Charles University, Faculty of Pharmacy in Hradci Králové Department of: Social and Clinical Pharmacy Author: Roman Vorel Supervisor: PharmDr. Jan Kostřiba, Ph.D. Title of Diploma Thesis: Pharmacovigilance of active substance zolpidem Introduction: Drug safety became very important topic in the second half of 20th century, even beyond pharmacy. It relates to increasing impact on testing of drugs before launch onto the market, but also following monitoring, so the benefit and risk ratio of drug can be determined. Pharmacovigilance takes care of monitoring of drug use risk. Zolpidem is active substance from class hypnotics and it is used for short-term treatment of insomnia. Most professionals recommend zolpidem as first line treatment of acute insomnia. That is why it can be considered as one of the most important hypnotic drugs. Objectives: The aim of this diploma thesis is to analyze spontaneous reports for adverse drug reaction for zolpidem from years 2004 to 2017. The thesis focus on reports from the Czech republic but also from the whole world. The information in SPC of medicinal products containing zolpidem which were distributed from 2004 to 2017 are compared. Methods: Following data from years 2004 to 2017 were used: 1) List of spontaneous reports for adverse reaction from the Czech republic...

Traditional medicines (TM) have been used for centuries to treat illnesses, but in many cases their modes-of-action (MOAs) remain unclear. Given the increasing data of chemical ingredients of traditional medicines and the availability of large-scale bioactivity data linking chemical structures to activities against protein targets, we are now in a position to propose computational hypotheses for the MOAs using in silico target prediction. The MOAs were established from supporting literature. The in silico target prediction, which is based on the “Molecular Similarity Principle”, was modelled via two models: a Naïve Bayes Classifier and a Random Forest Classifier. Chapter 2 discovered the relationship of 46 traditional Chinese medicine (TCM) therapeutic action subclasses by mapping them into a dendrogram using the predicted targets. Overall, the most frequent top three enriched targets/pathways were immune-related targets such as tyrosine-protein phosphatase non-receptor type 2 (PTPN2) and digestive system such as mineral absorption. Two major protein families, G-protein coupled receptor (GPCR), and protein kinase family contributed to the diversity of the bioactivity space, while digestive system was consistently annotated pathway motif. Chapter 3 compared the chemical and bioactivity space of 97 anti-cancer plants’ compounds of TCM, Ayurveda and Malay traditional medicine. The comparison of the chemical space revealed that benzene, anthraquinone, flavone, sterol, pentacyclic triterpene and cyclohexene were the most frequent scaffolds in those TM. The annotation of the bioactivity space with target classes showed that kinase class was the most significant target class for all groups. From a phylogenetic tree of the anti-cancer plants, only eight pairs of plants were phylogenetically related at either genus, family or order level. Chapter 4 evaluated synergy score of pairwise compound combination of Shexiang Baoxin Pill (SBP), a TCM formulation for myocardial infarction. The score was measured from the topological properties, pathway dissimilarity and mean distance of all the predicted targets of a combination on a representative network of the disease. The method found four synergistic combinations, ginsenoside Rb3 and cholic acid, ginsenoside Rb2 and ginsenoside Rb3, ginsenoside Rb3 and 11-hydroxyprogesterone and ginsenoside Rb2 and ginsenoside Rd agreed with the experimental results. The modulation of androgen receptor, epidermal growth factor and caspases were proposed for the synergistic actions. Altogether, in silico target prediction was able to discover the bioactivity space of different TMs and elucidate the MOA of multiple formulations and two major health concerns: cancer and myocardial infarction. Hence, understanding the MOA of the traditional medicine could be beneficial in providing testable hypotheses to guide towards finding new molecular entities.