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Wong Suk-kwan, Amy. / Thesis (M.Ph.)--Chinese University of Hong Kong, 1988. / Bibliography: leaves 184-206.

by Chiu Pui Yu. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (leaves 86-118). / Abstracts in English and Chinese. / Title Page --- p.i / Abstract --- p.ii-iv / Acknowledgement --- p.v / Table of Contents --- p.vi-viii / List of Tables --- p.ix / List of Figures --- p.x-xii / List of Abbreviations --- p.xiii / Chapter Section I: --- Introduction / Chapter Chapter 1: --- Overview --- p.1-2 / Chapter Chapter 2: --- Teratogenic Effects of Hyperglycemia / Chapter 2.1 --- What is Hyperglycemia --- p.3 / Chapter 2.2 --- Teratogenic Effects of Hyperglycemia --- p.4-6 / Chapter 2.2.1 --- Human Studies / Chapter 2.2.2 --- Animal Studies / Chapter 2.3 --- Timetables for Embryogenesis: Rats versus Humans --- p.7 / Chapter 2.4 --- Mechanisms of Hyperglycemia Induced Teratogenesis --- p.8-12 / Chapter 2.4.1 --- What are Free Radicals? / Chapter 2.4.2 --- Major Free Radical Species Involvedin Hyperglycemic Teratogenesis / Chapter 2.4.3 --- Molecular Damage Induced by Reactive Oxygen Species / Chapter 2.4.4 --- Supporting Evidence of Reactive Oxygen Species Causing Anomalies / Chapter 2.4.5. --- Hyperglycemia and Formation of Free Radicals / Chapter Chapter 3: --- Caffeine as Teratogen and Antioxidant / Chapter 3.1 --- Popularity of Caffeine --- p.13 / Chapter 3.2 --- Basic Metabolism of Caffeine --- p.14 / Chapter 3.3 --- Biological Actions of Caffeine --- p.15 / Chapter 3.4 --- Teratogenicity of Caffeine --- p.16-20 / Chapter 3.4.1 --- Animal Studies / Chapter 3.4.1.1 --- Teratogenic Effects of Caffeine in Animals / Chapter 3.4.1.2 --- Teratogenic Dose of Caffeine / Chapter 3.4.1.3 --- Interspecies Sensitivity / Chapter 3.4.2 --- Human Studies / Chapter 3.5 --- Possible Mechanisms for the Teratogenic Actions of Caffeine --- p.21 / Chapter 3.6 --- Caffeine as an Antioxidant --- p.22 / Chapter 3.7 --- Combined Effects of Caffeine with Other Substances --- p.23 / Chapter Chapter 4: --- Combined Effects of Hyperglycemia and Caffeine on Early Embryogenesis- A Question to be Answered / Chapter 4.1 --- Possible Links between Hyperglycemia and Caffeine --- p.24 / Chapter 4.2 --- Objectives of the Present Study --- p.25 / Chapter 4.3 --- Hypothesis --- p.26 / Chapter Section II: --- Research Designs and Methods / Chapter Chapter 5: --- Materials and Methods / Chapter 5.1 --- Licenses --- p.27 / Chapter 5.2 --- Overall Study Design --- p.28-40 / Chapter 5.2.1 --- Whole Embryo Culture Model / Chapter 5.2.1.1 --- Animals / Chapter 5.2.1.2 --- Explantation of Embryos and Serum Collection / Chapter 5.2.1.3 --- Preparation of Serum / Chapter 5.2.1.4 --- Culture Media / Chapter 5.2.1.5 --- Embryo Culture / Chapter 5.2.2 --- Experimental Groups / Chapter 5.2.3 --- Morphological Assessment / Chapter 5.2.4 --- Quantitation of Oxidative Stress / Chapter 5.2.5 --- Protein Assay / Chapter 5.3 --- Statistical Evaluation --- p.41 / Chapter Chapter 6: --- Laboratory Considerations / Chapter 6.1 --- Whole Embryo Culture Model --- p.42-43 / Chapter 6.1.1 --- Subjects / Chapter 6.1.2 --- Time Mating / Chapter 6.1.3 --- Culture Medium / Chapter 6.1.4 --- Gas Phase and Rotating Bottle Culture Method / Chapter 6.2 --- Quantification of Oxidative Stress --- p.47-49 / Chapter 6.2.1 --- 8-Isoprostaglandins F2a as a Marker / Chapter 6.2.2 --- Assay for 8-Isoprostaglandins F2a / Chapter 6.2.2.1 --- Enzyme Immunoassay versus Gas Chromatography/ Mass Spectrometry / Chapter Section III: --- Results / Chapter Chapter 7: --- Results / Chapter 7.1 --- Justifications of Methods of Statistical Analysis --- p.50 / Chapter 7.2 --- Effects of Hyperglycemia on Early Embryogenesis --- p.51-56 / Chapter 7.2.1 --- Effects of Hyperglycemia on Morphological Development / Chapter 7.2.2 --- Effects of Hyperglycemia on Production of 8-isoprostaglandins F2a / Chapter 7.2.3 --- Effects of Hyperglycemia on Total Protein Content / Chapter 7.3 --- Effects of Caffeine on Early Embryogenesis --- p.57-61 / Chapter 7.3.1 --- Effects of Caffeine on Morphological Development / Chapter 7.3.2 --- Effects of Caffeine on Total Protein Content / Chapter 7.4 --- Combined Effects of Hyperglycemia and Caffeine on Early Embryogenesis --- p.62-66 / Chapter 7.4.1 --- Combined Effects of Hyperglycemia and Caffeine on Morphological Development / Chapter 7.4.2 --- Combined Effects of Hyperglycemia and Caffeine on Production of 8-isoprostaglandins F2a / Chapter 7.4.3 --- Combined Effects of Hyperglycemia and Caffeine on Total Protein Content / Chapter Section IV: --- Discussion and Conclusions / Chapter Chapter 8: --- Discussion --- p.67-83 / Chapter Chapter 9: --- Conclusions and Future Directions --- p.84 / Appendices --- p.85 / References --- p.86-118

