Sunscreens ensure protection of the human skin against the harmful effects of the UV radiation in the UVB (290 – 320 nm) and UVA (320 – 400 nm) wavelength ranges. They commonly contain one or more organic UV absorbers that absorb light in the wavelength range of interest and/or inorganic particles, such as metal oxide semiconductors that absorb, scatter and reflect light. The efficiency of these formulations is measured by introducing the Sun Protection Factor (SPF). Currently, SPF is estimated from in vivo measurements, which is a time-consuming and expensive process. For a validated method, however, SPF can also be determined in vitro by measuring the diffuse optical transmittance as a function of wavelength. In this study, we show how in vitro SPF changes as a function of time upon i) evaporation of volatile components and ii) exposure under UV irradiation. We start by investigating the evaporation of solution films containing a selection of UV absorbers. We show that during solvent evaporation, an initial film, which is deposited on a smooth quartz plate, progressively dewets. The solvent loss causes an increase in the solute concentration until its solubility limit is reached. From that point onwards, solute precipitation is expected to occur. Hence, the combined effect of dewetting and solute precipitation during evaporation leads to a decrease in the absorbance and thus to the in vitro SPF values. We model the evolution of film spectra and we compare it with experiment. Results confirm that both are in reasonable agreement. The addition of either inorganic particulates in the nm size or polymer was also pursued. Our data confirm that their use aid film pinning at its base edge and suppressed dewetting. However, it did not tackle the problem of precipitation during solvent evaporation. Throughout our experimental procedure, the solvent of choice was the slow evaporating propane-1,2-diol (PG). We show that the same behaviour is observed when a fast- evaporating solvent, such as n-decane is used. Dewetting is also suppressed when alternative substrates such as Vitro Skin and keratin-lipid film are used. We have extended our investigation to the evaporation of particle-stabilised emulsion films, consisting of equal volumes of involatile squalane (SQ) and slow-evaporating PG and stabilised by partially hydrophobised silica particles. We show for these emulsions that the loss in the absorbance is due to the loss of light scattering. The loss of the latter results from the collapse of the emulsion structure during evaporation. We also examine how the in vitro SPF of solutions containing UV absorbers varies with standard solar irradiation. With the use of chemical actinometry, we have determined the overall quantum yields of the photochemical processes of photolabile UV absorbers. Using the obtained parameters, we have developed models to calculate the evolution of the film spectra and derived SPF values for both non-scattering films consisting of solutions of multiple UV absorbers and for highly scattering emulsion films. Finally, we are able to predict the SPF changes as a result of the photochemical processes upon “standard” sunlight exposure.

From my experience in the Sheffield Royal Hospital, I have reason to believe that the use of patent pills as an abortifacient is a fast growing evil and a social scandal. Any woman can procure "Female corrective Pills" from almost any so-called respectable chemist without running any risk of being asked difficult questions. From the analysis of some of these pills it is shown that she can get sufficient of a powerful drug, not only to remove so-called obstructions, but to produce grave disease of bowels, kidneys, central and peripheral nervous systems, not unfrequently wrecking the health temporarily but permanently and even leading to fatal results as evidenced by several writers. Added to this the desired result is not always secured as there is a wide margin of uncertainty in the action of the drug which always endangers life and sometimes destroys it, at least leaving behind it some temporary enfeeblement of body or mind.

Some adverse drug reactions (ADRs) are not detected before marketing approval is given because clinical trials are not suited for their detection, for various reasons [5, 23]. Drug regulatory bodies therefore weigh the potential benefits of a drug against the harms and allow drugs to be marketed if felt that the potential benefits far outweigh the harms [26,48]. Associated adverse events are subsequently monitored through various means including reports submitted by health professionals and the general public in what is commonly referred to as spontaneous reporting system (SRS) [19, 23, 69]. The resulting database contains thousands of adverse event reports which must be assessed by expert panels to see if they are bona fide adverse drug reactions, but which are not easy to manage by virtue of the volume [6]. This thesis documents work aimed at developing a statistical model for assisting in the identification of bona fide drug side-effects using data from the United States of America’s Food and Drugs Administration’s (FDA) Spontaneous Reporting System (otherwise known as the Adverse Event Reporting System (AERS)) [28]. Four hierarchical models based on the Conway-Maxwell-Poisson (CMP) distribution [43,78] were explored and one of them was identified as the most suitable for modeling the data. It compares favourably with the Gamma Poisson Shrinker (GPS) of DuMouchel [19] but takes a dimmer view of drug and adverse event pairs with very small observed and expected count than the GPS. Two results are presented in this thesis; the first one, from a preliminary analysis, presented in Chapter 2, shows that problems such as missing values for age and sex that militate against the optimal use of SRS data, enumerated in the literature, remain. The second results, presented in Chapter 5, concern the main focus of the research mentioned in the previous paragraph.