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Os crescentes investimentos na aquisiÃÃo de medicamentos nÃo tÃm manifestado melhorias significativas nos indicadores de saÃde e no Ãmbito da AssistÃncia FarmacÃutica (AF). Suprir as necessidades da populaÃÃo e garantir o acesso aos medicamentos com equidade e eficiÃncia tem sido um grande desafio para as autoridades sanitÃrias. O presente trabalho partiu da necessidade de um diagnÃstico da alocaÃÃo de recursos destinados a AF nas Ãreas administrativas de Fortaleza e suas Unidades de SaÃde (US). Trata-se de uma anÃlise retrospectiva de base de dados com caracterÃsticas de estudo ecolÃgico, descritivo onde foram pesquisados os dados secundÃrios de aquisiÃÃo e distribuiÃÃo de medicamentos entre Janeiro - Dezembro de 2007, nas US operantes no municÃpio. Teve como objetivo principal conhecer a distribuiÃÃo dos gastos com medicamentos em AtenÃÃo PrimÃria de SaÃde (APS) de Fortaleza-Ce entre as regionais e suas US e analisar os fatores associados. Para tal, caracterizou-se os gastos com medicamentos por nÃmero de atendimento em cada US, classificou-se segundo a ATC e dimensionou-se o consumo em DDD, sendo correlacionados com as caracterÃsticas do serviÃo por anÃlise de correlaÃÃo de Pearson e Teste t-student para identificaÃÃo de co-fatores influentes. O gasto total com medicamentos bÃsicos estimado foi de R$ 9,29 milhÃes sendo o gasto per capita de R$3,82 e o gasto por paciente atendido de R$2,41. O perÃodo do ano que mais se gastou com medicamentos foi no 2 trimestre (28,36%) sendo 9,57% no mÃs de Abril e 10,46% em Junho. A regiÃo que deteve o maior gasto foi a Regional II (R$2.216.886,94) que possui um alto Ãndice de Desenvolvimento Humano (IDH). O gasto mÃdio por paciente foi maior na Regional V (R$2,82) onde està concentrada a populaÃÃo com menor renda e Baixo IDH. As classes terapÃuticas com maior representatividade foram os antibacterianos sistÃmicos (18,8% do total dos gastos; representados principalmente pelos beta-lactÃmicos, penicilinas), seguido por antidiabÃticos (9,4% hipoglicemiantes orais) e antihipertensivos com aÃÃo no sistema renina-angiotensina (8,6% sendo 8,2% somente com captopril). Os medicamentos mais consumidos foram: Captopril (17,2DDDs/1,000 pacientes atendidos/dia), Hidroclorotiazida (11,9) e Ãcido acetilsalicÃlico (7,9). Os AntiasmÃticos representaram os mais caros (preÃo unitÃrio R$20,66 para Beclometasona 250mcg, R$18,36 Beclometasona 50mcg e Salbutamol 100mg R$8,57) entretanto na relaÃÃo gasto/DDD os mais custosos foram: Fenoterol 0,5% (R$ 11,88), penicilina benzatina 600.000UI (R$ 6,59) e noretisterona 0,35mg (R$ 5,03). A qualidade da AF nÃo mostrou associaÃÃo estatisticamente significante com os gastos com medicamentos, porÃm apresentou uma correlaÃÃo inversa (r= -0,110) com tendÃncia a reduÃÃo de gastos, a presenÃa do FarmacÃutico na US apresentou associaÃÃo positiva significativa com a qualidade da AF (p-value= 0,014) e exerce um impacto econÃmico nos gastos com medicamentos com potencial economia de R$0,32 em mÃdia por paciente. Conclui-se que apesar dos esforÃos da descentralizaÃÃo ainda verifica-se a inequidade na ponta do SUS, onde na regiÃo de classe mÃdia alta houve maior alocaÃÃo de recurso referente aos medicamentos e nas regiÃes mais carentes da cidade se concentra o maior volume de pacientes atendidos. Os gastos per capita com medicamentos bÃsicos na APS de Fortaleza e o gasto por paciente atendido nÃo condizem com os valores pactuados pelas esferas gestoras (R$ 6,20). Recomenda-se a presenÃa do FarmacÃutico nas US visando a racionalizaÃÃo dos gastos e consumo de medicamentos contribuindo para uma AF de qualidade e eficiente em Fortaleza. / The increased investment in the acquisition of drugs have shown significant improvements in health indicators and in the Pharmaceutical Assistance (P.A.). Addressing the needs of the population and ensure access to medicines with equity and efficiency has been a major challenge for health authorities. This work started from the need for a diagnosis of resource allocation for P.A. in the administrative areas of Fortaleza and its Health Units (H.U). This is a retrospective analysis of the database with features of ecological and descriptive study where we examined the secondary data acquisition and distribution of drugs between January - December 2007, the H.U. operating in the municipality. The main goal was to determine the distribution of drug costs in Primary Health Care (PHC) in Fortaleza, Brazil between