Following the stability analysis, a testing protocol was devised and the legal and ethical obligations of the pharmacist in the addition of drugs to PN considered

In order to investigate further the mode of action of these compounds, synthesis of proteomic probes was attempted. Synthetic design and attempts are presented chapter VII. To establish whether there was 24-SMT present in the blood stream form of T. b. brucei, a Northern blot was carried out. This confirmed transcription of the enzyme which was then cloned, over expressed and purified (Chapter VIII). Enzyme assays were carried out against the recombinant enzyme.

A dissertation submitted in partial compliance with the requirements for the Master's Diploma in Technology: Homoeopathy, Technikon NataI, 1994. / The efficacy of Pilocarpus Jaborandi in the management of emotional palmar hyperhidrosis was studied. It was hypothesised that this homoeopathic drug would cause a significant decrease in sweat production rates. The study was double blinded and consisted of thirty treated patients, with fifteen patients in group and fifteen patients in the the placebo group. Patients were chosen by convenience sampling with no specifications of age or sex. The treated group received Pilocarpus Jaborandi 9 CH, and were instructed to take five pills on waking everyday for ninety days. The other group received a placebo also for ninety days. Quantification of the first day, on ninetieth day of sweat production was done on the forty-fifth day and treatment, by means of on the sweat collection tests. In each test sweat was / M

Malaria continues to pose a significant global health and socio-economic burden on those regions where it is endemic. Despite substantial investment in the delivery of artemisinin-based combination therapies, causing a fall in malaria mortality, recent data suggest that this parasitic disease still imposes a significant impact. A major problem is the narrow drug discovery pipeline, made worse by reports of artemisinin resistance. In recent years, high-throughput screening of natural products derived from plants and marine organisms has led to the discovery of potent anti-malarial indole alkaloids (such as dihydrousambarensine), many of which contain an indoloisoquinoline core. Building on previously discovered methodology in our group, we have developed a series of novel, enantiomerically pure, synthetic indoloisoquinoline and their potential as anti-malarial leads was assessed. The structure-activity relationship of these compounds was investigated in several areas and a lead compound was generated with an activity close to that of a known anti-malarial natural product dihydrousambarensine.

In this thesis I studied La0.7Sr0.3MnO3/Alq3/AlOx/Co organic spin valves, which are multifunctional devices showing an interesting interplay between magnetoresistive effects and memristive switching. In particular this work aims at elucidating the elusive mechanisms for spin injection and transport in this archetypal structure. While spin injection in organic materials was demonstrated by different spectroscopic techniques, the origin of magnetoresistive effect in organic spin valves is still debated. In fact, the Hanle effect, considered to be the only reliable proof for spin transport across the organic spacer layer, has not been observed in such a device, yet. I investigated the thickness and temperature dependence of charge transport and magnetoresistive properties, and demonstrated the absence of the Hanle effect. Moreover I studied how the resistance and magnetoresistance of our devices were affected by memristive switching, which turned out to be a fundamental tool to enlighten the comprehensive picture. Two clearly distinguishable conduction regimes have been found for non magnetoresistive and magnetoresistive devices. The former is compatible with models for charge transport in organic materials, the latter can be described by an equivalent circuit where metallic paths and hopping channels act in parallel. In the framework of this model, a coherent description for the interplay between MR and memristive switching can be given. SV signals can be explained as tunnel magnetoresistance (TMR) or ballistic magnetoresistance (BMR) occurring across shortened regions of the organic bulk, which is an explanation compatible with the absence of Hanle effect. This work demonstrates that SV signals can be explained without resorting to spin injection and transport into the organic layer.

