Wang, Zexi. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 63-64). / Abstract --- p.i / Acknowledgement --- p.iii / Chapter 0 --- Introduction --- p.1 / Chapter 1 --- The Design of the Experiments --- p.4 / Chapter 1.1 --- Flies and the Devices --- p.5 / Chapter 1.2 --- Parameter Settings and Interested Information --- p.8 / Chapter 2 --- Video Processing --- p.11 / Chapter 2.1 --- "Videos, Computer Vision and Image Processing" --- p.11 / Chapter 2.2 --- Details in Video Processing --- p.14 / Chapter 3 --- Data Analysis --- p.20 / Chapter 3.1 --- Background --- p.20 / Chapter 3.2 --- Outline of Data Analysis in Our Project --- p.22 / Chapter 4 --- Effect of the Medicine --- p.25 / Chapter 4.1 --- Hypothesis Testing --- p.26 / Chapter 4.2 --- Two-sample t Test --- p.28 / Chapter 5 --- Significance of the Two Factors --- p.32 / Chapter 5.1 --- Background of ANOVA --- p.33 / Chapter 5.2 --- The Model of ANOVA --- p.35 / Chapter 5.3 --- Two-way ANOVA in Our Data Analysis --- p.42 / Chapter 6 --- Regression Model --- p.45 / Chapter 6.1 --- Background of Regression Analysis --- p.47 / Chapter 6.2 --- Polynomial Regression Models --- p.52 / Chapter 6.2.1 --- Background --- p.52 / Chapter 6.2.2 --- R2 and adjusted R2 --- p.53 / Chapter 6.3 --- Model Verification --- p.58 / Chapter 6.4 --- A Simpler Model As the Other Choice --- p.59 / Chapter 6.5 --- Conclusions --- p.60 / Chapter 7 --- Further Studies --- p.61 / Bibliography --- p.62

Erythromycin (ERY) is a macrolide antibiotic which is used in the treatment of acne vulgaris.Acne is a common skin condition that occurs when the sebaceous glands and hair shafts become infected by the bacteria Propionibacterium acnes. Acne is a chronic condition that may last for years and the severity of the effects of the disease on patients is often undermined especially in third world countries where more emphasis is placed on other more life-threatening diseases. It may cause considerable physical and emotional distress to sufferers along with the possibility of permanent scarring. Although use of topical ERY formulations is not the first line of treatment it has proven to be effective in treating inflammation of skin and skin structures cause by the responsible bacteria. To-date there are a variety of vehicles which are used in preparing topical ERY formulations namely ointment and gel bases, alcoholic solutions and pledgets. All the gel formulations on the market contain hydroxypropyl cellulose, alcohol and water along with the active ingredient(s). However, some gel formulations contain propylene glycol in addition to these excipients an example being Emgel®. Propylene glycol has been shown to affect the penetration of topically applied drugs through the skin suggesting that it would be highly likely that those formulations which contain propylene glycol may release more ERY into the skin following application. With this in mind, two ERY gel formulations were produced which contained different percentages of propylene glycol. According to the FDA guidelines, pharmacokinetic measurements in blood, plasma and/or urine of topical dermatological drug products are not feasible to document bioequivalence since the active ingredient(s) in topical formulations is/are not intended to be absorbed into the systemic circulation and in addition, concentrations in extracutaneous biological tissues would generally not be measurable. This limits determination of bioavailability and assessment of bioequivalence of such products to pharmacodynamic measurements, clinical trials and dermatopharmacokinetic (DPK) measurements such as tape stripping (TS) and microdialysis (MD).TS is a sampling technique which involves sequential removal of layers of the stratum corneum using strips of adhesive tape. This technique has found increasing use in DPK studies for investigation of drug kinetics in the skin following the application of a topical formulation. The technique has also been used as a diagnostic tool in assessing the quality of the stratum corneum in diseased skin. In the current research study, the tape stripping technique was used to investigate the pharmaceutical/biological availability of topical gel formulations containing ERY. MD is another DPK sampling technique which has been used to determine the amount of a topically applied drug that penetrates through the stratum corneum to reach deeper tissues of the skin. The in vivo sampling technique involves the insertion of microdialysis probes beneath the skin surface in the dermal tissue and allows for real-time sampling of the analyte at its target site. Recently in vitro MD has also been successfully used to assess the pharmaceutical availability of a topical corticosteroid, mometesone furoate, from topical formulations. Based on this work, microdialysis was used to determine the pharmaceutical availability of ERY from gel formulations which were developed for use in this research. The results of the pharmaceutical availability of ERY from in vivo tape stripping studies and the in vitro microdialysis studies were compared to establish correlation between the data. Pharmaceutical equivalence and bioequivalence data obtained from the respective studies on the gel formulations were investigated by statistical analysis of the data generated from both the in vitro and in vivo experiments. In summary the objectives of this research were: 1. To develop and validate a high performance liquid chromatography method suitable to analyse ERY concentrations obtained from in vitro microdialysis studies and in vivo tape stripping studies. 2. To prepare two different ERY gel formulations with different percentage content of propylene glycol. 3. To determine the pharmaceutical availability of ERY from two different gel formulations using in vitro microdialysis. 4. To develop and validate a tape stripping technique which could be used to determine percutaneous penetration and bioequivalence of the gel formulations. 5. To compare in vitro microdialysis and in vivo tape stripping data and attempt to establish a correlation between the two different approaches.