Adverse drug events (ADEs) are a significant cause of patient morbidity and hospital admissions. There are many studies in this area in Western countries. However, little is known about the prevalence and patterns of such events in Malaysia. Health care professionals are in the best position to reduce and prevent adverse drug events. In order to devise preventive strategies based on the prevalence studies, it is important to understand the current practices of health care professionals in this area. This study aimed to determine the different occurrences of ADEs in a Malaysian public hospital as well as the experiences of some Malaysian pharmacists’ of ADEs. A study of an observational chart review determined the prevalence of adverse drug event-related admissions in a tertiary public hospital and drugs implicated in such. This was achieved through a prospective review of the patients’ medical notes and charts in two medical wards. All cases were assessed using a classification tool which was developed after a pilot study. Following this, a postal survey of some Malaysian pharmacists explored their experiences about ADEs: the types of ADEs they have observed, actions taken in response to these incidents and their awareness of and involvement in adverse drug reaction reporting, and their attitudes towards this task. Both studies revealed that the occurrence of adverse drug events was high in Malaysia – the chart review study found that 39% of admissions to two medical wards were related to ADEs whilst more than half of the sample pharmacists revealed having observed them in their daily work activities. Moreover, cardiovascular drugs, anti-diabetics, anti-asthmatics, and analgesics were responsible for more than 80% of the admissions related to an ADE. Similar drug classes were also associated with ADEs as recounted by the pharmacists. Moreover they claimed to have communicated with patients about ADEs: on the ADE experienced by a patient, proper use of medicine, importance of adherence, alternate medicines and other appropriate measurements. Although more than 80% hospital and clinic pharmacists claimed to have reported adverse drug reactions, less than 20% of community pharmacists have claimed sending a report. This may have resulted from their lack of awareness of the procedures and processes of reporting an adverse drug reaction. Compared to other countries, the prevalence of ADEs is higher in Malaysia. It remains to be an important cause of patient injury and hospital admissions. Some useful strategies such as educational intervention on main causes of adverse drug events, monitoring of patients, and appropriate prescribing should be targeted at all health care professionals to prevent its likely future occurrences. Pharmacists play an important role in preventing ADEs by providing education and counselling to patients. Furthermore, as they were able to identify ADEs in their daily work activities, they should be included in any prevention programs. Documenting ADEs and interventions taken in relation to those ADEs should be encouraged, as this will be useful in monitoring the occurrence of ADEs and sharing the documented information with others could improve awareness and therefore improve prevention.

Density functional theory (DFT) and combined quantum mechanics/molecular mechanics (QM/MM) calculations have been used to model inter- and intra-molecular non-covalent interactions of transition metal complexes and where applicable their interactions with DNA. Two DFT functionals, BHandH and B97-D, which have shown to be efficient in modelling systems containing non-covalent interactions, have been tested against high level ab initio calculations on test transition metal complexes, designed to represent the intermolecular interactions present in the benzene dimer and methane benzene systems. The DFT functionals above show good agreement with the benchmark calculations and have been used to study ruthenium arene 'piano stool' type complexes, of the general form [h6(arene)Ru(en)Cl]+, which have shown potential as anticancer agents. The intramolecular interactions of these ruthenium complexes through coordination to guanine and adenine through the N7 nitrogen, has been explored using a selection of pure DFT, hybrid DFT, and post Hartree-Fock approaches against benchmark correlated wavefunction methods, where the best methods were found to be BHandH, B97-D2, and MP2(0.25). The B97-D2 functional was used to model these ruthenium complexes, with a selection of extended aromatic ligands with potential to act as intercalators, interacting with base pair steps. Calculated binding energies show a sensitivity to the nature of the arenes, where the more flexible ligands form more non-covalent interactions with DNA, as demonstrated by QTAIM analysis. Conformations and binding energies of a relatively new platinum anticancer drug, kiteplatin, with small single strand fragments of DNA, have been studied using B97-D and semi-empirical methods and compared to established drugs cisplatin and oxaliplatin. Isotropic shielding values and J coupling constants have also been calculated for these systems to relate these values to conformational data. Extended dual strand kiteplatin-DNA adducts have been studied using the QM/MM method ONIOM, combining BHandH with AMBER, to calculate binding energies and optimised structures. These results show that as the DNA adduct increases in size the values of the kiteplatin energies start to converge and comparison of base pair parameters show that around the site of coordination all fragments show comparable geometrical distortions.