Submitted in partial compliance with the requirements of the Master’s Degree in Technology: Homoeopathy, Durban University of Technology, Durban, South Africa, 2016. / Aim The purpose of this research study was to compare the similarity and differences of the rubrics from a proving of a homoeopathic complex (Cinnabaris 12CH, Hydrastis canadensis 12CH and Kalium bichromicum 12CH) in order to establish whether the symptoms are similar to the individual constituents, or whether a new remedy is produced when individual remedies are combined. The research questions addressed by the study were: 1) Will the twelfth centesimal potency (12CH) of the homoeopathic complex produce clearly observable signs and symptoms in healthy provers? 2) Will the majority of signs and symptoms of the complex be similar to those of its constituent parts? Methodology The proving was a randomised double blind placebo controlled study involving 20 participants who met the inclusion and exclusion criteria. The provers were randomly assigned to either a verum (80%) or placebo group (20%). Provers recorded their symptoms in their journals for one week prior to administration of the proving complex in order to establish a baseline for comparison. The proving complex was in form of lactose granules dispensed in lactose powders. Provers were given six lactose powders, one powder to be taken sublingually three times a day or until symptoms occurred. The provers recorded all mental or physical symptoms experienced in their journals. Once the proving was completed the journals were collected and symptoms derived from the recordings were collated and analysed. This information was converted to materia medica and repertory format. The researcher then analysed each rubric in order to establish if any or all of the three remedies of the complex appeared in that rubric. This comparison reflected the number of rubrics that contained the individual remedies of the complex. In this way the researcher established the rubrics that were unique to the complex as a whole. vi Results A total of 337 rubrics were produced by the proving. The analysis of rubrics showed that 216 rubrics did not contain any of the three remedies; 72 rubrics contained at least one of the three remedies; 29 rubrics contained two of the three remedies; and 20 rubrics contained all three remedies. Eighteen new rubrics were identified. In analysing the symptoms elucidated, a definite polarity between symptoms was noted, including within the same prover. This was the case with mental and physical symptoms. A vast range of symptoms was produced, spanning 29 sections of the repertory, with the majority being physical, related to headaches were quite common amongst provers, pain in the abdominal region, pain in the extremities, eye symptoms such as lachrymation and pain, pain in the throat, chest and neck, skin eruptions. Sinusitis or rhinitis symptoms such as nasal itching, sinus congestion, nasal discharge and sneezing were observed. A significant change in appetite and thirst was seen. The main regions that had an affinity for the complex were the head, abdomen and extremities with pain as the main symptom. Conclusion The substance did produce signs and symptoms in the provers, so Research Question 1 was answered with a “Yes”. Only a small proportion (0.05%) of the rubrics from the proving contained all three constituent remedies, therefore Research Question 2 was answered with a “No”. The results show that although the proving symptoms shared a small degree of similarity to the constituent remedies, the complex as an entity formed its own individual picture. / M