the H.U. and its regional and analyze the associated factors. To this end, characterized the cost of medication by number of patients in each H.U., it was classified according to ATC and scaled up consumption in DDD have been correlated with the characteristics of the service by examining the Pearson correlation test and t - student to identify co-influencing factors. Total expenditure on essential drugs was estimated at R$9.29 million and the per capita expenditure of R$3.82 and spending per patient from R$2,41. The period of the year that more was spent on drugs was in the 2nd quarter (28,36%) and 9,57% in April and 10,46% in June. The region had the highest spending was the Region II (R$ 2.216.886,94) that has a high Human Development Index (HDI). The average cost per patient was highest in Region V (R$2.82) which is concentrated the population with lower income and low HDI. The therapeutic classes with the highest representation were systemic antibiotics (18,8% of total spending, represented mainly by beta-lactam antibiotics, penicillins), followed by antidiabetics (9.4% oral hypoglycemic agents) and with antihypertensive action on the renin-angiotensin (8,6% and 8,2% only with captopril). The most frequently consumed drugs were: captopril (17,2 DDDs / 1,000 patients seen per day), hydrochlorothiazide (11,9) and aspirin (7,9). The Antiasthmatic represented the most expensive (unit price R$20,66 for Beclometasone 250mcg, R$18,36 Beclomethasone 50mcg and Salbutamol 100mg R$8.57) though the relationship cost / DDD were the most costly: Fenoterol 0.5% (R$11,88), penicillin 600.000 UI (R$6.59) and norethisterone 0.35 mg (R$5,03). The quality of P.A. showed no statistically significant association with the cost of medication, but had an inverse correlation (r = -0,110) with a tendency to reduce spending, the presence of the Pharmacist in the H.U. showed a significant positive correlation with the quality of P.A. (p -value = 0,014) and has an economic impact in spending on drugs with potential savings of R$ 0,32 on average per patient. We conclude that despite the efforts of decentralization still there is inequity in the tip of the Public Health System, which in the upper middle class there was a higher resource allocation relating to medicinal products and in the poorest regions of the city with the highest volume of patients served. Per capita spending on essential drugs in PHC Fortaleza and spending per patient are not consistent with the values agreed upon by management levels (R$6.20). It is recommended that the presence of the Pharmacist in the H.U. aimed at rationalizing spending and consumption of drugs contributing to P.A. quality and efficient in Fortaleza.

Submitted by Biblioteca da Faculdade de Farmácia (bff@ndc.uff.br) on 2017-03-21T17:23:01Z No. of bitstreams: 1 Nunes, Francine Sueth [Dissertação, 2015].pdf: 3994615 bytes, checksum: 4628c5fb64d2724c0b476de6f342d56e (MD5) / Made available in DSpace on 2017-03-21T17:23:02Z (GMT). No. of bitstreams: 1 Nunes, Francine Sueth [Dissertação, 2015].pdf: 3994615 bytes, checksum: 4628c5fb64d2724c0b476de6f342d56e (MD5) / O processo de seleção de medicamentos envolve uma fase de preparação, com a constituição de um grupo multidisciplinar denominado genericamente Comissão de Farmácia e Terapêutica (CFT), uma etapa de escolha propriamente dita dos itens que irão compor a lista do formulário do hospital e o monitoramento dos resultados alcançados. A qualidade do processo está atrelada à composição da comissão e ao seu funcionamento. Dada a diversidade de competências exigidas, o grupo deve ser composto por diferentes categorias profissionais, como médicos, farmacêuticos e enfermeiros. Assim sendo, a presente dissertação tem por objetivo descrever a incorporação de medicamentos em um Hospital Universitário de alta complexidade. Como metodologia foi utilizada análise dos documentos gerados pela CFT, a fim de descrever seu funcionamento; e foi proposto um novo fluxo de tramitação das solicitações, englobando os diversos atores envolvidos à luz do referencial teórico. Do total de 61 solicitações, 24 (39,35%) não foram adicionados e 37 (60,65%) adicionadas sendo 2 (5,40%) como equivalente terapêutico, 31 (83,79%) aprovado com restrição simples, 4 (10,81%) sem restrição. O estudo aponta a necessidade de adequação do funcionamento e padronização de condutas