The aim of this study was to evaluate seven GCC regulatory authorities and pharmaceutical companies active in the region in order to identify the strengths and weakness of the current GCC centralised procedure. The GCC regulatory authorities and the pharmaceutical companies who had registered their products through the GCC centralized registration procedure and the national registration systems were recruited into the study and asked to complete the questionnaires specifically designed for this study. The regulatory review process in Oman was evaluated to identify areas for improvement in the system. Information on the total application numbers and approval dates were obtained directly from the Oman Ministry of Health archives. Another study was conducted to evaluate the regulatory review process and approval times of the remaining six GCC countries (Bahrain, Kuwait, Qatar, Saudi Arabia, UAE and Yemen) and the GCC central registration, with respect to review time for new and existing substances, to identify the strengths and weaknesses of the process and to propose strategies that could help the policy maker in the GCC to enhance the review process. The results of the Omani regulatory system showed no significant increase (p>0.05) in the total number of registered pharmaceutical products from 2006 to 2010. The approval time in Oman showed that there was a significant increase in approval times for pharmaceutical products from 2006 to 2010 (p<0.001). The findings show that although there was an increase in the approval time for all pharmaceutical company products, the median approval time for the five year period was 117 days. This was within the time limit (4 months) fixed by the health authority for the overall registration time. The comparative study of the GCC States showed a downward trend in the median approval time for most of the GCC States, during 2008 to 2010. However, the approval time for all approved products in the GCC States during this period varied from 60 days in Qatar and Oman (2009 and 2010) to 609 days in Saudi Arabia (2008). The main reasons for the decrease in approval time in the Gulf States were due to the positive effect of the Gulf Central Registration, the rise in the number of reviewers in some GCC drug authorities, and the parallel procedure used in the regulatory approval review process. The study of the regulatory review process of the GCC central registration showed that a total of 413 products (96 NASs and 317 EASs) were approved during the period 2006-2010 with an overall significant increase in the EASs (p<0.001). The approval times increased from 107 calendar days in 2006 to 265 in 2010 (p<0.001). The lowest approval time was for EASs submitted by the Gulf companies (134 days) and the longest for NASs submitted by international companies (346 days) (p<0.001). VI Both the regulatory authorities and the pharmaceutical companies agreed that the centralised procedure is an effective system for authorising medicinal products in all seven GCC countries in one procedure and is the way forward in the future but there is room for improvement in the procedure and the follow ups. They also agreed that clear guidelines, transparency of procedures, effective interactions between authorities and companies, increase in the number of the committee meetings per year, use of electronic on-line submissions will improve approval time for registration of new medicines, enhance the quality of review practice and encourage the pharmaceutical companies to use the GCC central registration system. This research has enabled development of a new model of the GCC central registration procedure to be proposed for the GCC Health Authorities which could improve patient access to medicines in the GCC states.

This study aimed to evaluate the antimicrobial efficacy of medicinal hemp plant extracts to determine the antibacterial effects of indigenous Sansevieria species and exotic Cannabis sativa phytotherapy varieties. This study also assessed whether aqueous o

<p>Since Helichrysum is known by the indigenous people of Africa for therapeutic properties, such as against colds, flu and wounds, the aim of this study was to focus on the patulum species found predominantly in the Western Cape region of South Africa and by means of isolation and identification of the plant constituents, be able to relate the therapeutic activity on the basis of literature precedents, to the compounds extracted.</p>

<p>Leonotis leonorus and Mentha longifolia are two herbs commonly used in South Africa, mostly in oral liquid dosage forms. Several disadvantages are associated with these traditional dosage forms which can perhaps be remedied by using an appropriate oral solid dosage form, provided the actual plant material in the latter still resemble, as closely as possible, the traditionally used material and provide products of suitable pharmaceutical quality. The objectives of this study were to prepare and evaluate the pharmaceutical suitability of the freeze-dried aqueous extracts of Leonotis Leonorus and Mentha Longifolia as plant raw material for the capsule dosage of these two therapies and to formulate and manufacture capsules of Leonotis Leonorus and Mentha Longifolia aqueous extract that would contain amounts of the plant materials equivalent to that found in their traditional liquid dosage forms, and have immediate release characteristics and suitability stability.</p>

