Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Lucie Hlinková Supervisor: Prof. MUDr. Radomír Hrdina, CSc. Title of diploma thesis: Treatment of schizophrenia Schizophrenia is a serious mental disease, mostly chronic. It affects about 1 % of population, first episode of the disease occurs mostly between the age of 15 and 35. It manifests itself with disorders of perception, behavior and thinking. The specific symptoms include hallucinations, delusions, disorganized speech and behavior, catatonia, disorders of attention and volition and social withdrawal. Etiopathogenesis of schizophrenia is likely affected by both genetic and environmental factors, the true cause of the disease has not been discovered yet. The goal of the treatment is to improve the patient's quality of life and prevent the occurrence of relapses. Drugs acting on the dopaminergic system are effective in the treatment of schizophrenia, where as antagonists bind to the dopamine receptors. These medicines are called antipsychotics, they are divided into two generations. The first generation is characterized by high affinity mainly for dopamine receptors, the second one in addition by binding to serotonin receptors. Each class of antipsychotics is characterized by the...

Azole-resistance in Candida albicans is becoming common and is associated with the widespread prophylactic use of azoles. Resistance to one azole is usually associated with resistance to other structurally dissimilar azoles. C.albicans is also inherently resistant to a wide range of eukaryotic inhibitors such as cycloheximide and gentamycin. Certain studies have shown that azole-resistance in some strains of C.albicans is associated with alterations in the cell membrane. This project has sought to determine whether azole-resistance in C.albicans strain 3302 was due, at least in part, to a multidrug resistance mechanism. An assay was developed using the fluorescent dye Rh123 to measure P-glycoprotein like activity. Active efflux of Rh123 has been shown to correlate with P-glycoprotein activity in a number of organisms. Results from this assay suggest that an energy-dependent efflux mechanism for Rh123 is present in azole-resistant strain 3302 but not in azole-sensitive strain 3153. The P-glycoprotein inhibitor, reserpine, inhibited Rh123 efflux. However, azoles did not appear to compete with Rh123 for efflux in the azole-resistant strain 3302, suggesting that azole-resistance in this strain is not mediated by a P-glycoprotein like mechanism. Southern analysis showed that sequences homologous to MDR genes existed in C.albicans. A PCR strategy was used to clone gene fragments containing the Walker motif which is found in MDR genes.

LD2668 .T4 1949 W7 / Master of Science

D.Tech. (Biomedical Technology) / Photodynamic therapy (PDT) is an alternative treatment modality for malignant tumours based on the photodamage to tumour cells through a photochemical reaction (Ahn et al., 2013). PDT utilizes a light sensitive photosensitizer (PS) that selectively localizes in tumour cells and is excited by light of a specific wavelength in the presence of molecular oxygen. The excited PS leads to the generation of singlet oxygen or other reactive oxygen species(ROS) which induces cytotoxic damage to cellular organelles and eventually cell death. Singlet oxygen has a very short life and its generation is controlled by the presence of the PS and the laser light (Senge and Radomski, 2013).The subcellular localization site of the PS plays a vital role in determining the effectiveness and the extent of cellular damage as well as the mechanism involved in cell death. Lung cancer is the leading cause of cancer death worldwide in both males and females, with an estimated 1.4 million deaths each year (American Cancer Society, 2011). Therapeutic modalities used in the treatment of lung cancer such as chemotherapy, radiotherapy and immunotherapy have rarely yielded a good prognosis and effective treatment remains a challenging problem to date. An alternative treatment modality with minimal complications such as PDT needs to be explored. Most in vitro PDT experiments are conducted on monolayer cultures and the cellular environment of these cultures does not correspond to that of in vivo studies. Multicellular tumour spheroids (MCTSs) serves as an important model in cancer research for the evaluation of therapeutic interventions since they mimic different aspects of the human tumour tissue environment.

