<p>Zbog visoke stope morbiditeta i mortaliteta od kardiovaskularnih bolesti, udeo lekova za terapiju kardiovaskularnih bolesti značajno učestvuje u ukupno utro&scaron;enoj količini lekova u svetu. Evidentan je porast potro&scaron;nje lekova za kardiovaskularne bolesti. Radi postizanja &scaron;to je moguće vi&scaron;eg stepena racionalizacije terapije u većini zemalja stručna tela donose farmakoterapijske smernice kako bi se mogućnost pogre&scaron;nog lečenja svela na najmanju moguću meru. Na ovaj način lekaru-praktičaru pružena je sigurnost pravilnog izbora i najadekvatnijeg postupka u datim okolnostima. Ciljevi ovog istraživanja bili su: 1) izračunavanje ukupne vanbolničke potro&scaron;nje lekova za lečenje kardiovaskularnih bolesti na teritoriji Novog Sada i njeno poređenje sa propisivanjem u Republici Srbiji i u zemljama sa razvijenom farmakoterapijskom praksom; 2) analiza strukture propisanih lekova za lečenje kardiovaskularnih bolesti (grupa C prema ATC klasifikaciji) po grupama i njeno poređenje sa propisivanjem u Republici Srbiji i u zemljama sa razvijenom farmakoterapijskom praksom; 3) analiza strukture propisanih lekova po dijagnozama i provera usklađenosti sa farmakoterapijskim smernicama; 4) komparacija propisanih lekova sa morbiditetnom statistikom kardiovaskularnih bolesti; 5) analiza farmakoekonomskih aspekata propisivanja lekova za kardiovaskularne bolesti. Sprovedeno istraživanje spada u IV fazu kliničkih ispitivanja-farmakoepidemiolo&scaron;ko, retrospektivno, opservaciono. Podaci su prikupljeni na osnovu izve&scaron;taja iz elektronske baze podataka za period od 6 meseci (01. 01. 2012 &minus; 01. 07. 2012), na teritoriji grada Novog Sada. Na osnovu ovih podataka na teritoriji grada Novog Sada analizirana je upotreba lekova za kardiovaskularne bolesti na 100% uzorku stanovnika. Ispitivanje se sastojalo iz dva dela. Prvi deo obuhvata prikupljanje, obradu i analizu podataka o ukupno propisanoj količni lekova za kardiovaskularne bolesti na teritoriji grada Novog Sada. U drugom delu istraživanja kori&scaron;ćenjem podataka dobijenih iz državne &bdquo;Apoteke Novi Sad&ldquo; detaljnije je analizirana upotreba lekova za lečenje kardiovaskularnih bolesti izdatih na recept. Upotreba lekova analizirana je: prema uzrastu i polu pacijenata, prema dijagnozama za koje su lekovi propisani i prema ceni. Sruktura upotrebe lekova po indikacijama za dijagnoze kod kojih je ukupna upotreba propisanih lekova bila veća od 1 DDD/1000stanovnika/dan upoređena je sa postojećim nacionalnim vodičima i sa upotrebom u zemljama sa razvijenom farmakoterapijskom praksom, odnosno sa međunarodnim vodičima. Ovi podaci upoređeni su sa morbiditetnom statistikom na teritoriji grada Novog Sada. Ukupno propisana količina lekova za kardiovaskularne bolesti u posmatranom periodu iznosila je 399,79 DDD/1000st/dan. Od te količine, preko polovine (201,11DDD/1000st/dan) propisivanih lekova za kardiovaskularne bolesti su lekovi koji deluju na sistem renin-angiotenzin, slede blokatori kalcijumskih kanala, zatim blokatori beta-adrenergičkih receptora, a na četvrtom mestu po ukupno propisanoj količini su lekovi za terapiju bolesti srca. Od najče&scaron;ćih dijagnoza za koje su propisivani lekovi za kardiovaskularne bolesti, najzastupljenije su bile arterijska hipertenzija, a potom ishemijska bolest srca. Upotreba lekova za kardiovaskularne bolesti u vanbolničkoj sredini na teritoriji grada Novog Sada (399,79 DDD/1000st/dan) vi&scaron;a je u odnosu na zemlje u okruženju (Hrvatsku, Crnu Goru), a niža u odnosu na zemlje sa razvijenom farmakoterapijskom praksom. U odnosu na zemlje sa razvijenom farmakoterapijskom praksom postoje odstupanja u pogledu strukture propisivanja. Struktura propisivanja lekova za kardiovaskularne bolesti odstupa od važećih nacionalnih vodiča o racionalnoj upotrebi lekova za kardiovaskularne bolesti u Republici Srbiji. Istovremeno struktura propisanih lekova nije u skladu sa morbiditetnom statistikom kardiovaskularnih bolesti prema zvaničnim podacima. Među 10 najče&scaron;će propisanih lekova nalaze se i skupi lekovi, koji imaju adekvatne, a mnogo jeftinije paralele. Nedovoljno i neracionalno lečenje kardiovaskularnih bolesti verovatno su jedan od značajnih razloga za visoku smrtnost od kardiovaskularnih bolesti u Srbiji.</p> / <p>Due to high rates of morbidity and mortality from cardiovascular diseases, the share drugs for the treatment of cardiovascular diseases significantly contributes to a total utilization among drugs in the world. There is an evident increase in the consumption of drugs for cardiovascular diseases. In order to achieve as much as possible a higher level of rationalization of therapy in most countries the professional bodies making pharmacotherapeutic guidelines to the possibility of the wrong treatment was reduced to a minimum. In this way, the physician-practitioner provided the security proper selection and the most appropriate procedure in the circumstances. The objectives of this study were: 1) the calculation of the total outpatient consumption of drugs for the treatment of cardiovascular diseases on the territory of Novi Sad and its comparison with