Anticipated Synchronization (AS) is a form of synchronization that occurs when a unidirectional influence is transmitted from an emitter to a receiver, but the receiver system leads the emitter in time. This counterintuitive phenomenon can be a stable solution of two dynamical systems coupled in a master-slave configuration when the slave is subject to a negative delayed self-feedback. Many examples of AS dynamics have been found in different systems, however, theoretical and experimental evidence for it in the brain has been lacking. In this thesis work we investigate the existence of AS in neuronal circuits when the delayed feedback is replaced by an inhibitory loop mediated by chemical synapses. At the neuronal level, we show the existence of AS in 3-neuron or 3-neuron-populations microcircuits, where the self-feedback is provided either by an interneuron or by a subpopulation of inhibitory neurons. A smooth transition from delayed synchronization (DS) to AS typically occurs when the inhibitory synaptic conductance is increased. The phenomenon is shown to be robust for a wide range of model parameters within a physiological range. The role of spiketiming- dependent plasticity in DS-AS transitions is also investigated. The results obtained from the model are compared with those obtained experimentally in monkeys performing certain cognitive tasks. In some cases a dominant directional influence from one cortical area to another is accompanied by either a negative or a positive time delay. We present a model for AS between two brain regions and compare its results to the experimental data, obtaining an excellent agreement. / La sincronización anticipada (SA) es una forma de sincronización que se produce cuando una influencia unidireccional se transmite desde un emisor a un receptor, pero el sistema receptor adelanta al emisor en el tiempo. Este fenómeno, contrario a la intuición, puede ser una solución estable de dos sistemas dinámicos acoplados en una configuración maestro – esclavo cuando el esclavo está sujeto a una retroalimentación negativa retardada. Hay muchos ejemplos de SA que se han encontrado en diferentes sistemas, sin embargo, no existe evidencia ni teórica ni experimental de que ocurra en el cerebro. En este trabajo de tesis se investiga la existencia la SA en circuitos neuronales cuando la realimentación retardada se sustituye por un bucle inhibitorio mediado por sinapsis químicas. A nivel neuronal, se muestra la existencia de SA en circuitos de 3 neuronas o 3 poblaciones de neuronas, donde la retroalimentación la proporciona una interneurona o una subpoblación de neuronas inhibitorias. Una transición de sincronización retrasada (SR) a SA se produce suavemente cuando se incrementa la conductancia sináptica inhibitoria. Se encuentra que el fenómeno es robusto para una amplio espectro de parámetros del modelo dentro del rango fisiológico. También se investiga el papel de la plasticidad neuronal en la transición SR-SA. Los resultados obtenidos a partir del modelo se comparan con los obtenidos experimentalmente en monos cuando realizan ciertas tareas cognitivas. En algunos casos, una influencia direccional dominante de un área cortical a otra se acompaña de un retardo que puede ser negativo o positivo. Se presenta un modelo para las relaciones entre dos regiones corticales del cerebro y se compararan los resultados numéricos con los datos experimentales, obteniendo un excelente acuerdo.

The work in this thesis had two main aims. The first aim was to study the use of a number of precipitation methods to control the size and morphology of precursor phosphor materials for potential applications in a new generation of high definition and field emission displays. The morphological and luminescent characteristics of these precursor phosphor materials were studied after they were annealed to form their respective luminescent oxides using electron microscopy and light measuring techniques. The first set of experiments presented describes the development of a range of spherical submicron europium-doped yttrium oxide phosphor particles and their optimisation for use in the aforementioned applications. A homogeneous precipitation technique exploiting a hydrothermal decomposition of urea that provides hydroxycarbonate phosphor precursor ligands is at the centre of this work. In the presence of rare earth element nitrates the hydroxycarbonate ligands form spherical phosphor precursor particles that after annealing yield the luminescent oxides. This is followed by the presentation of a novel synthetic method using a micellar phase of rare earth element chlorides, after annealing, yielding europium-doped yttrium oxide. This method produces a variety of morphologies with crystallites as small as a few nanometres and up to hundreds of nanometres. Next is described a new precipitation method using ammonia and carbon dioxide gases that are introduced in a controlled manner into a solution of rare earth element chlorides at room temperature. Rare earth element hydroxycarbonates rapidly precipitate upon supersaturation, yielding a range of morphologies and particles sizes. The second aim of the thesis was to prepare a novel range of three-dimensional photonic band gap materials composed of conventional phosphor materials.

