data from the six samplings at the area of the village Horní Beřkovice with regard to the observed drugs or their residues in surface and ground waters. I have compared the results with data from the sewage treatment plants in the river basin of Želivka. Keywords: ground water, surface water, sewage treatment plant, drugs, contamination

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Botany and Ecology Candidate: Tereza Olivová Supervisor: RNDr. Jitka Vytlačilová, Ph.D Title of diploma thesis: The occurrence of pharmaceuticals in the environment II. Pharmaceuticals are biologically active substances used for treatment or prevention of human and animal diseases. Some of these substances remain active even after being excreted from an organism and they can enter the environment. The residues of pharmaceuticals are present not only in rivers, but also in sea, groundwater and in soil, into which the contaminated water and manure are applied. The concentration of pharmaceuticals in water and in soil differ from place to place (it is higher e. g. in close proximity of sewage treatment plants) and from season to season (it depends on levels of precipitations and sunshine). Nowadays, thanks to sensitive analytical methods it is not a problem to detect these xenobiotics even in very small amounts, in which they usually occur in nature (usually in order of units or tens of ng/l or ng/g). However, even these low concentrations might have a negative impact on the life of non-target organisms (e. g. reproduction disorders) and therefore, the calculations, which measure the lever of risk of particular...

BACKGROUND AND OBJECTIVES: Standard meta-analysis compares two treatments whereas network meta-analysis compares multiple treatments. In light of the increasing number of treatments available, we have seen a shift from using standard meta-analysis towards using network meta-analyses to support regulatory and reimbursement decisions. This thesis (composed of nine separate papers) applied network meta-analysis to a series of real world problems which simultaneously addressed many of these methodological issues while also supporting healthcare decision making. METHODS: In the first chapter, background information on network meta-analysis and outline the rationale for each of the subsequent chapters is provided. In Chapter 2, an applied example is presented where we use FDA Public Summary documents to populate a network meta-analysis of antithrombotic therapies for atrial fibrillation. In Chapter 3, the advantages and disadvantages of rapid network meta-analysis using ClinicalTrials.gov are investigated by re-doing Chapter 3 but only using data available in ClinicalTrials.gov and examining concordance. In Chapter 4, the application of network meta-analysis when events are rare are investigated using an illustrative example investigating the risk of serious infection in biologics. In Chapter 5, the application of network meta-analysis to a complex network – triptans for migraine – are presented where there are a large number of studies and treatments. In Chapter 6 a network meta-analysis which assesses both a benefit and harm and integrates findings using a benefit harm methodology is presented. In Chapter 7, methods to incorporate non-randomized studies into network meta-analysis are investigated using data on riskof myocardial infarction derived from the Mini-Sentinel distributed data network. FINDINGS AND CONCLUSION: Pragmatic research around methodological areas in network meta-analysis were conducted to address real world problems for decision makers. It is my hope that this thesis and the approaches used in this thesis for the application of network meta-analysis will be disseminated to enhance research capacity in conducting network meta-analysis in Canada.

The trade-off between innovation and access is a critical problem in pharmaceutical innovation policy. Without adequate intellectual property protection, knowledge is insufficiently appropriable and the output of innovation is sub-optimal. Patents and sui generis forms of intellectual property are policies utilized by the state to foster innovation, creating temporary monopolies for firms to reward their investments in research and development. This paper explores the topic of pharmaceutical innovation policy by discovering the key legal developments that influence the creation of internationally protected and harmonized minimum standards of IP rights. Equipped with a theoretical understanding of IP as a social contract and knowledge about incentives that the law provides, the status quo system of rewarding pharmaceutical innovation is observed though an analysis of the market for new chemical entities, developing an understanding of the relationship between incentives for innovation and market outcomes. Utilizing an extensive analysis of literature, promising policy options are explored for realigning incentives to better optimize the incremental benefits of pharmaceutical innovation while improving access, including public funding of clinical trials, incorporating value-for-money stipulations into reimbursement and marketing approval decisions, and creating prize-based rewards that delink the market for innovations from the market for pharmaceutical products.