Pharmaceuticals have become, arguably, one of the fastest changing forms of health care. Advancements in pharmaceuticals are constantly bringing better treatments to illnesses previously untreatable. These advancements, however, come with a hefty price tag: In many countries they also represent the fastest growing source of health care expenditures. Innovative drugs often come to the market with high prices, and the prices of existing drugs can creep up if they are not reined in. These high prices can threaten patient access to the pharmaceuticals they need. Fortunately, there is a lot public policy can do, if it is designed to interact well with clinical, economic, and commercial factors, to safeguard this access. This thesis contains three studies on the effects of public policy on the price-accessibility of pharmaceuticals. Its objectives are as follows: 1) To develop the definitions of a fair pricing of pharmaceuticals in terms of price-accessibility, 2) to present two case studies where public policy changes pharmaceutical prices and affects their utilization, and 3) discuss the significance of these case study policies on access to these drugs. This thesis contributes to the existing body of literature by developing new theoretical models about what constitutes fair pricing of pharmaceuticals and about the relationships between the main parties responsible for making pharmaceuticals accessible to the people who need them. A new evaluation of the policy that delisted high-strength opioids from public formularies in Ontario is also presented with new regression models that allow the analysis of the effects of the policy across sociodemographic categories. Finally, this thesis also contains the first empirical analysis of OHIP plus, the policy that extended the public drug benefits to all individuals under 25 years of age; in this case, with the focus on oral chemotherapy drugs for cancer. / Dissertation / Doctor of Philosophy (PhD) / The rising prices of some pharmaceuticals have made them inaccessible to patients and their families, who must make big financial sacrifices to afford the drugs they need. This thesis contains three studies on the impact of ethical pricing and public policy on the accessibility of pharmaceuticals. Its objectives are to develop definitions of fair pricing in terms of access, to analyze two public policies that sought to change the utilization of pharmaceuticals by changing the price people pay for them, and to elaborate on what these policies mean for the accessibility of these drugs. This thesis’ contributions to the literature include novel theoretical models about pharmaceutical pricing and new evaluations of the effects, by sociodemographic category, of a policy designed to combat the ongoing opioids epidemic in Ontario, Canada, and the effects of OHIP plus on the emerging use of expensive oral-delivery cancer drugs in the same province.

This thesis is organized in “sandwich” format, as recommended by my supervisory committee. It consists of three main chapters. Chapter one is a general introduction and outlines the background information leading to the objectives and hypotheses of my thesis research. Chapter two is a manuscript prepared for submission to a peer-reviewed scientific journal. Chapter three is an overview of the major findings of this thesis, their implications in fish physiology and ecotoxicology, including suggestions of future directions of research. Appendix A contains data from an additional series of experiments that were conducted during my thesis but are not included as a full data chapter. It will be prepared for publication after my defence. / Hypoxia often occurs in aquatic ecosystems that receive effluent from municipal wastewater treatment plants (WWTP). WWTP effluent contains contaminants that could disrupt the complex physiological pathways fish use to cope with hypoxia (e.g., pharmaceuticals, polychlorinated biphenyls, and polycyclic aromatic hydrocarbons), but the effects of WWTP effluent on the physiological responses of fish to chronic hypoxia is poorly understood. We exposed mummichog killifish (Fundulus heteroclitus) to hypoxia (5 and 2 kPa O2) and/or WWTP effluent for 21 days in a full factorial design. We then measured hypoxia tolerance, whole-animal metabolism, gill morphology, haematology, and tissue metabolites. In clean water, killifish responded to chronic hypoxia with improvements in hypoxia tolerance – increases in time to loss of equilibrium at 0.5 kPa (tLOE) and decreases in critical O2 tension (Pcrit) – in association with increased gill surface area as a result of regression of the interlamellar cell mass (ILCM). Concurrent exposure to wastewater attenuated the increases in tLOE and gill remodeling in chronic hypoxia, and nearly depleted brain glycogen stores. Therefore, exposure to WWTP effluent can disrupt the physiological mechanisms fish use to cope with chronic hypoxia and impair hypoxia tolerance. My research suggests that the combination of stressors near WWTPs can have interactive effects on the physiology and health of fish. / Thesis / Master of Science (MSc) / Low oxygen conditions, known as ‘hypoxia’, frequently occur in aquatic ecosystems that receive municipal wastewater treatment plant (WWTP) effluent. WWTP effluent is a continuous and complex source of pollution, including contaminants that can disrupt fish physiology, affecting their ability to cope with stressors, like hypoxia. The effects of WWTP effluent on the responses of fish to chronic hypoxia are poorly understood. To address this research gap, I examined the effects of hypoxia and WWTP effluent on chronically exposed mummichog killifish. I provide evidence that combined exposure to hypoxia and wastewater affected hypoxia tolerance, gill structure, and depleted energy stores in the brain. My thesis demonstrates that WWTP effluent can disrupt mechanisms that fish use to cope with chronic hypoxia and impair hypoxia tolerance. These findings contribute to the existing body of work that documents the interactive effects of combined stressors in effluent-dominated ecosystems on the physiology and health of fish.