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A Research Report submitted to the Faculty of Science in partial fulfilment of the requirements for the degree of Master of Science. 26 October 2016. / The cost of healthcare has become generally expensive the world over, of which the greater part of the money is spent buying drugs. In order to reduce the cost of drugs, drug manufacturers came up with the idea of manufacturing generic drugs, which cost less as compared to brand name drugs. The challenge which arose was how safe, effective and efficient the generic drugs are compared to the brand name drugs, if people were to buy them. As a consequence of this challenge, bioequivalence studies evolved, being statistical procedures for comparing whether the generic and brand name drugs are similar in treating patients for various diseases. This study was undertaken to show the existence of bioequivalence in drugs. Bioavailability is considered in generic drugs to ensure that it is more or less the same as that of the original drugs by using statistical tests. The United States of America’s Food and Agricultural Department took a lead in the research on coming up with statistical methods for certifying generic drugs as bioequivalent to brand name drugs. Pharmacokinetic parameters are obtained from blood samples after dosing study subjects with generic and brand name drugs. The design for analysis in this research report will be a 2 2 crossover design. Average, population and individual bioequivalence is checked from pharmacokinetic parameters to ascertain as to whether drugs are bioequivalent or not. Statistical procedures used include confidence intervals, interval hypothesis tests using parametric as well as nonparametric statistical methods. On presenting results to conclude that drugs are bioequivalent or not, in addition to hypothesis tests and confidence intervals, which indicates whether there is a difference or not, effect sizes will also be reported. If ever there is a difference between generic and brand name drugs, effect sizes then quantify the magnitude of the difference. KEY WORDS: bioequivalence, bioavailability, generic (test) drugs, brand name (reference) drugs, average bioequivalence, population bioequivalence, individual bioequivalence, pharmacokinetic parameters, therapeutic window, pharmaceutical equivalence, confidence intervals, hypothesis tests, effect sizes. / TG2016

Faculty of Health Sciencs School of Public Health 961299p muzi@hst.org.za / Most leading causes of death and disability in developing countries can be prevented, treated, or at least alleviated with cost effective essential drugs. However, hundreds of millions of people do not have regular access to essential drugs despite the fact that essential drugs can prevent many deaths. The aim of this study was to determine factors associated with essential drugs shortages in Primary Health Care (PHC) facilities (i.e. clinics and community health centres) in Mopani District in the Limpopo Province. Forty-five facilities were selected by means of stratified (by sub-district) random sampling. Forty-five professional nurses, who were in charge of the facility on the day of the interviews, were interviewed. A structured questionnaire was used for the data collection. Six pharmacists, from the six hospitals that supply drugs to the PHC facilities, were interviewed using a structured questionnaire. A one-on-one informal interview was held with 2 Hospital Superintendents and the Acting Provincial Chief Pharmaceutical Director. The study was both a retrospective and prospective observational study based on review of historical data, interviews with key players and direct observation of current practice. The tools used to collect and analyse the data were based on those developed by the World Health Organisation (WHO) and the Health Systems Trust (HST) with some adjustments and adaptation. The District STI Quality of Care (DISCA) Tool was used in the other thirty-six facilities, at which the structured questionnaire was not administered, to test prescribing indicators in relation to diagnosis, the correctness of and dosage of drugs dispensed and also drugs availability.

Thesis (Ph. D.), Faculty of Health Sciences, University of the Witwatersrand, 2009 / With the high prevalence and high mortality rate of cancer in the global community, it is increasingly essential to accelerate our understanding of the disease, to identify new genetic targets for therapy, and to pursue avenues for improving on the therapies in development and in current use. The aim of this study is to identify cell cycle-related genes whose expression is influenced by the chemotherapeutic drugs curcumin, SAHA, lycopene and thalidomide in breast and colon cancer and normal cell lines. These drugs are currently not in clinical use for cancer in South Africa, and while there have been investigative studies of these chemotherapeutic agents, this study aims to identify the specific genes that are influenced by the drugs. The result of this is that several genes that were not previously documented as targets of these drugs are highlighted. The cell cycle pathway is the area of focus as loss of regulation in the cell cycle is one of the important factors involved in promoting cancer initiation and progression. In the first instance, flow cytometry was used to identify optimal drug concentrations relative to the cell cycle stages. Following this, alterations in gene expression were assessed using a PCR-based differential display after each drug treatment. Subsequently, a more focussed approach was taken in a PCR-array analysis of panels of cell cyclerelated genes. A subset of genes is identified that is implicated in oncogenic transformation in breast cancer. This has the potential to inhibit the genetic pathways involved in breast malignancy by providing targets that perhaps may not be manipulated in current therapies. The gene expression studies here suggest that lycopene and thalidomide function in inhibiting this transformation, and play significant roles in suppressing the oncogenic state of breast cancer. Curcumin and SAHA also exhibit important functions in inhibiting tumourigenesis in colon cancer. While the results propose that the drugs have clear roles in inhibiting breast and colon cancer, they are also implicated in promoting cancer. This research has defined the genes that must be carefully monitored during drug administering as they may promote these and other cancers. The availability of these results to researchers will aid in selecting the criteria for assessing the success rate of these drugs.