da comissão no hospital, não apenas para a otimização dos gastos com medicamentos, de forma planejada e eficiente, como também para a criação de diretrizes, protocolos e parâmetros para que estes possam oferecer maior segurança / The process of selection of drugs involves a preparatory phase, with the establishment of a multidisciplinary group called generically Pharmacy and Therapeutics Committee (CFT), a choice stage itself of the items that make up the hospital formulary list and monitoring the results achieved. The quality of the process is related to the composition of the committee and its functioning. Considering the diversity of skills required, the group should be composed of different professional groups such as doctors, pharmacists and nurses. Therefore, this dissertation aims to describe the incorporation of drugs in a university hospital of high complexity. The methodology used was analysis of documents generated by the CFT in order to describe its operation; and proposed a new processing flow of requests, covering the various actors involved in the light of the theoretical framework. Of the 61 requests, 24 (39.35%) were not added and 37 (60.65%) being added 2 (5.40%) as a therapeutic equivalent, 31 (83.79%) with simple restriction, 4 (10.81%) without restriction. The study points to the need for adequate functioning and standardization of the committee conducts the hospital, not only for the optimization of drug spending in a planned and efficiently, but also to the creation of guidelines, protocols and parameters so that they can offer greater security

No description available.

La prise de conscience de l’implication des médicaments dans la genèse des accidents de la route date d’une vingtaine d’années. Les médicaments psycho-actifs peuvent altérer les capacités de conduite par leur action sur le système nerveux (par exemple, un effet sédatif le lendemain d’une prise d’hypnotique). D’autres médicaments sont susceptibles d’affecter les fonctions psychomotrices par leur action sur les fonctions physiologiques (tel que les hypoglycémies liées à un traitement antidiabétique). L’étude CESIR-A a été mise en place pour contribuer à la connaissance du lien épidémiologique entre médicaments et accidents de la route. L’étude utilise trois bases de données françaises : le Système National d’Information Inter-Régimes de l’Assurance Maladie (SNIIR-AM), les Procès Verbaux d’accidents (PV) et les Bulletins d’Analyse des Accidents Corporels de la circulation (BAAC). L’appariement de ces données a conduit à l’inclusion de 72,685 conducteurs impliqués dans un accident corporel sur la période juillet 2005-mai 2008. L’analyse a été réalisée grâce à deux méthodes: une analyse cas-témoin comparant les responsables aux non-responsables des accidents et une analyse dite en case-crossover. Les périodes d’exposition aux médicaments ont été estimées à partir des dates de délivrances de médicaments prescrits, puis remboursés par l’assurance maladie. L’étude des médicaments regroupés selon les quatre niveaux de risque sur la conduite définis par l’Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSAPS) [du niveau 0 (pas de risque) au niveau 3 (risque élevé)], a montré que les utilisateurs de médicaments prescrits de niveau 2 et de niveau 3 ont un risque significativement plus élevé d’être responsables de leur accident (OR=1,31 [1,24-1,40] et OR=1,25 [1,12-1,40], respectivement). La fraction de risque attribuable à l’utilisation de ces médicaments était de 3,3% [2,7%-3,9%]. Le risque d’être responsable d’un accident était augmenté chez les utilisateurs de zolpidem (OR=1,28 [1,07-1,53]) mais pas chez les utilisateurs de zopiclone ou de benzodiazépines hypnotiques. Plus particulièrement, ce risque était augmenté chez les 139 conducteurs ayant eu plus d’un comprimé de zolpidem délivré par jour au cours des cinq mois précédant l’accident (OR=2,38 [1,61-3,52]). L’analyse case-crossover a mis en évidence un sur-risque d’accident de la route chez les utilisateurs de benzodiazépines hypnotiques seulement (OR=1,42 [1,09-1,85]). Les conducteurs exposés aux hypnotiques partagent les mêmes caractéristiques au regard du type d’accident, qui survenaient plus fréquemment sur autoroute. Dans notre base de données, 196 conducteurs ont été exposés à la buprénorphine et/ou à la méthadone, le jour de leur accident. Cette