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Since the introduction of Sodium-glucose cotransporter 2 (SGLT2) inhibitors as guideline therapy for both uncontrolled type 2 diabetes mellitus and heart failure, these medications have become popular options as add-on therapy. This class of medication reduces blood glucose levels via inhibition of glucose reabsorption in the proximal convoluted tubules leading to enhanced renal excretion. Not only do SGLT2 inhibitors provide advantages in improved glucose control, but also have proven to reduce cardiovascular mortality. Generally, SGLT2 inhibitors are well tolerated, however adverse reactions of genitourinary tract infections secondary to glucosuria and hypotension from associated osmotic diuresis have been reported. Less commonly, pancreatitis has been associated with use of SGL2 inhibitors. We present a case of suspected empagliflozin induced pancreatitis notable for delayed onset at approximately 120 days since SGLT2 inhibitor initiation.

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

Some studies have demonstrated that the effects of a drug may be different, depending on whether the drug is self-administered or passively received by the subject. Most of the studies which have examined this phenomenon have not examined the effects of a drug following each of a series of administrations. Moreover, the mechanism mediating differences between self-administered and passively received drugs has not been determined. The present experiments used a yoked-control design to examine the development of tolerance to the ataxic effects of heroin and of ethanol in rats that self-administer the drugs and rats that passively received them. Results demonstrate that rats that passively received heroin, but not those that self-administered the drug, were significantly impaired following the initial administrations. During the first administration sessions, rats that self-administered ethanol were as impaired as their partners that passively received, but within a few sessions self-administering rats developed tolerance to the ataxic effect of the ethanol, while their yoked partners did not. The results also suggest that the faster tolerance development in rats that self-administered ethanol may have been mediated by differences in Pavlovian conditioning in these subjects, which demonstrated larger compensatory conditional responses in the form of “hypertaxia” than did their yoked partners. The results indicated that some component of the self-administration process contributed to the Pavlovian conditioning, and hence, faster tolerance development, of self-administering animals. The data suggest that studies in which drugs are passively received may overestimate the dose that is necessary to produce tolerance in self-administering animals. Models based on such studies, then, may require modification before they are applied to situations which involve self-administration of drugs. / Thesis / Doctor of Philosophy (PhD)