The public international backlash against the TRIPS Agreement and the global pharmaceutical industry that followed in the wake of the March 2001 lawsuit brought by 39 pharmaceutical companies against the government of South Africa prompted a critical investigation into how the current order came into being and how it might be in a process of changing. To do this the thesis follows Cox’s insight in Critical IPE that each successive historical structure generates the contradictions and points of conflict that bring about its transformation (Cox, 1995: 35). The research therefore first looks at the making of the patent provisions in TRIPS as a case study in institutional capture by the transnational drug industry (TDI), dominated by American interests. This question is developed theoretically as well as empirically by first developing a theoretical framework that explains continuity in the global political economy (GPE) as a way of intimating how the TDI was able to secure all of its demands for pharmaceutical patents under TRIPS despite the prevalence of conflict and opposition from developing countries in the Uruguay Round (UR), and notwithstanding the single undertaking of the UR package. The thesis then examines the negotiations on patents in the UR to determine the nature of decision-making and to probe the questions of conflict and contradictions in the present that provide a framework of analysis on the shakiness of the prevailing order. The thesis then looks at how, why and under what circumstances the initial ‘capture’ of TRIPS by the TDI was arguably successfully challenged by probably the weakest global economic actor, the African Group (AG) at the WTO. Specifically looking at the role of conflict in change this question probes further points of conflict and contradictions in the present to set the scene for the wide scale offensive against TRIPS as a result of its implications for access to healthcare in the poorest countries which already suffer overwhelmingly from a high disease burden. The post-TRIPS challenge mounted by transnational civil society and the AG (the two constituting a counter-society) take the thesis from its analysis of continuity in the GPE, towards theorising the circumstances under which the prevailing historical structure can at least partially be transcended to render legitimate the demands of the poor. The thesis advances its contribution, both theoretically and empirically, to Critical International Political Economy, particularly as it concerns the work of Robert Cox.

Las plantas de uso medicinal son una respuesta del conocimiento ancestral para el tratamiento y/o cura de diversas enfermedades, que debe ser contrastado científicamente. Dicha investigación debe partir de la identificación botánica de los ejemplares utilizados por la población; asimismo, el conocimiento de sus metabolitos nos ayuda a explicar el o los principios activos implicados en la actividad atribuida a la planta. El material empleado en este estudio son tres helechos comercializados bajo el nombre común de “cuti cuti” en el mercado de plantas medicinales del distrito de La Victoria en Lima-Perú, cuya identidad taxonómica corresponde a las especies: Argyrochosma nivea (Poir.) Windham “cuti cuti hembra”, Cheilanthes pruinata Kaulf. “cuti cuti macho” y Cheilanthes scariosa (Sw.) C. Presl “cuti cuti”, los cuales son empleados en la medicina tradicional para tratar la diabetes. Se ha podido establecer características descriptivas que conlleva a la presentación de una clave que permite diferenciarlos. Se demuestra que los helechos llamados “cuti cuti” son de tres especies distintas. Se procedió a realizar ensayos de colorimetría y precipitación, a partir de extractos hidroalcohólicos resolubilizados en agua al 2%, encontrándose similitudes en los tres helechos respecto a la presencia de metabolitos.