the prescribing in the Republic of Serbia and the countries with developed pharmacotherapeutical practice; 2) analysis of the structure of prescribed drugs for the treatment of cardiovascular diseases (group C according to the ATC classification) by the groups and its comparison with the prescribing in the Republic of Serbia and the countries with developed pharmacotherapeutical practice 3) analysis of the structure of prescribed drugs per diagnosis and verification of compliance with pharmacotherapeutic guidelines; 4) comparison of prescribed drugs with morbidity statistics cardiovascular diseases; 5) analysis of pharmacoeconomic aspects of prescribing drugs for cardiovascular diseases. A research conducted among the phase IV clinical trials-pharmacoepidemiological, retrospective observational. Data were collected on the basis of a report from the electronic database for the period of 6 months (01. 01. 2012 - 01. 07. 2012), on the territory of the city of Novi Sad. Based on these data on the territory of the city of Novi Sad analyzed the use of drugs for cardiovascular diseases at 100% sample of the population. The research consisted of two parts. The first part comprises the collection, processing and analysis of data on the total quantity of the prescribed cardiovascular drugs on the territory of the city of Novi Sad. In the second part of this research using data from the public &quot;Pharmacy Novi Sad&quot; is a more detailed analysis of the utilization of drugs for the treatment of cardiovascular diseases of prescription. The utilization of drugs is analyzed: according to the age and sex of patients, in diagnosis for which the drugs prescribed and to the cost. Structure of the use of drugs by indications for diagnosis in which the total utilization of prescribed drugs was greater than 1 DDD/1000inhabitants/day was compared with the existing national guidelines and use in countries with developed pharmacotherapeutical practice, and with international guidelines. These data were compared with morbidity statistics on the territory of the city of Novi Sad. Total amount of prescribed drugs for cardiovascular diseases in the examined period was 399.79 DDD/1000inh/day. Of this amount, more than half (201.11 DDD/1000inh/day) were drugs acting on the renin-angiotensin system, followed by calcium channel blockers, beta adrenergic receptor blockers, and fourth in total prescribed quantity drugs for treatment of heart diseases. Of the most common diagnosis for which drugs for cardiovascular diseases were prescribed, the most common were arterial hypertension, and then ischemic heart disease. The use of drugs for cardiovascular diseases in outpatient environment on the territory of the city of Novi Sad (399.79 DDD/1000inh/day) is higher compared to neighboring countries (Croatia, Montenegro), and lower than in countries with developed pharmacotherapeutical practice. Compared to countries with developed pharmacotherapeutical practice there are variations in terms of the structure of prescribing. Structure of prescribing of drugs for cardiovascular diseases deviates from the existing national guidelines on rational use of drugs for cardiovascular diseases in the Republic of Serbia. At the same time the structure of prescribed drugs is not in compliance with morbidity statistics cardiovascular diseases according to official data. Among the 10 most commonly prescribed drugs are costly drugs, that have adequate, and much cheaper parallels. Insufficient and irrational treatment of cardiovascular diseases are probably one of the major reasons for the high mortality from cardiovascular diseases in Serbia.</p>

Cheng Wai Ring Caroline. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (leaves 74-84). / Abstracts in English and Chinese. / Acknowledgement --- p.i / Abstract --- p.ii / 摘要 --- p.iv / Table of contents --- p.vi / Publications --- p.x / List of figures --- p.xi / List of tables --- p.xii / Abbreviations --- p.xiii / Chapter Chapter 1 --- Introduction / Chapter 1.1 --- Coronary Heart Disease --- p.2 / Chapter 1.1.1 --- Epidemiology --- p.2 / Chapter 1.2 --- Hypercholesterolemia and CHD --- p.3 / Chapter 1.2.1 --- Atherosclerotic plaque and lipoprotein --- p.4 / Chapter 1.2.2 --- NCEP ATP III guidelines --- p.5 / Chapter 1.2.2.1 --- CHD risk assessment --- p.5 / Chapter 1.2.2.2 --- Target lipid control --- p.8 / Chapter 1.2.2.3 --- Therapeutic lifestyle changes --- p.9 / Chapter 1.2.2.4 --- Pharmacological interventions --- p.10 / Chapter 1.2.2.5 --- Adherence to lipid-lowering therapy --- p.13 / Chapter 1.3 --- Adherence to drug therapy --- p.14 / Chapter 1.3.1 --- Definition of adherence --- p.14 / Chapter 1.3.2 --- Methods to assess adherence --- p.16 / Chapter 1.3.2.1 --- Expressions of adherence measurements --- p.20 / Chapter 1.3.3 --- Time effect on adherence --- p.21 / Chapter 1.3.4 --- Predictors of adherence --- p.22 / Chapter 1.3.5 --- Impact of poor adherence to statins --- p.23 / Chapter 1.4 --- Objectives and hypotheses --- p.25 / Chapter Chapter 2 --- Materials and Methods / Chapter 2.1 --- Study site --- p.27 / Chapter 2.2 --- Patient selection criteria --- p.28 / Chapter 2.2.1 --- Inclusion criteria --- p.28 / Chapter 2.2.2 --- Exclusion criteria --- p.29 / Chapter 2.3 --- Patient recruitment --- p.30 / Chapter 2.4 --- Assessments --- p.32 / Chapter 2.4.1 --- Adherence assessment --- p.32 / Chapter 2.4.1.1 --- Electronic monitoring --- p.32 / Chapter 2.4.1.2 --- Patient report --- p.33 / Chapter 2.4.1.3 --- Pill count --- p.34 / Chapter 2.4.1.4 --- Predictors of adherence --- p.34 / Chapter 2.4.2 --- Clinical outcome assessment --- p.35 / Chapter 2.4.2.1 --- Lipid control --- p.35 / Chapter 2.4.3 --- Economic outcome assessment --- p.35 / Chapter 2.4.3.1 --- Total direct medical cost --- p.35 / Chapter 2.4.3.2 --- Healthcare cost per member per month --- p.36 / Chapter 2.5 --- Sample size --- p.36 / Chapter 2.6 --- Statistical analysis --- p.37 / Chapter Chapter 3 --- Results / Chapter 3.1 --- Study sample --- p.40 / Chapter 3.1.1 --- Demographic characteristics --- p.41 / Chapter 3.1.2 --- Co-morbidity factors --- p.42 / Chapter 3.2 --- Adherence measurement --- p.44 / Chapter 3.2.1 --- Electronic monitoring --- p.44 / Chapter 3.2.2 --- Patient report --- p.45 / Chapter 3.2.3 --- Pill Count --- p.46 / Chapter 3.2.4 --- Correlation among methods for measuring adherence --- p.47 / Chapter 3.2.5 --- Trend of adherence and persistence over time --- p.48 / Chapter 3.2.6 --- Independent predictors of adherence --- p.49 / Chapter 3.3 --- Outcome assessment --- p.52 / Chapter 3.3.1 --- Clinical outcomes --- p.52 / Chapter 3.3.2 --- Economic outcomes --- p.52 / Chapter 3.4 --- Association between adherence and clinical outcomes --- p.53 / Chapter 3.4.1 --- Adherence and LDL-C reduction --- p.53 / Chapter 3.4.2 --- Adherence and NCEP ATP III target --- p.55 / Chapter 3.5 --- Association between adherence and economic outcomes --- p.55 / Chapter 3.5.1 --- Adherence and healthcare utilization --- p.55 / Chapter Chapter 4 --- Discussion and Conclusion / Chapter 4.1 --- Discussion --- p.59 / Chapter 4.1.1 --- Accuracy of patient report and pill count --- p.59 / Chapter 4.1.2 --- Persistence to statin therapy over time --- p.62 / Chapter 4.1.3 --- Predictors for patient adherence --- p.63 / Chapter 4.1.4 --- Clinical impacts of patient adherence --- p.66 / Chapter 4.1.5 --- Economic impacts of patient adherence --- p.68 / Chapter 4.1.6 --- Limitations --- p.70 / Chapter 4.2 --- Conclusion --- p.71 / References --- p.74 / Appendices / Appendix A-1. Framingham risk scoring system for male --- p.86 / Appendix A-2. Framingham risk scoring system for female --- p.87 / Appendix B-1. Information sheet provided to nurses of the Cardiology clinic --- p.88 / Appendix B-2. Information sheet provided to nurses of the Diabetes clinic --- p.89 / Appendix B-3. Information sheet provided to nurses of the Lipid clinic --- p.90 / Appendix C. Data collection form --- p.91 / Appendix D. Instruction sheet provided to the study patient --- p.94 / Appendix E. Unit cost of items from electronic dispensing record and Hong Kong Gazette 2003 for estimating total direct medical cost --- p.95

3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG CoA) reductase is a 97 kDa glycoprotein located in the endoplasmic reticulum responsible for cholesterol biosynthesis in mammalian liver and intestine. HMG CoA reductase inhibitors (statins) (e.g. simvastatin, mevastatin and parvastatin) are used clinically to treat and prevent coronary artery diseases by reducing plasma LDL-cholesterol level. Recent studies have demonstrated that statins can provide beneficial effects (pleiotropic effects) beyond its lipid-lowering activity. However, the modulatory effects of statins on ion channels activities have not been fully explored. Hence, this study is designed to demonstrate the existence of the HMG CoA reductase in various human isolate cardiovascular preparations and the modulatory effect(s) of simvastatin on both large-conductance calcium-activated (BKCa) and ATP-sensitive (IKATP) potassium channels of porcine isolated coronary vascular smooth muscle cells. / In conclusion, our results demonstrated the biochemical existence of HMG CoA reductase in various human isolated cardiovascular preparations and porcine isolated coronary artery. Simvastatin modulates the BKCa and IKATP channels of the porcine isolated coronary artery via different and multiple cellular mechanisms. / In this study, we demonstrated the biochemical existence of the HMG CoA reductase in various human isolated cardiovascular preparations and porcine isolated coronary artery. In addition, we demonstrated that simvastatin modulates both the BKCa channels and IKATP channels of porcine isolated coronary artery via different mechanisms. Acute application of simvastatin (100 nM) slightly enhanced whereas simvastatin (&ge; 1 muM) inhibited the BKCa amplitude of porcine coronary artery smooth muscle cells. The classical HMG CoA reductase-mevalonate cascade is important in mediating the inhibitory effect of simvastatin observed at low concentrations (1 and 3 muM), whereas an increased PKC-delta protein expression and activation is important in simvastatin (10 muM)-mediated inhibition of BKCa channels. In contrast, the basal activity of the IKATP channels was not affected by simvastatin (1, 3 and 10 muM). However, acute application of simvastatin (1, 3 and 10 muM) inhibited the opening of the IKATP channels by cromakalim and pinacidil in a PP2A-dependent manner (sensitive to okadaic acid, a PP2A inhibitor). The okadaic acid-sensitive, simvastatin-mediated inhibitory effect on IKATP channel is mediated by an activation of AMPK in a Ca2+-dependent manner. Activation of AMPK probably increased the activity of the Na+/K+ ATPase and subsequently caused an influx of glucose via the SGLT1 down the Na + concentration gradient for the ouabain-sensitive, glucose-dependent activation of PP2A. / Seto, Sai Wang. / Adviser: Yiu-Wa Kwan. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3456. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 221-254). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

A total of 146 Chinese patients with various degrees of hyperlipidaemia and high cardiovascular risk, suitable for treatment with rosuvastatin 10 mg daily and in whom it was possible to obtain baseline lipid profiles measured on no lipid lowering drug, were enrolled in to the study. The drug compliance was assessed by personal interview and 9 patients were excluded from the efficacy analysis because they stated their compliance was less than 80%. From the remaining 137 subjects, 62 had a clinical diagnosis of familial hypercholesterolaemia. Data for dietary intake were available in 121 of the 137 subjects. The average reduction in LDL-cholesterol in these subjects was 48.8 +/- 12.8% and as anticipated there was a wide range between individuals. The percentage reductions in LDL-cholesterol were significantly greater in the female than in the male subjects (-51.35 +/-10.89% vs. -46.38 +/-13.96%; p = 0.025), but this was no longer significant after adjustment for body weight. In patients with familial hypercholesterolaemia the absolute reductions in total cholesterol and LDL-cholesterol were significantly greater (p&lt;0.001) than in those without familial hypercholesterolaemia, but the percentage reductions were not significantly different in the two groups. The increases in HDL-cholesterol and the decreases in triglycerides were significantly greater in the subjects with familial hypercholesterolaemia than in those without familial hypercholesterolaemia, both for the absolute changes and for the percentage changes. There were no significant effects on the percentage changes in lipids with rosuvastatin treatment due to age, measurements of body fatness, smoking or alcohol drinking status, or having hypertension or diabetes. / Polymorphisms in the CYP2D6 gene were analyzed and the subjects were divided into 4 groups as wild-type or extensive metabolisers, heterozygotes for CYP2D6*10 and wild-type, homozygotes for CYP2D6*10, and subjects with one allele for poor metaboliser status. The groups in this order would be expected to have decreasing activity of the CYP2D6 enzyme. There was a tendency for greater reduction in LDL-cholesterol in groups with lower CYP2D6 activity, most obvious in male subjects and this was significant in the patients with familial hypercholesterolaemia comparing the first 3 groups. The fourth group had a low number of subjects, which may have biased that result. In the subjects without familial hypercholesterolaemia, the % change in LDL-cholesterol was similar in all genotype groups, but the % reduction in triglycerides was numerically higher in the wild-type group than in groups with CYP2D6*10 alleles and the group with poor metaboliser status showed a lower % reduction. These differences were not significant and may be influenced by the baseline levels of triglycerides, which were not corrected for in this analysis. / The daily calorie intake and percentage of different macronutrient intake was obtained by using seven days food recall records. Dietary intake of most nutrients with higher in male than in female patients and was higher in the patients compared to gender-matched population data. Higher intake of most nutrients was associated with higher baseline triglyceride levels, but not LDL-cholesterol levels in all patients, and in lower HDL-cholesterol levels in the patients without familial hypercholesterolaemia. Higher intake of total calories was associated with less percentage reduction in LDL-cholesterol with rosuvastatin in the patients without familial hypercholesterolaemia and a similar non-significant tendency was seen with higher intake of total fat, saturated fat and cholesterol. / The study described in this thesis examined the role of the CYP2D6*10 polymorphism on the lipid response to rosuvastatin in addition to a number of phenotypic factors such as diet, gender, measures of obesity and other medical conditions. / These findings suggest that the CYP2D6 genotype may have some influence on the lipid response to rosuvastatin, but it appears to interact with other factors including, gender, diet and the presence of familial hypercholesterolaemia. (Abstract shortened by UMI.) / Lui, Siu Hung. / "February 2007." / Adviser: Brian Tomlinson. / Source: Dissertation Abstracts International, Volume: 69-01, Section: B, page: 0248. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (p. 165-190). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Although the clinical efficacy of statins has been well established, there is a wide inter-individual variation in the lipid responses to statins. Pharmacogenetic studies have identified some genetic differences that contribute to the variation, but overall the results have been disappointing. The studies described in this thesis were performed to examine whether certain genetic variants predicted the lipid responses to rosuvastatin in Chinese patients. Over 400 Chinese patients with increased risk of cardiovascular disease (CVD) who were treated with rosuvastatin 10 mg daily for at least 4 weeks (more than 97% of patients had at least 6 weeks treatment) were studied, including 166 having familial hypercholesterolaemia (FH) and 36 having rheumatoid arthritis (RA). They were genotyped for 135 polymorphisms in 62 candidate genes/loci potentially related to pharmacokinetics or pharmacodynamics of statins and lipid metabolism. Associations between genetic polymorphisms and the lipid responses to rosuvastatin were analyzed in 386 patients with good compliance. The associations between genetic polymorphisms and some risk factors for CVD including baseline lipid levels, high-sensitivity C-reactive protein (hsCRP), uric acid and bilirubin levels were also analyzed. / Some novel genetic determinants of the LDL-C response to rosuvastatin treatment have been identified in this study. The responses in HDL-C and triglycerides were related more closely to the baseline levels of these lipids than to any of the polymorphisms examined. Genetic associations with baseline lipid parameters, hsCRP, uric acid and bilirubin were identified and generally correspond with some of the previous reports of studies in Chinese and other ethnic groups. / The key findings of the study are as follows: 1. The polymorphisms most highly associated with the low-density lipoprotein cholesterol (LDL-C) response were 421C>A in the ATP-binding cassette G2 (ABCG2) gene (P=9.2x10 -7), followed by 18281G>A (V257M) in the flavin-containing monooxygenase 3 (FMO3) gene (P=0.0002), 1421C>G in the lipoprotein lipase (LPL) gene (P=0.002), and rs4420638 in the apolipoprotein E/C-I/C-IV/C-II (APOE/C1/C4/C2) gene cluster (P=0.004). These genetic polymorphisms and having FH totally explained 13.6% of the variance in percentage change in LDL-C in response to rosuvastatin. The greater percentage reduction in LDL-C in patients with the ABCG2 421AA genotype compared to those with the ABCG2 421CC genotype was equivalent to at least doubling the dose of rosuvastatin. 2. Three SNPs (glucokinase regulator [ GCKR] rs1260326, apolipoprotein AS [APOA5] -1131T>C and the solute carrier organic anion transporter 1B1 [SLCO1B1] 521T>C) tended to be associated with percentage changes in high-density lipoprotein cholesterol (HDL-C) (P&lt;0.05), but none of these reached the overall significance level. In multivariate stepwise regression analysis, baseline HDL-C (P=1.6x10 -6), having diabetes (P=0.0004) or RA (P=0.002) and the SLCO1B1 521T>C polymorphism (P=0.03) were determinants of HDL-C responses, contributing 9.9% of the variance in percentage change in HDL-C, but the genetic factors only contributed to 0.8% of the variance. 3. The triglyceride response to rosuvastatin was highly variable and was strongly related to baseline levels. The diacylglycerol acyltransferase-2 (DGAT2) rs10899113 C>T polymorphism tended to be associated with reduced triglyceride response in a gene-dose dependent manner. However, in multivariate stepwise regression analysis, baseline triglyceride level was the only factor that strongly related to the triglyceride response, explaining 14.4% of the variance. 4. This study has also analyzed relationships between on-treatment plasma hsCRP concentrations and cardiovascular risk factors and 14 single nucleotide polymorphisms in CRP and other candidate genes, which showed that central obesity, low HDL-C and CRP polymorphisms are major determinants of higher hsCRP levels in Chinese patients on treatment with rosuvastatin. 5. The association between genetic polymorphisms and lipid traits were analyzed in FH and non-FH patients separately due to their different lipid profiles. The analysis has shown that there were different genetic predictors of lipid levels in patients with and without FH and that more genetic factors appeared to affect the baseline lipid levels in patients with FH compared to non-FH patients, suggesting complex interactions between genetic and environmental factors and plasma cholesterol levels in patients with and without FH. 6. The SLC2A9 (solute carrier family 2, member 9) rs1014290 T>C was significantly associated with plasma uric acid levels in a gene-dose dependent manner (P=1.0x10-5) and the relationship was more pronounced in women or in patients without hypertension than in men or patients with hypertension. The ABCG2 421 C>A did not show a significant effect on uric acid levels. 