Cannabis has been used as a medicinal and natural product for thousands of years. Whether it has been used to make rope or paper, or been used to treat pain or depression, cannabis has always had a place in human civilisation. With the isolation of the psychoactive compounds responsible for cannabis’ effects, the discovery of two human cannabinoid receptors and an expanding knowledge of the therapeutic uses of cannabis, interest in the development of novel cannabinoids grew. The CB2 cannabinoid receptor has gained particular attention, as the often unwanted central and psychoactive effects of cannabinoids has been attributed to the CB1 cannabinoid receptor. Development of CB2 receptor selective ligands offers treatment opportunities in many areas, but most especially for pain, multiple sclerosis and immunomodulation. The preparation of fluorescently labelled ligands for a variety of receptors has improved compound screening techniques, as well as allowing use as biomolecular probes for aiding our understanding of the receptor in situ. The aim of this work is to design, synthesise and evaluate novel fluorescently labelled cannabinoids, with a particular interest in CB2 selective compounds. Focusing on the CB2 receptor selective alkylindole JWH-015, targeted substitutions were made to its naphthyl ring to identify sites that might be suitable for fluorophore attachment. With a site chosen, a series of fluorescent JWH-015 analogues was synthesised and evaluated for their CB2 receptor binding affinities. Though none of the evaluated compounds showed sufficient binding affinity for them to be used as biomolecular tools, the structure activity relationships gained suggested that improved design of fluorescent JWH-015 analogues in future could lead to the first ever active fluorescent cannabinoid.

Day case surgery is expanding in the UK and is the favoured approach to elective surgery by the Government and patients alike. However studies have revealed patients' experience unacceptable postoperative pain when they return home after day surgery, leading to a variety of negative consequences, stemming many years, affecting many lives, with emotional and financial cost. It is imperative that pain is adequately controlled following day surgery to reduce these consequences and ensure the potential of day surgery is reached. Previous research has investigated barriers to pain management in this area, one barrier that has received little attention is that posed by the patient, and it has been suggested that patients may not utilising their analgesics appropriately with papers calling for further research in this area. Employing Interpretative Phenomenological Analysis (IPA) this study explored patients' use of analgesics on returning home following day surgery. Using IPA for analysis, interviews with twenty eight patients revealed many to avoid analgesics enduring severe postoperative pain during their recovery, and provided new understanding showing patients' use of analgesics to be as a result of a complex intentional decision making process based on a matrix of beliefs they held surrounding pain, analgesics and day surgery. These beliefs were found to be influenced by past experience, and cultural context, with this research being the first to identify many of these beliefs and make further sense of them by producing an explanatory framework illustrating how they exert their influence upon patients' decisions regarding analgesic use. One implication of these findings is that day surgery is not as straightforward as suggested, and simply providing patients pain management information and effective analgesics underestimates the complexity of the patient's experience when they return home. Further research is now required to identify alternative ways to reduce pain following day case surgery. One recommendation is to overcome erroneous beliefs held by patients. In particular the explanatory framework produced by this research provides a unique insight into the mechanism by which these beliefs may exert their influence upon patients' analgesic use, and may prove a useful tool to achieving this, overcoming pain and its negative consequences, paving the way for day case surgery to reach its full potential.