In addition to their potential value for in situ bioremediation, the earthworm as a laboratory model may offer insight into mechanisms of xenobiotic toxicity. Using the filter paper contact toxicity test, the LD50s of a series of salicylates and phenolics were determined. The rank order in toxicity of these chemicals was compared with mammalian (rat, oral dosing) LD50s and found to be similar. To determine if protein secretion from chemical stress would be a more sensitive toxicity marker for the above xenobiotics, worms were exposed to either sodium salicylate or acetaminophen at a no effect level (NOAEL) and at the LD100 through filter paper contact. The ability of L. terrestris to metabolize drugs was investigated by using worm homogenate to treat various drugs in both encapsulated and free enzyme forms.

Yes / This paper aims to evaluate the implementation of innovative programmes within the downstream domain of the pharmaceutical supply chain (PSC), with the aim of informing improved service provision. A mixed-method approach was used to assess to what extent innovation could be adopted by hospital and community pharmacies to improve the delivery process of pharmaceutical products. Unstructured interviews and 130 questionnaires were collected and analysed to identify factors that facilitate or prevent innovation within PSC processes. The analysis led to the creation of the innovative pharmaceutical supply chain framework (IPSCF) that provides guidance to health-care organisations about how supply chain management problems could be addressed by implementing innovative approaches. The results also indicated that the implementation of Lean and Reverse Logistics (RL) practices, supported by integrated information technology systems, can help health-care organisations to enhance their delivery in terms of quality (products and service quality), visibility (knowledge and information sharing), speed (response to customers and suppliers needs) and cost (minimisation of cost and waste). The study’s recommendations have potential implications for supply chain theory and practice, particularly for pharmacies in terms of innovation adoption. The IPSCF provides guidance to pharmacies and health-care organisations to develop more efficient and effective supply chain strategies. This research contributes to the academic literature as it adds novel theoretical insights to highly complex delivery process innovation.

No / Budesonide is a mixture of 22R and 22S epimers. The epimeric content of budesonide was reported in both British and European pharmacopoeias to be within the range of 60-49/40-51 for R and S epimers, respectively. In this work, contribution of the two epimers to the overall infrared spectrum of budesonide has been investigated by quantum chemical calculations.