7. The UGT1A1 (uridine diphosphate glucuronosyltransferases family, polypeptide A1) variants *28 (P=1.5x10 -9) and *6 (P=2.2x10-7) were independently associated with increased baseline bilirubin levels. Polymorphisms in SLCO1B1 did not appear to affect bilirubin levels in this study. / Hu, Miao. / Adviser: Brian Tomlinson. / Source: Dissertation Abstracts International, Volume: 72-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 230-264). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Experiments were conducted to investigate the role of free radicals in exercise induced cardiac adaptations and to determine if statin administration would adversely affect cardiac adaptations to exercise. In the first experiment myocardial antioxidant enzymes, cardiac function and cardiac hypertrophy were assessed following a chronic exercise protocol previously used by our lab. MPG effectively reduced myocardial oxidative stress and activation of the signaling proteins Akt and S6 following an exercise bout. Skeletal muscle mitochondria content increased to similar levels in E and E+MPG. Similar increases (P<0.05) in both exercised groups were observed for heart wt and heart wt to body wt ratio. Cardiac function at the high workload improved in E vs S as indicated by higher (P<0.05) peak systolic pressure (SP), cardiac output (CO), coronary flow, COxSP and mechanical efficiency (COxSP/VO2). MPG prevented these exercise-induced functional improvements. This study provides evidence that free radicals do not play a role in the development of exercise-induced cardiac hypertrophy, however, they are involved in functional cardiac adaptations, which may be mediated through the PI3K/Akt pathway. In the second experiment a similar exercise protocol was used to determine if statins which have been shown to prevent pathological forms of cardiac hypertrophy, would be detrimental to exercise induced cardiac adaptations. In addition to the sedentary and exercise groups sedentary+statin and exercise+statin groups were assessed. Hearts were isolated and perfused and assessed for function at low and high workloads. Exercise treatment resulted in cardiac hypertrophy in absolute and relative terms to a similar extent in statin-treated and untreated exercised rats. Additionally it resulted in significant functional increases for SP, CO, COxSP, VO₂, and EFF in both exercised groups. In conclusion, these studies provide evidence that exercise in the cold is a valid model for physiological cardiac hypertrophy and that pathological and physiological cardiac hypertrophy signal through different pathways due to the fact that two well established treatments (mpg and statins) that prevent pathological cardiac hypertrophy did not affect exercise induced cardiac hypertrophy. / text

[Formulae and special characters can only be approximated here. Please see the pdf version of the abstract for an accurate reproduction.] Atherosclerosis is a common degenerative disease in which the clinical manifestations are often through stroke or myocardial infarction. Some of the established risk factors for atherosclerosis include elevated plasma low-density lipoprotein (LDL)-cholesterol levels, obesity, diabetes mellitus (DM) and cigarette smoking. Of the risk factors, an elevation in plasma LDL is one of the most established and the most researched. This is partly a consequence of the deposition of cholesterol within arterial intima being a crucial step in the progression of atherosclerosis, combined with the finding that LDL particles are a major transporter of cholesterol in circulation. Recently there is increasing evidence showing a role of the other major transporter of cholesterol in circulation, chylomicron remnants, in the progression of atherosclerosis. The notion of atherosclerosis as a postprandial phenomenon has been further substantiated by the emergence of evidence showing a direct role of chylomicron remnants in arterial cholesterol deposition. Based on evidence that chylomicron remnants are proatherogenic, the suggestion arises that accumulation of postprandial lipoproteins in plasma may add another dimension of risk to the development of coronary artery disease (CAD). This thesis tests the general hypothesis that individuals with or at high risk of CAD have postprandial dyslipidaemia and that this metabolic abnormality is correctable with a class of lipid-lowering drugs called statins. To test the hypothesis, clinical studies were conducted in normolipidaemic CAD patients, heterozygous familial hypercholesterolaemia (FH) and postmenopausal women with type 2 DM. Determination of postprandial dyslipidaemia by comparison with control populations were conducted initially in each patient group (Studies 1, 3 and 5), followed by intervention studies investigating possible modulation of the dyslipidaemia with a statin (Studies 2, 4 and 6). Six observation statements based on case-control comparisons of postprandial lipaemia in patients with or at risk of CAD and the effects of statins on postprandial dyslipidaemia in the patient groups were derived from the general hypothesis. The observation statements were examined in the individual