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The liver is a multi-functional and highly regenerative organ. While resilient, the liver is susceptible to organ damage and failure. In both the acute and chronic settings liver disease has dire consequences for health. A common cause of liver damage is adverse reactions to drugs which can lead to drug induced liver injury (DILI). This creates major problems for patients, clinicians, the pharmaceutical industry and regulatory authorities. In the context of drug overdose or serious adverse reactions, liver failure can be acute and life threatening, and in some cases require orthotopic liver transplantation. While transplantation is highly successful, such an approach has limitations and justifies basic science attempts to develop better human models to study liver injury and to develop scalable intervention strategies. With this in mind, we have studied the importance of microRNAs (miRs) in regulating human drug metabolism in pluripotent stem cell – derived hepatocytes and their potential to reduce liver toxicity in response to toxic levels of paracetamol. miRs are small non-coding RNAs that are approximately 20 - 24 nucleotides long and their major function is to fine tune gene expression of their target genes. Recently, it has been demonstrated that microRNAs play a role in regulating the first phase of drug metabolism however the second phase of drug metabolism, drug conjugation, has not been studied in detail. Drug conjugation is a crucial stage in human drug metabolism, and any alterations in this process can lead to changes in compound pharmacology, including therapeutic dose and clearance from the body. To test the importance of miRs in regulating phase II drug metabolism we opted to study the metabolism of a common used analgesic, paracetamol. When taken in the appropriate amounts paracetamol is modified by sulfotransferases (SULTs) and UDP - glucuronosyltransferases (UGTs) and removed from the body without organ damage. However, when paracetamol is taken above the recommended dose it is metabolised by phase I enzymes to generate a toxic intermediate N-acetyl-p-benzoquinone imine (NAPQI), which if untreated can lead to massive hepatocyte cell death and liver failure, placing the patient in a life threatening situation. In order to promote non-toxic drug metabolism, in the context of drug overdose, we employed candidate miRs to regulate different parts of the paracetamol metabolism pathway. In summary, we have focused on studying human drug metabolism in the major metabolic cell type of the liver, the hepatocyte. We have identified a novel microRNA (called miR-324-5p) which regulates phase II drug metabolism and reduces cell cytotoxicity. Additionally, a supportive role of anti-microRNA- 324 in response to fulminant plasma collected from paracetamol overdose patients is also observed. The findings of this project are novel, provide proof of concept and exemplify the power of stem cell based models to identify new approaches to treating human liver damage.

Idiosyncratic drug reactions (IDRs) are unpredictable adverse drug reactions. Their exact mechanisms are unknown but most appear to be immune-mediated. Mechanistic studies require valid animal models, but there are very few available and none for the study of drug-induced agranulocytosis. Thus, the first part of my thesis has focused on the development of an animal model of agranulocytosis. We pursued many attempts to develop one in rabbits, guinea pigs, and rats by treatment with aminopyrine, amodiaquine, and clozapine and manipulating the factors hypothesized to be involved in the mechanism of IDRs such as reactive metabolite formation/detoxication and immune stimulation. Clozapine-induced agranulocytosis is not associated with immune memory, which suggests that it may not be immune-mediated. Therefore, other factors, specifically selenium and vitamin C deficiencies, were assessed as possible risk factors for clozapine-induced agranulocytosis. Despite many attempts, we were not able to develop an animal model of idiosyncratic drug-induced agranulocytosis. The second part of this thesis was focused on investigating the effects of clozapine on neutrophils. It is known that the reactive metabolite of clozapine increases neutrophil apoptosis in vitro; however, it was not clear that the conditions of these experiments reflect in vivo conditions. Therefore, the effect of clozapine on neutrophil kinetics in vivo was examined. We found that clozapine treatment decreased the half-life of circulating neutrophils and increased the rate of release of neutrophils in rabbits. Thus, even though these animals did not develop agranulocytosis clozapine did appear to cause neutrophil damage that was compensated for by an increased production of neutrophils. Failure of the bone marrow to keep up with the increased rate of neutrophil destruction in certain individuals could result in agranulocytosis. Alternatively, damage to neutrophils could lead to an immune response in some patients that results in agranulocytosis. The failure to develop an animal model of drug-induced agranulocytosis despite many attempts using interventions based on the current mechanistic hypotheses suggests that these hypotheses are wrong. However, it is also possible that we are just unable to overcome the default response of immune tolerance; future studies will examine this possibility and the mechanism of clozapine-induced neutrophil damage.