population spécifique était jeune, essentiellement masculine, avec d’importantes co-consommations, notamment d’alcool de médicaments de niveau 3. Les conducteurs exposés à la buprénorphine et/ou à la méthadone présentaient un risque accru d’être responsables de leur accident (OR= 2,19 [1,51-3,16]). Notre étude fournit des informations importantes sur la contribution des médicaments au risque d’accident de la route. D’après nos résultats, la classification de l’AFSSAPS semble appropriée concernant les médicaments de niveaux 2 et 3. Les sur-risques d’être responsable d’un accident chez les exposés au zolpidem ou aux traitements de substitution pourraient être liés, au moins en partie, au comportement à risque de ces conducteurs. L’amélioration du comportement des conducteurs représente un des défis pour la sécurité routière. L’objectif de la classification française et de la signalétique apposée sur les boîtes de médicaments est donc de fournir aux patients une information appropriée sur les effets des médicaments sur leur capacité de conduite. / In recent decades, attention has been increasingly focused on the impact of disabilities and medicinal drug use on road safety. Psychoactive medicines may impair driving abilities due to their action on the central nervous system (e.g. sedation in the morning following administration of a hypnotic), while other medicines may affect psychomotor functions by their action on physiological functions (e.g hypoglycaemic seizures related to diabetic treatment). The CESIR-A project was set up to improve the epidemiological knowledge on medicines and the risk of road traffic crashes. The study matched three French nationwide databases: the national healthcare insurance database, police reports, and the police national database of injurious crashes, leading to the inclusion of 72,685 drivers involved in an injurious road traffic crash from July 2005 to May 2008. Two methods were performed for data analysis: a case-control analysis in which cases where responsible drivers and controls non-responsible ones and a case-crossover analysis. Medicine exposures were estimated from prescription drug dispensations in the healthcare reimbursement database. The study of medicines grouped according to the four levels of driving impairment risk of the French classification system [from 0 (no risk) to 3 (high risk)], showed that users of level 2 and level 3 prescribed medicines were at higher risk of being responsible for the crash (OR=1.31 [1.24-1.40] and OR=1.25 [1.12-1.40], respectively). The fraction of road traffic crashes attributable to levels 2 and 3 medicines was 3.3% [2.7%-3.9%]. Zolpidem use was associated with an increased risk of being responsible for a road traffic crash (OR=1.28 [1.07-1.53]) whereas use of zopiclone and benzodiazepine hypnotics use was not. Responsibility risk was only increased in the 139 drivers with dispensing of more than one pill of zolpidem a day during the five months before the crash (OR=2.38 [1.61-3.52]). Case-crossover analysis showed an increased risk of crash for benzodiazepine hypnotic users only (OR=1.42 [1.09-1.85]). Hypnotic users shared similar crash characteristics, with crashes more likely to occur on highways. In our database, 196 drivers were exposed to buprenorphine and/or methadone on the day of crash. This specific population was young, essentially males, with important co-consumption of other substances, in particular alcohol and level 3 medicines. Injured drivers exposed to buprenorphine and/or methadone on the day of crash, had an increased risk of being responsible (OR=2.19 [1.51-3.16]). The case cross-over analysis did not demonstrate any association (OR=1.26 [0.93 - 1.70]). Our study provides evidence of the contribution of medicines to the risk of road traffic crashes. According to our results, the French risk classification seems relevant regarding medicines classified as levels 2 and 3 of risk for road traffic crashes. The observed increased risks of being responsible for a crash for zolpidem and substitution maintenance treatment users may be linked to risky behaviors. Improving driver behaviour is one of the challenges for road safety. Providing patients with proper information on the potential effect of medicines on their driving abilities is the main objective of drug and risk classifications such as the French one.