studies described below. Postprandial lipoprotein metabolism was assessed using a number of methods. For comparison of postprandial lipaemia in Studies 1 and 2, a classic oral fat challenge was utilised. As markers of chylomicrons and chylomicron remnants, retinyl palmitate and triglyceride were measured postprandially as well as apolipoprotein (apo) B48 concentrations, a specific marker of intestinal lipoproteins. ApoB48 was also measured in the fasting state and found to predict the postprandial responses of retinyl palmitate, triglyceride and apoB48. This suggested that fasting measurement of apoB48 could be used as a simple indicator of postprandial dyslipidaemia. Consequently for Studies 3 - 6, fasting apoB48 measurements were used as primary markers of postprandial dyslipidaemia. Other markers for chylomicrons and their remnants utilised were fasting plasma concentrations of remnant-like particle-cholesterol (RLP-C) and apoC-III. As well as these static markers, chylomicron remnant catabolism was measured using a stable isotope breath test. The breath test involves the intravenous injection of a chylomicron remnant-like emulsion labelled with ¹³C-oleate and measurement of enriched ¹³CO2 in expired breath by isotope ratio mass spectrometry. The fractional catabolic rate (FCR) of the injected emulsion was subsequently calculated using multi-compartmental modeling (SAAM II). The studies are presented in this thesis as published and unpublished works. In Study 1, postprandial lipoprotein metabolism was compared between 18 normolipidaemic CAD patients (cholesterol 4.54 ± 0.12 mmol/L, triglyceride 1.09 ± 0.16) with 13 asymptomatic healthy controls using an oral fat challenge. Normolipidaemic CAD patients had higher postprandial area-under-curve (AUC) for triglyceride (+34%, p=0.019), retinyl palmitate (+74%, p=0.032) and apoB48 (+36%, p<0.001). Fasting apoB48 was also higher (+41%, p=0.001) and found to correlate significantly with AUC of triglyceride (p=0.017), retinyl palmitate (p=0.001) and apoB48 (p<0.001). The data suggest that normolipidaemic CAD patients have increased concentrations of intestinal lipoproteins in the fasting and postprandial state. In addition to these findings, significant correlations of fasting apoB48 with postprandial markers (p<0.02) suggests the fasting marker to be a simpler surrogate marker for the degree of total postprandial lipaemia. Study 2 investigated the effect of atorvastatin treatment on postprandial dyslipidaemia found in the 18 near-normolipidaemic CAD patients from Study 1. The trial was conducted in a randomised, placebo-controlled design, using oral fat challenges before and after 12-weeks atorvastatin/placebo treatment. Compared with the placebo group, atorvastatin decreased the total postprandial AUC for iii triglyceride (-22%, p=0.05) and apoB48 (-34%, p=0.013). Fasting markers of apoB48 (-35%, p=0.019) and RLP-C (-36%, p=0.032) also decreased significantly. Atorvastatin was also found to increase LDL-receptor activity by +218% (p<0.001) as reflected in binding studies. The data suggest atorvastatin reduces the fasting levels of intestinal lipoproteins as well as total postprandial lipaemia, but without acute dynamic changes in postprandial lipaemia. The reduction in fasting and total postprandial lipoprotein levels could be partly attributed to an increase in LDL-receptor mediated removal from circulation. In Study 3, postprandial lipaemia was compared in 15 heterozygous FH patients with 15 healthy controls. FH patients had higher fasting concentrations of apoB48 (+56%, p<0.001) and RLP-C (+48%, p=0.003). The elevation in these fasting markers of chylomicrons and their remnants suggests FH patients have postprandial dyslipidaemia due to an accumulation of these particles in plasma. Study 4 examined the effects of long- (> 6 months) and short-term (4 weeks) simvastatin treatment on modulating postprandial dyslipidaemia found in the 15 FH patients from Study 3. Short- and long-term simvastatin treatment decreased the fasting concentrations of apoB48 (-29% and 15% respectively, p<0.05) and RLP-C (both -38%, p<0.001), but did not significantly alter the FCR of the injected chylomicron remnant-like emulsion. The data suggest that in heterozygous FH both long- and short-term simvastatin treatments decrease the fasting markers of postprandial lipoproteins by mechanisms that may not be mediated via processes differentiated by the 13CO2 breath test. This implies that the effect on postprandial lipaemia may be from a decrease in production and/or a possible increase in catabolism of triglyceride-rich lipoproteins (TRLs). In Study 5, postprandial lipaemia was compared in 24 postmenopausal women age and body mass index matched with 14 postmenopausal women with type 2 DM. Postmenopausal diabetic women were found to have higher fasting concentrations of apoB48 (+21%, p=0.021) and apoC-III (+16%, p=0.042) as well as lower FCR of the chylomicron remnant-like emulsion (-50%, p<0.001). The data suggest that postmenopausal diabetic women have postprandial dyslipidaemia, and that this is due to delayed catabolism of chylomicron