Thesis advisor: Tracy Regan / This study analyzes the response of pharmaceutical firms’ stock prices to the release of information regarding successful Phase III clinical studies and final FDA marketing approval. I employ an event study methodology to show that positive abnormal returns occur at these drug development stages, and that larger abnormal returns occur over a three-day window surrounding a sample of successful Phase III trial announcements in comparison to a sample of FDA approval announcements. To my knowledge, all previous literature of this kind has compared a random sample of firms making Phase III announcements to a random sample of FDA approval announcements. This study advances drug development literature by conducting a second set of event studies that compares the abnormal returns of the same drugs at the two drug development stages, and it finds that controlling for the unique characteristics of the drugs analyzed in event studies leads to a smaller difference in returns at the two drug development stages. The drugs selected for analysis were taken from IMS Health’s lists of the top 100 (or 200) best-selling pharmaceuticals from 2003 to 2010. They were split into 13 therapeutic classes, such as drugs for cardiovascular ailments and drugs for respiratory ailments. Regression analysis was conducted on the returns of the three-day window to find a positive relationship between the FDA approval of alimentary and cardiovascular drugs and stock price increases for larger pharmaceutical firms and the approval of nervous system drugs and stock price increases for smaller pharmaceutical firms. To my knowledge, this is the first study to show these relationships. / Thesis (BA) — Boston College, 2015. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Departmental Honors. / Discipline: Economics.

A three-part project was devised to investigate the origins of and potential methods to reduce the risk of occupational exposure to cytotoxic drugs. The first phase involved researching the current decontamination methods applied in UK hospital pharmacies, which manipulate cytotoxic drugs. The second phase evaluated practical decontamination methods, and the third phase investigated one intervention aimed at reducing or preventing contamination occurring in an isolator. A questionnaire was sent out to ASU managers in NHS hospital pharmacies to gain information about the disinfection and decontamination procedures and products used. The practical decontamination methods investigated were mechanical removal and degradation by detergents (pH range from 1.7 - 13.2) and cleaning agents, and degradation by vaporised hydrogen peroxide. Analytical methods were developed and validated to recover and quantify the amount of cytotoxic marker drug remaining after the decontamination tests carried out in phase two, and to recover and quantify cytotoxic surface contamination from various surfaces in phase three of this work. This composed an attempt to evaluate the effectiveness of a closed-system e.g. PhaSeal® device for fluid-transfer, in reducing contamination produced from the compounding of cytotoxic drugs in an isolator. The detergents and cleaning agents were effective in removing or reducing cytotoxic surface contamination. Alkaline detergents caused degradation of doxorubicin (maximum 81% at pH 13.2 after 1 hour exposure); the other detergents tested did not xi x degrade the cytotoxic drugs investigated. Exposure to vaporised hydrogen peroxide (1.6g min-1 for 2 hours) caused the degradation of cyclophosphamide (98.9%), 5-Fluorouracil (29.3%), doxorubicin (71.0%) and epirubicin (65.9%) when exposed in pharmaceutical diluents. The closed-system (PhaSeal®) device was effective in reducing contamination produced in an isolator from the compounding of cytotoxic drugs. The risk posed by handling and manipulation of cytotoxic drugs and products to the operator and the environment may be reduced, if not eliminated by considering additional approaches to the methods already in place. Firstly, the application of effective decontamination methods; and secondly, by using an effective closed-system, for example the PhaSeal® drug transfer device in a controlled environment.