Magister Legum - LLM / The underlying rational behind the protection of intellectual property rights is to strike a balance between the interests of intellectual property rights holders on the one hand and users of protected knowledge on the other hand. This thesis sought to achieve the following objectives: to create a good understanding of the historical development of the primary and secondary legal instruments related to the intellectual property rights/public health debate; to determine to what extent a balance is struck by the Agreement on Trade Related Aspects of Intellectual Property Rights with reference to the flexibilities provided for in the Treaty, read together with the subsequent World Trade Organization Ministerial Declarations and TRIPS Council Decisions; to evaluate the extent to which selected developing and least developed country members of the World Trade Organization have taken measures to implement the said flexibilities, taking cognizance of their relevant strengths and weaknesses; to suggest ways in which select countries in the developing world specifically India and Zambia can take greater advantage of the flexibilities to promote better access to medicines which taking into consideration various opportunities and threats that are foreseeable; to identify public health aspects of TRIPS that the developing country and least developed countries World Trade Organization members would do well to address in further negotiations. / South Africa

Masters of Science / Problem and significance: Off-label use of medicines is not illegal; however, it can be risky and harmful, or beneficial and innovative. The main problem of this practice is the lack of systems for monitoring adverse drug reactions, since the drugs are used in a manner that is not approved by regulatory agencies. For this reason public health protection is not guaranteed. Purpose: To identify the various systems employed in different regions to monitor/manage the risks and benefits of off-label use; and to ascertain their extent of implementation. Method/search strategy: Electronic and manual literature search was done. Articles referring to off-label medicine use were reviewed. The literature included journal articles, national MRA guidelines, international guidelines, etc. The articles were sourced from databases such as Pubmed and Google Scholar. Data was collected from both developed and emerging markets. There was no limit to publication date. Findings: Pharmacovigilance systems for off-label use do exist although the degree of commitment and advancement differs per country. Explicit off-label laws are present in the developed countries but not in the developing ones. Implications of findings: Stakeholder involvement is very important in monitoring off-label use. Reporting of ADRs can be improved by asserting the role of off-label PV in drug repositioning. The regulator is under pressure to maintain public trust through efficient control of off-label use.

Magister Public Health - MPH / Background: South African medical scheme members needlessly purchase high cost originator prescription medicines which attract out of pocket co-payments at pharmacies. This is despite availability of low priced generic medicines that are paid for in full by medical schemes. Co-payments result from misalignment between prices of the dispensed medicine and that of the alternative medicine which appears on the medical scheme's formulary list and for which the scheme is prepared to pay for in full. To establish what factors caused such misalignment, perspectives of medical scheme members and key informants which included pharmacists, regulators and representatives of medical schemes were explored. The study focused on co-payments for prescription medicines dispensed at private sector retail pharmacies in Pretoria, South Africa. Aim: The aim of the study was to explore views about co-payments and identify factors that motivate and influence Pretoria medical scheme members to co-pay when purchasing prescription medicines at pharmacies, despite being insured by medical scheme insurance organizations. Methodology: An exploratory qualitative research study was performed. Semi-structured interviews were conducted among purposefully selected medical scheme members (12) and 9 key informants. Key informants consisted of dispensing pharmacists (6), regulators of health professionals and medical schemes (2) and a senior official (1) with experience in the regulation of medicines and operations within medical scheme organizations. From a total of twelve interviewed medical scheme members, eight were interviewed at preselected retail pharmacies after they had made a co-payment and the other four selected because they did not make a co-payment. To ensure diversity in views about co-payments and related factors, dispensing pharmacists, co-paying and non co-paying medical scheme members were accessed from six pharmacies that are located in two separate locations of different socioeconomic status in Pretoria, that is, the Pretoria East suburban area and Pretoria city centre which is close to Pretoria central station and taxi routes. Three pharmacies were identified from each of the two different geographical locations, one independent and two corporate pharmacies per socioeconomic area. One pharmacist was interviewed from each of the selected pharmacies and medical scheme members were accessed