In recent years the pharmaceutical industry has seen a rise in the number of drug compounds with low aqueous solubility, and consequently poor oral bioavailablility. One potential solution to this problem is to formulate such compounds as solid dispersions, whereby the drug is dispersed in a carrier matrix in the solid state. In this thesis, the hypothesis that a number of drug-drug and drug-polymer intermolecular interactions influence the physical stability and dissolution performance of solid dispersions is considered. The aim is to use correlations between drug molecular structure and solid dispersion performance to develop a platform to rapidly assess whether drug compounds will have favourable properties when formulated as a solid dispersion. Amorphous felodipine/copovidone solid dispersions are used as a model system to develop a suitable testing regime with regards to physical stability and dissolution performance. A laser light scattering technique developed in this work shows that morphological changes in felodipine/copovidone films exposed to water are due to polymer swelling. A combination of dissolution testing methodologies is also used to suggest a mechanism for the dissolution of bulk solid dispersion samples. Contributions of individual functional groups in the felodipine analogues to the physical stability and dissolution performance of their amorphous solid dispersions are assessed. Blocking of the felodipine amine hydrogen-bond-donor with an N-methyl, and the removal of chlorine substituents are both shown to reduce the physical stability of the solid dispersions. Correlations between molecular descriptors and data from the above experiments show that drug compounds are more likely to crystallise from solid dispersions with copovidone if they have a low log P, low relative molecular mass and low polarizability. Such correlations can form the basis of a screening method for the molecular design of analogous drug compounds likely to form high-performance solid dispersions with copovidone.

Mucosal delivery of biotherapeutics as a non-invasive means of delivery could potentially be enhanced using nanoscale therapeutic carriers. However, nanoparticles do not readily cross the mucosal barriers, with the epithelium severely restricting their translocation into the systemic circulation. Translocation of nanocarriers across the mucosae may be improved by employing ligands capable of exploiting receptor-mediated cell uptake processes. This work explores the potential of vitamin B12 transport pathway for mucosal delivery of B12-decorated model nanoparticles and investigates the cell trafficking pathways involved in these processes. Cyanocobalamin (vitamin B12) was chemically modified to produce the α-ω-aminohexylcarbamate B12 derivative – as a suitable bioconjugate – which was then conjugated to fluorescent, carboxy-functional nanoparticles (<200 nm). These systems were applied to intestinal Caco-2 monolayers, expressing the relevant proteins involved in B12 trafficking and endocytic processes. Vitamin B12-conjugated nanoparticles demonstrated notably increased cell uptake and transport capacities in Caco-2 monolayers, compared to their unconjugated counterparts. Importantly, the cell uptake of B12-conjugated nanoparticles occurred via a pathway that was different to that used by both soluble B12 and unmodified nanoparticles. B12-conjugated nanoparticles circumnavigated the lysosomal compartment and were transported by a route perturbed by caveolae-specific inhibitors, unlike the clathrin-mediated trafficking of soluble vitamin B12. These previously unreported observations are important and have potential implications in the field of bioconjugate and nanocarrier-mediated drug delivery. Epithelial cell uptake and transport of B12-conjugated nanoparticles was also investigated in airway-derived Calu-3 cells, shown to express the B12-intrinsic factor receptor, cubilin. B12-nanoparticles showed markedly larger cell uptake and transport capacities in Calu-3 layers, with B12-conjugation dramatically influencing the intracellular trafficking of the particles in a similar way to Caco-2 cells. The B12 endocytotic machinery therefore shows potential for delivery of nanocarrier-associated therapeutics across the airways. Present work also aimed to establish methods for the production of stable nano-sized protein crystals displaying a slow drug release profile, based on evidence that protein therapeutics which are formulated in this manner, offer beneficial drug-delivery properties and can be targeted using biological ligands. Nano- and micron-sized insulin crystals were prepared by an adaptation of the batch crystallisation approach. The crystals were stabilised using a chemical crosslinker, namely β-[Tris(hydroxymethyl) phosphino] propionic acid (THPP). The resulting insulin crystals were generally stable in the absence of crystalisation buffer, displayed a slow-release profile, with the released insulin retaining its biological activity. This study therefore shows that formulating protein bioactives in this form is possible and may provide a promising strategy to develop biotherapeutics with improved drug delivery properties.