published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Thesis (M. Med. Sc.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 30-35).

Thesis (M.Med.Sc.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 30-35). Also available in print.

Hypercholesterolemia is one of the most prevalent, yet underdiagnosed diseases faced by the medical community today. Its prevalence can largely be attributed to diet, lack of exercise, and lifestyle choices such as smoking or drinking, but there is also a genetic component. Familial Hypercholesterolemia is the genetic disorder in which a person is unable to properly eliminate levels of low-density lipoprotein, mostly due to an ineffective receptor in the liver. Hypercholesterolemia has been positively correlated with the prevalence of cardiovascular disease, and patients with the severe homozygous familial hypercholesterolemia typically have abbreviated lifespans. In these situations, and also those less acutely dire, it’s necessary to rely on medication to help maintain one’s cholesterol levels to within low risk ranges. High does statin therapy has been shown to be the most effective therapy for maintaining LDL cholesterol. It has become the standard regardless of the cause of hypercholesterolemia because of its few side effects, its high tolerability, its ease of administration, its safety, and most of all because of its immense efficacy. This has not, however, prevented the exploration into other types of cholesterol therapies that may work in concurrence with statins. Drug classes such as PCSK9 inhibitors, ApoB inhibitors, MTP inhibitors, and thyromimetics have all been explored with varying success. Each of these potential therapies has a separate mechanism of action, allowing for modulation in conjunction with statins. PCSK9 inhibitors and ApoB inhibitors appear to provide the most upside by virtue of LDL lowering capabilities, followed by a drug known as ezetimibe that reduces dietary cholesterol uptake in the gut. MTP inhibitors have been shown to be effective therapies for homozygous familial hypercholesterolemia specifically due to their function of lowering LDL particle creation rather than LDL receptor number or function as statins and PCSK9 inhibitors do. Thyromimetics have yet to yield an effective therapy for cholesterol treatment, but the hope remains alive that this could come to fruition in the future.

Statins and fibrates are the most widely used pharmaceuticals in developed countries for the treatment of hyperlipidemia. They reach the aquatic environment mainly via wastewater treatment plants and have been detected at concentrations of ng to µg/L. They are “pseudopersistent” due to their continuous and increasing input into the aquatic environment. Cholesterol is essential to all animals, so inhibition of its synthesis by these drugs could have negative consequences in non-target species. Currently little is known regarding the possible effects of statins and fibrates on aquatic organisms. Thus, this thesis investigates the effects of atorvastatin (ATV; statin) and gemfibrozil (GEM; fibrate) on rainbow trout and zebrafish in vivo and in vitro. Intraperitoneal injection of ATV, GEM, or the combination of the two drugs (A+G) into rainbow trout resulted in a nearly 30% reduction of cellular cholesterol content. Additionally, gene expression related to lipid homeostasis (LDL-r, HMGCR-1, and SREBP-1) was elevated. Furthermore, plasma creatine kinase activity and skeletal muscle gene expression related to rhabdomyolysis (atrogin-1 and f-box 25) were elevated. Plasma cortisol concentration was reduced in injected trout, suggesting that either the reduction in cholesterol resulted in treated fish lacking a proper stress response or that the treated fish were simply not responsive to the stress protocol. Feeding zebrafish ATV, GEM, or A+G daily over a 30 day period resulted in nearly a 30% reduction of whole-body cholesterol content and a concomitant change in gene expression related to lipid homeostasis (SREBP-1, SREBP-2, HMGCR-1, PPARα, and PPARγ). Moreover, sex steroids (testosterone and estradiol) were also reduced. Finally, exposing rainbow trout hepatocytes to ATV at 4.5 or 45 µg/L for 3 or 6 h resulted in reduced 14C incorporation into cholesterol and cholesteryl ester. Elevated gene expression related to lipid homeostasis (HMGCR-1, SREBP-1, and PPARγ) also occurred. This thesis demonstrated that ATV and GEM affected fish cholesterol and steroid hormone contents, as well as molecular markers of rhabdomyolysis. Whether these changes impact fish fitness remains to be determined.