Folate uses the natural endocytosis pathway via the folate receptor (FR) to enter the cells. Folate conjugation to small or macromolecular therapeutics has hence been exploited for intracellular delivery to, particularly, cancerous cells. This work reports on the expression and functionality of FR in polarised cell monolayer models of respiratory and gastrointestinal mucosa with the view to assess its potential for delivery of folate-modified macromolecular therapeutics either intracellularly or across the epithelium. Four cell lines representing bronchial and intestinal epithelium; cancer-derived intestinal Caco-2 and bronchial cell line Calu-3, and noncancerous intestinal and bronchial cell lines IEC-6 and HBEC were cultured on permeable membranes to produce polarised monolayers. Expression of FR was confirmed by RT-PCR and Western blot analysis for all the tested cell types and shown to be dependent on culturing time. The functionality of the receptor for endocytosis was demonstrated by a model macromolecular folate conjugate (fluorescent ovalbumin-folate (OVA-FA)), whereby significantly higher cellular uptake of the folate-conjugate, relative to non-folate control, was clearly demonstrated. Importantly the data showed that the expressed folate receptor was capable of mediating transport of the macromolecular folate conjugate across (transcytosis) the cells in the polarised monolayers. Preliminary studies led to investigation of the folate mediated uptake and transport of folate modified nanoparticles (NPs). It was shown that folate modified NPs traversed the Calu-3 layers and studies characterizing this transport indicated folate involvement in this process. Adsorption of OVA-FA on the surface of NPs was seen to promote their cellular uptake and transport across the cell layers. To examine the mechanism of cellular uptake and transport of folate modified nanoparticles, various endocytic inhibitors were employed. The study demonstrated an involvement of the caveolar pathway in internalization of folate modified nanoparticles; as judged from a significant reduction of internalization in filipin (inhibitor of caveolar pathway) treated cells. Moreover, the work also showed evidence of transport of folate-modified nanoparticles via the caveolar pathway, since translocation of nanoparticles across the cell monolayer was absent when this path was inhibited. Disruption of actin filament and microtubules caused no difference in cellular uptake of NPs but increased the transcytosis of folate modified NPs. Confocal microscopy, Transmission Electron Microscopy (TEM), Total Internal Reflection Microscopy (TIRM) and Total Internal Reflection Florescence microscopy (TIRFM) were used to confirm and visualize quantitative data. This study also investigated the effects of surface ligand distribution pattern (ligand clustering and density) on the internalization of nanoparticles by Calu-3 cells cultured as polarised layers. The density of the displayed ligand was manipulated by controlling the conjugation level of folate-ovalbumin, while ligand clustering was achieved by co-adsorption of varying mixtures of folate-ovalbumin conjugate (at different ligand density levels) and unconjugated ovalbumin. Increasing ligand density on the nanoparticle surface resulted in increased internalization of modified nanoparticles by the cells, up to a saturation level. Surface ligand density also affected the cellular uptake pathway; from predominantly clathrin to predominantly caveolae-mediated as the ligand density was increased. It was further demonstrated that surface clustering of the folate ligand enhanced cellular internalization of nanoparticles, relative to its dispersed surface distribution.

The tropical rainforest of Malaysia is considered as one of the most evolved and complex ecosystems in the world that serves a vast untapped biodiversity of natural resources. Exploitation of medicinal plants for bioactive compounds is of great potential and could be an imperative source of providing new vistas for novel drug discovery and development. The study was undertaken to evaluate the in vitro pharmacological properties of Artabotrys crassifolius including antibacterial, antifungal, anticancer and antioxidant activities of the plant. The leaves and bark of Artabotrys crassifolius were extracted sequentially using hexane, chloroform and ethanol. The prepared crude extracts were subjected to phytochemical screenings for the presence of alkaloids, cardiac glycosides, flavonoids, phenolic compounds, saponins, tannins and terpenoids. Kirby-Bauer disc diffusion assay was conducted to examine the antibacterial and antifungal activities of crude extracts against ATCC and clinical strains. The anticancer effect of crude extracts was investigated against human breast and colorectal carcinoma cell lines using MTT assay whereas the antioxidant potential of crude extracts was assessed using TPC, TFC, ABTS, DPPH and FRAP assays. Among the crude extracts studied, hexane and chloroform extracts of bark exhibited pronounced antibacterial activities against ATCC and clinical strains with zones of inhibition ranging from 8.23±0.25 mm to 13.70±0.26 mm and 7.75±0.25 mm to 13.68±0.28 mm respectively. However, all the crude extracts were found to be devoid of antifungal activity except for hexane extract of bark which was able to inhibit the growth of the tested Candida species with zones of inhibition ranging from 7.81±0.27 mm to 9.77±0.25 mm. In addition, chloroform extract of bark was highly active against all of the tested carcinoma cell lines with GI50 values ranging from 4.23 µg/mL to 9.45 µg/mL, while hexane extract of bark potently inhibited the growth of MDA-468 breast and HCT-116 colorectal carcinoma cell lines with respective GI50 values of 6.10 µg/mL and 16.45 µg/mL. Furthermore, ethanol extract of bark that possessed the highest total phenolic and flavonoid contents (268.29±12.36 mg GAE/g and 179.54±4.98 mg CE/g) was shown to demonstrate prominent scavenging activities against ABTS cation and DPPH radicals with IC50 values of 16.50 µg/mL and 16.54 µg/mL respectively, as well as exceptionally high antioxidant power with FRAP value of 1884.35±83.78 µmol Fe(II)/g. The chromatographic separation of chloroform extract of bark led to the isolation of four alkaloids, namely artabotrine, liridine, atherospermidine and lysicamine. Among the compounds isolated, artabotrine displayed high antibacterial properties with respective MIC and MBC values ranging from 1.25 µg/mL to 5 µg/mL and 1.25 µg/mL to 20 µg/mL against all of the tested ATCC and clinical bacterial strains, with the exception of Actinobacillus sp. and Klebsiella sp. Moreover, artabotrine was highly active in HCT-116 colorectal and MCF-7 breast carcinoma cell lines with GI50 values of 3.34 μM and 3.49 μM respectively. In conclusion, exploration of the in vitro pharmacological properties of Artabotrys crassifolius revealed that artabotrine with dual antibacterial and anticancer activities may represent a new generation of potential drug candidates for the treatment of bacterial infections and cancer. Hence, further in vivo studies and clinical trials are required to ascertain the efficacy, safety and mechanisms of action of artabotrine prior to application in the pharmaceutical industry as natural therapeutic agents.