The aim of this thesis is to investigate the physicochemical parameters which can influence drug loading within liposomes and to characterise the effect such formulations have on drug uptake and transport across in vitro epithelial barrier models. Liposomes composed of phosphatidylcholine (PC) or distearoyl phosphatidylcholine (DSPC) and cholesterol (0, 4, 8, 16 µM) were prepared and optimised in terms of drug loading using the hand-shaking method (Bangham et al., 1965). Subsequently, liposomes composed of 16 µM PC or DSPC and cholesterol (4 µM) were used to monitor hydroxybenzoate release and transport from Iiposomes. The MIT (3[4,5-Dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) and crystal violet assays were employed to determine toxicity of the Iiposome. formulations towards the Caco-2 cell line, employed to model the epithelial barrier in vitro. Uptake and transport of mannitol, propranolol, glutamine and digoxin was measured in the presence and absence of Iiposome formulations to establish changes in absorption resulting from the presence of lipid formulations. Incorporation of the four hydroxybenzoates was shown to be influenced by a number of factors, including liposome composition and drug conformation. Methyl hydroxybenzo.ate (MP) was incorporated into the bilayer most effectively with percentage incorporation of 68% compared to 45% for butyl hydroxybenzoate (BP), despite its increased Iipophilicity. This was attributed to the decreased packing ability of BP within the hydrocarbon core of the lipid bilayer compared to MP. Release studies also suggested that the smaller MP was more strongly incorporated within the lipid bilayer with only 8% of the incorporated solute being released after 48-hours compared to 17% in the case of BP. Model transport studies were seen to reflect drug release profiles from the liposome bilayers with significantly (p < 0.01) higher amounts of BP partitioning from the liposome compared to MP, Caco-2 cell viability was maintained above 86% in the presence of all Iiposome formulations tested indicating the liposome formulations are non-toxic towards Caco-2 cells. Paracellular (apical-to-basolateral) transport of mannitol was significantly increased in the presence of DSPC, PC / DSPC:Cholesterol (16:4 µM; 1000 µg). Glutamine uptake and transport via the carrier-mediated route was Significantly (p < 0.01) increased in the presence of PC I DSPC:Cholesterol (16:0; 16:4 µM). Digoxin apical-to-basolateral transport was significantly increased (p < 0,01) in the presence of PC / DSPC:Cholesterol (16:0; 16:4 µM); thus reducing digoxin efflux via P-glycoprotein. In contrast, PC:ChoJesterol (16:0; 16:4 µM) significantly (p < 0.01) decreased propranolol uptake via the passive transcellular route. Bi-directional transport of propranolol was significantly (p < 0,01) decreased in the presence of PC/DSPC:Cholesterol (16:0; 16:4 µM). The structure of a solute is an important determinant for the incorporation and release of a solute from liposome formulations. PC, DSPC and cholesterol liposome formulations are nontoxic towards Caco-2 cell monolayers and improved uptake and transport of mannitol, glutamine. and digoxin across Caco-2 cell monolayers; thus providing a potential alternative delivery vehicle.

The genesis and outgrowth of pituitary adenomas is consequent to the combined contributions of genetic and epigenetic aberrations. Although the relative contribution of each is not known it is likely that particular aberration may be common or particular to an adenoma subtype(s). The impact of subtype specific changes presents significant challenges for clinical management options. In this thesis the potential impact of epigenetic aberrations, that target the Dopamine D2 Receptor (D2R) and the cytokine, Bone Morphogenic Protein 4 (BMP-4) were investigated. In these cases their expression patterns are frequently comprised in a subtype-specific context. This thesis reports that in pituitary cell lines, reduced expression of D2R and that of BMP4 are associated with CpG island methylation and histone modifications indicative of gene silencing. In these cases, incubation of cells with epidrugs, designed to reverse epigenetic silencing, restores their expression.

The reduction of bacteria on the skin results in prophylactic and therapeutic benefits by reducing the occurrence of skin infections. Currently, chlorhexidine digluconate, a conventional topical antiseptic, permeates the skin poorly leaving viable opportunistic pathogens below the superficial layers of the stratum corneum. The aim of this study was to use polyamidoamine (PAMAM) dendrimers to enhance the topical delivery of chlorhexidine digluconate to improve its antimicrobial efficacy.