Yes / Purpose Pharmaceuticals are a key input into healthcare operations and so their effective management is vital. This issue is of key importance in Thailand and is aligned with the Thailand’s 2nd National Logistics and Supply Chain Research Strategies (2012-2016) focusing on healthcare green logistics. Pharmaceuticals in hospitals account for more than 50% of the total hospital purchasing budget. Moreover, the overuse of medicine was generally found to be prevalent in Thai hospitals despite serious financial concerns. The aim of this study was twofold: Phase (i) to investigate the movement and lifecycle of pharmaceuticals within Thai hospital sites and Phase (ii) identify the GL practices that effectively control/minimize the use of pharmaceuticals. Research Approach Using a case research method six hospitals were examined, to give coverage of the different types/sizes, locations and a range of environmental performance issues. Hospital visits were undertaken during January to July 2014, to obtain data by using a multi-method approach: interviews, documentation reviews and in situ observation. Purposive respondent sampling was undertaken to ensure that data was collected from staff with experience of pharmaceutical management and a bespoke form of content analysis used for the data review before further cross-case analysis. Findings and Originality The result of Phase (i) revealed that pharmaceutical flows appeared to be sophisticated and problematic, caused by issues such as limited budget allocation, ineffective governmental processes, and the over-prescribing of medicine for chronic patients. The findings also identified effective GL practices such as: (i) prescribing medicines for only 1-2 months for some patient conditions/drug types and increasing the frequency of follow-up reviews, (ii) conducting a medicines return programme and (iii) having a clearly defined system of pharmaceutical product review. The outcomes of the study proposed key practices to support a Sustainable Health System at both policy and hospital levels. Within this were: (i) a representation of stakeholder views, (ii) the provision of healthcare education and communication, (iii) addressing self-health management issues and (iv) planned system review and improvement. The design and execution of such a system should be grounded in Thailand’s Sufficiency Economy Philosophy (SEP) concept. Research Impacts In the GL research paradigm public healthcare, developing nations, human elements and life-cycle products have received limited attention; this study therefore contributes to the reduction of these gaps. The SEP concept was highly recommended by the United Nations, instead of Sustainable Development, in addressing GL practices in Thai culture to promote sustainable health standards and this underpins the focus and the originality/impact of this study. Practical Impacts This study recommends that staff in Thai hospitals focus on effective pharmaceutical management to contribute to the sustainability of good GL practices (as identified) and to the design and delivery of a Sustainable Health System in Thailand. The study presents guidance and support to do this.

No description available.

The objective of this study was to evaluate the status of the counterfeit pharmaceuticals in Jordan. Four types of pharmaceuticals Lipitor (Atorvastatin-calcium), Concor (bisoprolol fumarate), Co-Diovan (Valsartan, hydrochlorothiazide) and Plavix (clopidogrel) were subjected to physical and chemical analysis. 173 samples of these four medicines were collected from the three most populated cities in the country, namely Amman, the capital of Jordan, Zarqa and Irbid. A sample of confiscated counterfeited medicines was obtained from the health authorities and tested utilising the HPLC and dissolution testing, in order to validate the reliability of the testing procedures. Samples were then tested using High Performance Liquid Chromatography (HPLC) and dissolution tests in order to assess the quality of these samples. Results of both chemical and physical analyses revealed that all samples were found to fall within the specification limits of United States Pharmacopoeia (USP) and no evidence was found of any counterfeit drug products in the samples examined. Since this study found no indication of a drug counterfeiting problem in Jordan, the researcher has concluded that there seemed to be two contributing factors to this result: first, the very effective legislative campaigns conducted by the health authorities’ in Jordan against counterfeit trade through new public health and pharmacy law which has been launched in 2008. Second, the rigorous tough enforcement measures conducted by health and law enforcement agencies in the country.

In recent years, a growing number of human pharmaceuticals have been detected in the aquatic environment, generally at low concentrations (sub-ng/L to low μg/L). These compounds are characterised by highly specific mechanisms of action, high potency and prolonged activity in order to minimise dosing requirements and potential toxicity in patients. Among the various classes of pharmaceuticals, steroids and anti-steroids are widely used, as shown by the analysis of their clinical use carried out at the beginning of this Ph.D. project. Although the amounts used are much lower than the amounts of some other pharmaceuticals (e.g. analgesics), their ability to affect important physiological processes in fish (e.g. reproduction) at very low concentrations (ng/L) suggest that this class of compounds should represent a high priority for ecotoxicological research. In particular, this Ph.D. project addressed the question of whether or not dutasteride, a human pharmaceutical mainly used to treat benign prostatic hyperplasia, may cause adverse effects in the teleost fathead minnow (Pimephales promelas) by inhibiting the activity of both isoforms of 5α-reductase (5αR), the enzyme which convert testosterone into dihydrotestosterone (DHT). The theoretical framework used to guide the design of the experimental studies was based on the combination of several conceptual approaches, including the study of the evolutionary degree of conservation and functionality of the drug target in non-target species, and the cross-species extrapolation of pharmacological and toxicological information generated during pre-clinical and clinical studies in mammals during drug development. The results obtained during the first phase of this Ph.D. project strongly suggested that DHT has a physiological role in the fathead minnow. In fact, 5αRs are evolutionary conserved in this species, 5αRs genes are expressed in tissues such as the testis, and DHT circulates in fathead minnow plasma at concentrations similar to those detected in humans. These findings represented the rationale for testing the effects of dutasteride in the fathead minnow. Dutasteride caused significant adverse effects in all the in vivo studies performed in order to evaluate its potential toxicity on fish, including early life stage and short term reproduction studies, and all the tested life stages were sensitive to the inhibition of 5αRs activity; however, none of the observed adverse effects occurred at concentrations of exposure lower than 32 μg/L (measured concentration). The results also showed that female fish are highly sensitive to disruption of the androgenic pathways, highlighting their utility for the evaluation of potential adverse effects caused by anti-androgens on fish. In conclusion, the results presented in this Thesis suggest that, at present, the potential presence of dutasteride in the environment does not represent a risk to wild fish populations, due to the high concentrations required to elict significant adverse effect (LOEC = 32 μg/L) and the low volume of drug prescribed every year (5.07 kg in UK in 2006). However, the high bioaccumulation factor of dutasteride suggest that further studies should be conducted to elucidate the role played by the bioaccumulation process in the toxicity responses observed in fish.