Pharmacy as a profession is changing rapidly in the UK. Over recent years, the increased utilization of ready-prepared drugs has led to a decline in the need for the traditional skills of formulation, while computerization has resulted in a situation where much of the routine dispensing work can be undertaken by less qualified personnel. The decline in the traditional aspects of pharmacy has been matched by the emergence of a much greater advisory role. Pharmacy practice researchers have been drawn to support these developments by investigating related areas, but the common factor linking this research is its focus on clinical as opposed to communication issues. Rather than investigating the nature of face-to-face interaction between pharmacists and clients as a topic in itself, researchers instead have been largely concerned with patient/health care system mteractions as a function of drug therapy. Those few studies that have focused exclusively on communication have done so from a quantitative, social psychology framework, thus ignoring the two way, reactive nature of the interaction process. This study, using data collected from patients' and carers' consultations with pharmacists in a hospital paediatric oncology outpatient clinic, uses the sociological methodology of Conversation Analysis (CA) in order to analyze the encounters which take place. In so doing, it aims to shed some light upon what is actually involved in the process of "patient counselling" in this setting. The body of CA literature which considers advice-giving in health care settings provides the starting point for a consideration of the ways in which pharmacists give advice in this setting, and how this is responded to. The aims are thus twofold: to enlarge the methodological resources of PPR, and also to begin an examination of the communicative competencies required of pharmacists in this setting. NB. This ethesis has been created by scanning the typescript original and may contain inaccuracies. In case of difficulty, please refer to the original text.

The cannabinoid receptors CB1 and CB2, which belong to the rhodopsin family of GPCRs, are implicated in the pathology of various disease states. As drugs targeting these receptors remain limited, novel cannabinoid receptor ligands represent an unmet need with substantial therapeutic potential. We present here the construction and application of homology models of the human CB1 and CB2 cannabinoid receptors based on the crystal structure of the human adenosine A2A receptor for the structure-based design of novel ligands based on the fenofibrate scaffold. Models were refined through molecular dynamic simulations in a lipid bilayer, and were validated via the prediction of known ligand binding affinities, enrichment studies and assessment of predicted ligand binding modes. These validated models were subsequently used in predicting the binding mode of fenofibrate derivatives to the cannabinoid receptors. The predicted binding mode of these fenofibrate derivatives to the CB2 receptor showed good agreement with known mutagenesis data, indicating the binding of these compounds to be stabilized primarily by hydrogen bonds with W5.43 and C7.42, aromatic stacking with F2.57, F3.36 and W6.48, and hydrophobic contact with F2.64, V3.32 and I5.47. A series of novel ligands was derived based on these findings, docked into our model, synthesized and pharmacologically evaluated at the CB2 receptor. The pharmacology of these ligands validated our modelling predictions and binding mode hypothesis, with several of these ligands showing unique pharmacology by binding in an allosteric manner. These findings may be used to guide the design of further derivatives and highlight the promise of the fenofibrate scaffold in the development of novel CB2 receptor ligands.