from across the six pharmacies. The remainder of the key informants such as the regulators, were interviewed during office hours at venues of their choice which included areas of work. A pilot study was conducted among medical scheme members and pharmacists to test the applicability of interview tools. All interviews were conducted face-to-face by the researcher and recorded. The electronic record was independently compared with the researcher's enhanced notes for data accuracy. Codes identified during data analysis were derived from the interview notes and recordings and translated into organized text for theme development in a manner that referenced them to each study objective. Themes were arrived at after combining similar codes which were noted as representing a particular description for use during data interpretation and report writing. Ethics: Ethical clearance was sought from the UWC Senate Research Committee and granted. Prior to conducting interviews, written consent was obtained from all participants. Research details were explained and also provided on the participant information sheet wherein voluntary participation was emphasized. Anonymity and confidentiality was maintained throughout. Results: All patients and pharmacists expressed confusion about the medical scheme rules and related co-payments. There were differing co-payment perspectives among scheme members depending on socioeconomic status, with affordability being a key factor among those of lower socio-economic status whilst convenience and lack of comprehensible information about co-payments was prioritised amongst those members of higher socioeconomic status. Key influences on patient's purchasing decisions were health professionals (both doctors and pharmacists), with friends, family members and advertisements less influential. Patients and medical schemes generally preferred to utilise large chain pharmacies and patients, in particular, had a poor perception of the quality of generics. In general, the first prescribed medicine was highly favoured by patients and this influenced medicine preferences during subsequent prescriptions, especially for non communicable disease (NCD) medicines. Pharmacists did not apply the generic substitution policy in a manner that benefited the consumer because the lowest priced generic was frequently not kept as pharmacy stock. Co-payments appeared to create a divide between corporate and independent pharmacies. Some regulators tended to blame patients, pharmacists and medical schemes rather than the lack of adequate enforcement of national policies and regulations. Inadequate monitoring and enforcement of pro-consumer policies were found to be the main factors that contributed to co-payments. Conclusions and Recommendations: The introduction of regulations on minimum requirements for stock available at private sector retail pharmacies should be considered to ensure availability of the lowest priced generic at all times. This would ensure that co-payments are reduced and the desired consumer benefits that should accrue from the existing generic substitution policy are realized and maximized. To prevent perception-based and self-initiated co-payment behavior among consumers, vigorous and continued education about the value and equivalence of generics should be championed at the highest level of government with the execution of this critical responsibility not left to those with profit driven motives. Consumers might benefit from extensive education about the purchasing choices made at pharmacies and, in particular, the negative financial consequences associated with choosing a preferred but highly priced originator versus a low cost generic medicine which is used to treat the same ailment. Enforcement of policies by dedicated government agencies could further protect consumers from preventable high cost of healthcare and of medicines in particular.

It is evident that herbal medicines continue to be the mainstay of healthcare systems and source of livelihoods of many local communities in South Africa and other developing countries. As a result, there is an overwhelming dependence on medicinal products harvested from natural populations. This dependence has led to local extinction of some important medicinal plants that include Warburgia salutaris and Cassine transvaalensis in South Africa. Cultivation has great potential to relieve the pressure on natural populations. However, some traditional practitioners and scientists believe that cultivation may weaken medicinal properties and that increased secondary metabolites may form only under stress conditions, respectively. This is certainly true in some cases especially where infections with pathogens, browsing by herbivores or competition takes place in nature. It is however not clear how true this is with environmental stresses. The overall aim of this study was to evaluate to what degree different environmental conditions influenced antimicrobial and antioxidant activities of plants cultivated outside their natural environment. In order to address the aim of the study, exploratory and in-depth studies were undertaken. The exploratory study comprised long-lived Combretum collinum Fresen. (Combretacea), Terminalia sericea Burch. ex DC. (Combretaceae) and Sclerocarya birrea (A. Rich.) Hochst. (Anacardiaceae). Short-lived herbaceous Tulbaghia violacea Harv. (Alliaceae) and Hypoxis hemerocallidea