In 2005, the House of Commons (HoC) Health Committee produced a report on The Influence of the Pharmaceutical Industry – the first of its kind since 1914. The inquiry concluded that there were ‘over-riding concerns about the volume, extent and intensity of the industry’s influence, not only on clinical medicine and research but also on patients, regulators, the media, civil servants and politicians’, and stressed the need ‘to examine critically the industry’s impact on health to guard against excessive and damaging dependencies’ (HoC 2005, p. 97). It also noted that it is important to comprehensively analyse pharmaceutical regulation in order to ascertain whether there are systemic problems: In some circumstances, one particular item of influence may be of relatively little importance. Only when it is viewed as part of a larger package of influences is the true effect of the company’s activity recognised and the potential for distortion seen. The possibility that certain components of any such campaign are covert and their source undeclared is particularly worrying. (HoC 2005, p. 97) This study addresses this recommendation and was primarily conducted to examine whether recognised concerns are merely ad hoc or as a result of systemic flaws in the current system of pharmaceutical regulation. The work addresses a gap in the academic literature by drawing on the fragmented criticisms of the pharmaceutical industry in order to produce a model to illustrate how various stakeholders collaborate with drug companies to promote licensed products, and to explore the nature of the relationships between these elite stakeholders. The thesis begins with a literature review which determines who is involved in pharmaceutical regulation; how the regulatory system works; and explores the key role of communication in this process (Chapters 1 to 3). The recurrent theme is the neglect or exclusion of the patient/consumer, which leads to the development a model of intra-elite communication in drug regulation called Pharmaffiliation (Chapter 3). The thesis then looks for evidence to support or refute this model, using multiple methods (Chapter 4). Four case studies (with specific selection criteria) are chosen to test the model’s constructs and indicators (Chapters 5 to 8). The research uncovers systemic problems in the current system of pharmaceutical regulation which can ultimately harm the patient/consumer, and the implications of these findings are discussed (Chapter 9). Solutions on a micro-level include consumer involvement in decision making processes, which can be enhanced through public education and awareness campaigns and the instigation of public inquiries whenever drugs are withdrawn from the market (HoC 2005, p. 105). On a macro-level, however, this will involve critically exploring neoliberal capitalism and the empowerment of the citizenry (Street 2001).

Indiana University-Purdue University Indianapolis (IUPUI) / Model-based drug development has become an essential element to potentially make drug development more productive by assessing the data using mathematical and statistical approaches to construct and utilize models to increase the understanding of the drug and disease. The modeling and simulation approach not only quantifies the exposure-response relationship, and the level of variability, but also identifies the potential contributors to the variability. I hypothesized that the modeling and simulation approach can: 1) leverage our understanding of pharmacokinetic-pharmacodynamic (PK-PD) relationship from pre-clinical system to human; 2) quantitatively capture the drug impact on patients; 3) evaluate clinical trial designs; and 4) identify potential contributors to drug toxicity and efficacy. The major findings for these studies included: 1) a translational PK modeling approach that predicted clozapine and norclozapine central nervous system exposures in humans relating these exposures to receptor binding kinetics at multiple receptors; 2) a population pharmacokinetic analysis of a study of sertraline in depressed elderly patients with Alzheimer’s disease that identified site specific differences in drug exposure contributing to the overall variability in sertraline exposure; 3) the utility of a longitudinal tumor dynamic model developed by the Food and Drug Administration for predicting survival in non-small cell lung cancer patients, including an exploration of the limitations of this approach; 4) a Monte Carlo clinical trial simulation approach that was used to evaluate a pre-defined oncology trial with a sparse drug concentration sampling schedule with the aim to quantify how well individual drug exposures, random variability, and the food effects of abiraterone and nilotinib were determined under these conditions; 5) a time to event analysis that facilitated the identification of candidate genes including polymorphisms associated with vincristine-induced neuropathy from several association analyses in childhood acute lymphoblastic leukemia (ALL) patients; and 6) a LASSO penalized regression model that predicted vincristine-induced neuropathy and relapse in ALL patients and provided the basis for a risk assessment of the population. Overall, results from this dissertation provide an improved understanding of treatment effect in patients with an assessment of PK/PD combined and with a risk evaluation of drug toxicity and efficacy.