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biological and Medical Sciences Evaluatiton of the expresion and co-expresion of endoglin and VCAM-1 in the aorta on apoE- deficient mice Diploma thesis Lucie Minaříková Supervisor: Mgr. Jana Rathouská Background: The aim of this work was to monitor the expression and a possible co-expression of endoglin (TGF-β receptor III) and VCAM-1 in mouse aortic endothelium. As an experimental model, we used the mouse strain C57BL/6J, that was genetically modified, and is characteristic by a deficit of apolipoprotein E. Methodes: In the study, we focused on testing the mouse strain C57BL/6J with gene knockout for apolipoprotein E in different stages of the atherosclerotic process. 10 weeks old female mice were divided into three groups and fed diets with different content of cholesterol. One experimental group was fed a standard diet (called "chow type diet") for a period of two months. The other two groups were fed a diet containing 21% fat (called "Western type diet") for a period of two and four months. For the determination of the levels of total cholesterol, a biochemical analysis of blood was performed. Obtained parts of ascending aorta were analyzed by ImmPRESSTM immunohistochemical method with the detection reagent DAB....

Class of 2006 Abstract / Objectives: To evaluate the efficacy of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, in reducing all-cause mortality and death due to rejection when administered to thoracic organ transplant patients. Methods: Using the following Medical Subject Heading (MeSH) terms and text words: hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, heart transplantation, and lung transplantation, the following data bases were searched: Cochrane Central Register of Controlled Trials (First Quarter 2006), Cochrane Database of Systematic Reviews (First Quarter 2006), Database of Abstracts and Reviews of Effects (First Quarter 2006), ACP Journal Club (1991to January/February 2006), International Pharmaceutical Abstracts (1970-February 2006), and Medline (1966 to February 2006) for English language reports. Three prospective randomized controlled trials (RCTs) and 3 retrospective observational studies were identified as using statins to reduce mortality and death due to fatal rejection in thoracic organ transplant patients. Results: Using all 6 studies (n= 1770 patients), statins decreased mortality by 77% (OR=0.23; [95% confidence interval 0.16-0.34] Z test, P<0.001). Sub-analysis using only RCT heart transplant data showed that statins decreased mortality by 69% (OR=0.31; [95% confidence interval 0.09-1.07] Z test, P<0.003). Sub-analysis using retrospective heart transplant data showed that statins decreased mortality by 75% (OR=0.25; [95% confidence interval 0.16-0.39] Z test, P<0.001). Retrospective lung transplant results (1 study) showed statins decreased mortality by 90% (OR=0.10; [95% confidence interval 0.03-0.34] Z test, P<0.001). Statins also significantly reduced death due to rejection (OR=0.22; [95% confidence interval 0.13-0.37]). Using all 6 studies (n= 1770 patients), statins decreased death due to rejection by 78%. Conclusions: In patients undergoing thoracic organ transplantation, statins significantly decrease all-cause mortality and death due to rejection. Therefore, statins should be routinely administered to these patients following transplant surgery.

Thesis (M.S.)--Ball State University, 2009. / Title from PDF t.p. (viewed on Nov. 30, 2009). Includes bibliographical references (p. 61-67).

Phosphoinositide 3-kinases (PI3Ks) are a family of proteins involved in many different aspects of cell signaling. To date, eight different human PI3K isoforms have been identified, and distinct roles are beginning to emerge for each family member. Statins, HMG co-A reductase inhibitors used clinically to lower LDL cholesterol levels, also act through the PI3K signaling pathway to regulate cholesterol independent of their lipid-lowering effects. In an effort to discover the role of pl 10f3 in mediating non-lipid lowering effects of pravastatin, a mutant of p110(3 was overexpressed in human coronary artery endothelial cells (HCAEC) to form a dominant negative model (p110(3 DN). Silence si-RNA as an alterative tool was also optimized to diminish p110(3 protein expression successfully. HepG2 3: RE was used to monitor statins function by assaying luciferase expression. Results from these studies will determine the contribution of p110f3 in mediating selective cellular responses to statin. / Department of Biology

Thesis (M.S.)--University of Toledo, 2010. / Typescript. "Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Masters of Science Degree in Pharmaceutical Sciences, Administrative Pharmacy Option." "A thesis entitled"--at head of title. Title from title page of PDF document. Bibliography: p. 61-69.