Fish, C.A.Mey,&Avé- Lall, (Hypoxidaceae), were included as part of the exploratory study. The in depth studies were further undertaken, also with short-lived herbaceous Leonotis dysophylla Benth. (Lamiaceae), Bulbine frutescens (L.) Willd. (Asphodelaceae) and T. violacea. Acetone leaf extracts of all plants were studied for antimicrobial activity against bacteria (Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Enterococcus faecalis) and fungi (Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus). Extracts were also studied for antioxidant activity against Trolox and L-ascorbic acid standard oxidants using 2,2’-azinobis-(3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS) and 2,2- diphenyl-2-picryl-hydrazyl (DPPH) free radicals, respectively. The exploratory study tested the effect of different rates of annual rainfall (≥870 mm/year, 651 mm/year and 484 mm/year) on the antibacterial activity of C. collinum, T. sericea and S. birrea growing in nature. The minimum inhibitory concentration (MIC) of acetone extracts of air-dried leaves was determined by using microplate serial dilution technique. Thin layer chromatography (TLC) and bioautography determined chemical constituents and antibacterial activity of extracts, respectively. The majority of extracts had low MIC values, which indicated good antibacterial activity against test bacteria (MIC of 240 μg/ml - 60 μg/ml). Leaf extracts of C. collinum and S. birrea against S. aureus (range of 390 – 100 μg/ml), E. coli (310 -70 μg/ml) and P. aeruginosa (520 - 70 μg/ml) had antibacterial activity increased significantly with low rate of annual rainfall. However, extracts of T. sericea against P. aeruginosa (240 - 100 μg/ml) and E. faecalis (150 - 820 μg/ml) had antibacterial activity significantly increased and decreased, respectively. Extracts of C. collinum and S. birrea against E. faecalis as well as T. sericea against S. aureus and E. coli did not show any clear correlation between activity and different rates of annual rainfall. Inconsistent results suggest that other factors in nature such as genetic variability, age difference, pathogens, herbivores or allelopathy (competition) might have influenced the antibacterial activity of extracts. The results indicate that the antimicrobial activity of plants growing in nature may be highly variable. In order to eliminate possible effect of those factors common in nature, another exploratory study was undertaken using clone T. violacea and H. hemerocallidea of similar age (Chapter 3). Plants were grown under controlled conditions that included irrigation with 1000 ml of distilled water in intervals of 3, 14 and 21 days outside natural environment. Dry mass of all plants was reduced significantly (P≤0.05) with watering interval of 21 days, which indicated the effect of water stress. Air-dried leaves of all plants were finely ground and extracted with acetone. Extracts had good antibacterial activity as attested by low MIC values (< 1 mg/ml) across watering intervals. Differences in the antibacterial activity of the extracts against test bacterial between water treatments were not statistically significant (P≤0.05). Furthermore, there was no clear correlation between the activity of extracts and water treatments in terms of the MIC and total activity values or chemical constituents. The results in general suggest that cultivation under optimal watering intervals may not necessarily weaken the biological activity of extracts. To complement the above findings, in depth studies were also undertaken with clone L. dysophylla, T. violaceae and B. frutescens of similar age growing under controlled conditions outside natural environment. The studies determined the influence of a wide range of water (50 ml – 500 ml) and temperature (15°C and 30°C) treatments on antibacterial, antifungal and antioxidant of extracts. With the exception of a crassulacean acid metabolism (CAM) plant, B. frutescens, transpiration, dry mass and leaf areas of the other two plants were reduced significantly (P 0.05) under high temperature of 30°C and lowest water supply of 50 ml. Acetone leaf extracts had some biological activity. Differences in the majority of antibacterial and antifungal activities of extracts between water and temperature treatments were not statistically significant. With the exception of the influence of temperature, the majority of the antioxidant activity of extracts was almost similar between water treatments. However, the significant reduction of the antioxidant activity of all extracts under high temperature of 30°C was indicative of great sensitivity to high temperatures. The overall findings suggest that the biological activity of plants is more likely to vary widely in nature than under controlled conditions outside the natural environment. This is an indication that natural environment cannot always guarantee high and stable biological activity. As a result, beliefs by some traditional practitioners and scientists that cultivation weakens medicinal properties and good secondary metabolites form only under stress, respectively, cannot be widely substantiated. Therefore, the study encourages cultivation of medicinal plants. It has potential to optimise yield of biomass production, and ensure uniform and quality biological activity as well as reduce misidentification. / Thesis (PhD)--University of Pretoria, 2012. / Paraclinical Sciences / unrestricted