Fish may be exposed to an array of pharmaceuticals that are discharged into the aquatic environment, paralleling advances in medical knowledge, research and technology. Pharmaceuticals by their nature are designed to target specific receptors, transporters, or enzymes. Nuclear receptors (NRs) are often a key component of the therapeutic mechanism at play, and many of these are conserved among vertebrates. Consequently, fish may be affected by environmental pharmaceutical exposure, however there has been relatively little characterisation of NRs in fish compared with in mammals. In this thesis common carp (C. carpio) were exposed to selected pharmaceuticals in vitro and in vivo to investigate effects centred on the pregnane X receptor (PXR) and peroxisome proliferator-activated receptor alpha (PPARα), two key NRs involved in organism responses to pharmaceutical exposure. The PXR acts as a xenosensor, modulating expression of a number of xenobiotic metabolising enzymes (XMEs) in mammals. In a primary carp hepatocyte model it was shown that expression of a number of XMEs was altered on exposure to rifampicin (RIF), as occurs in mammals. This response was repressed by addition of ketoconaozle (KET; PXR-antagonist), indicating possible PXR involvement. The genes analysed showed up-regulation on exposure to ibuprofen (IBU) and clofibric acid (CFA), but not clotrimazole (CTZ) or propranolol (PRP). The lack of response to mammalian PXR-agonist CTZ was unexpected. In contrast, the same XME genes were found to be up-regulated in vivo after 10 days of exposure of carp to CTZ, although this response occurred only for a relatively high exposure concentration. CTZ was found to concentrate in the plasma (with levels up to 40 times higher than the water). Development and application of a reporter gene assay to measure PXR activation in carp (cPXR) and human PXR showed CTZ activation of cPXR, supporting data from the in vivo studies. Furthermore, activation was seen at concentrations as low as 0.01 μM. Interestingly RIF did not induce a response in the cPXR reporter gene assay, contrasting with the hepatocyte culture work. Taken together, the data presented here suggests divergence in the PXR pathway between mammals and fish in terms of ligand activation and downstream gene targets. PPARα was investigated in carp in vivo using CFA as a mammalian PPARα-agonist. Overall the resulting data suggested a broadly similar role for this NR in lipid homeostasis in fish as for mammals, with a number of PPARα-associated genes and acyl-coA oxidase (ACOX1) activity up-regulated in response to CFA exposure. A number of XMEs were also up-regulated by CFA (in vivo and in vitro), potentially extending the role of PPARα in fish (carp) to regulation of xenobiotic metabolism. The work presented has provided further characterisation of PXR and PPARα in fish. Elucidation of these pathways is vital to provide meaningful data in terms of establishing toxicity and mechanism-of-action data for pharmaceuticals and other compounds in fish, to allow validation of read-across approaches and ultimately aid in their environmental risk assessment. In vitro approaches are attractive ethically, financially and can provide useful mechanistic characterisation of compounds and the primary hepatocyte model and reporter gene assays used here show potential for the screening of pharmaceutical compounds in fish. However, further understanding of the metabolism of drugs and chemicals in fish is required to establish the true value of these methods for informing on possible effects in fish, in vivo.