remnants. Study 6 was an hypothesis-generating exercise examining the effects of 4-weeks pravastatin treatment on postprandial dyslipidaemia found in 7 postmenopausal women with type 2 DM from Study 5. Although plasma LDL-cholesterol was reduced (-19%, p=0.028), there were no significant effects found on fasting apoB48 concentrations (-12%, p=0.116) or the FCR of the chylomicron remnant-like emulsion (+38%, p=0.345). A larger sample size of patients and/or treatment with a more potent statin at a dosage known to affect chylomicron remnant metabolism would be required to demonstrate a significant reduction in postprandial dyslipidaemia in postmenopausal women with type 2 DM. The results of the above mentioned studies combined support the general hypothesis that postprandial dyslipidaemia is a feature of patients with or at risk of CAD. This defect may be demonstrated using fasting apoB48 as an indicator of the degree of postprandial lipaemia. Postprandial dyslipidaemia may reflect a reduction in catabolism, as suggested with the breath test in type 2 DM, and/or an over overproduction of chylomicrons. Both these mechanisms would also increase competition for lipolysis and clearance pathways between hepatically and intestinally-derived lipoproteins. The exact mechanisms by which postprandial dyslipidaemia occurs are yet to be determined. Statins appear to improve defective postprandial lipaemia in patients with or at risk of CAD, which is in agreement with the general hypothesis. The effectiveness of a statin is dependant on their potency in inhibiting cholesterol biosynthesis and increasing receptor mediated clearance of LDL and chylomicron remnants. The studies conducted in this thesis show that postprandial dyslipidaemia can be reduced by statins but not to the extent demonstrated in controls. However, the demonstrated reduction in fasting and total postprandial lipaemia translates to a lowering in overall arterial exposure to circulating proatherogenic particles. The elevation in fasting and postprandial levels of proatherogenic chylomicron remnants found in the patient groups described in this thesis indicates another dimension to their risk of coronary disease. The reductions in the overall levels of proatherogenic particles in patients with or at high CAD risk, infers a possible reduction in the risk of coronary disease in these patients.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Clinical evidence suggested patients with lower plasma C-reactive protein (CRP) levels after statin therapy could have better clinical outcome. The last part of the study was to measure on-treatment high sensitivity CRP (hsCRP) levels among 229 Chinese patients with hyperlipidaemia undergoing treatment with simvastatin 40 mg daily. The patients were genotyped for 15 SNPs or haplotypes in 11 candidate genes that would have significant allele frequency among Chinese patients and may be linked to statin efficacy or hsCRP levels. The analysis suggested BMI is the largest single contributing factor of 15.0% of the variation in hsCRP levels, followed by plasma triglycerides levels contributing 4.7% and male gender 1.6% (all P&lt;0.05). However comparisons of hsCRP levels among genotype groups did not reveal any significant findings, with or without adjustment with covariate genotypic or phenotypic factors. To further categorize individuals as high or medium risk, we set a threshold hsCRP level of 1 mg/L as the benchmark for evaluation. The CRPc.3872G>A SNP was related to lower risk compared to the homozygous wild-type genotype (adjusted odds ratio AOR = 0.289; P = 0.014) after adjusting for phenotypic factors of age, gender, smoking status, BMI, waist circumference, hip circumference, plasma lipid profiles, co-existing disease and co-medications. Another marginal finding included the HNF1A c.79A>C SNP (AOR = 0.575; P = 0.118). / Polymorphisms in the drug transporters are likely to be more important with hydrophilic statins such as pitavastatin, which undergoes transporter mediated distribution. The SLCO1B1 c.388A>G polymorphism in the gene encoding the uptake transporter organic anion transporting polypeptide (OATP1B1) is common in Chinese and the variant was associated with increases of 63--68% in maximum plasma concentration and 44--47% in systemic exposure of both the lactone and acid compared to wild-type subjects (P&lt;0.05). Co-administration of pitavastatin with grapefruit juice (GFJ) resulted in a small increase of the area under the plasma concentration time curve (AVC) by 15--16% for both the acid and lactone (P&lt;0.05). However, there was no significant effect on the drug-food interaction in relation to relevant SNPs in the enzymes and transporters examined. / The SNPs examined included those in the genes for the enzymes and transporters involved in the metabolic pathway or the distribution of simvastatin. Cytochrome P450 (CYP) enzymes are involved in hepatic and intestinal metabolism of several statins and simvastatin is known to undergo extensive metabolism via the CYP3A4/3A5 pathway. The common candidate SNPs in the CYP3A4/3A5 enzymes found in Chinese populations include CYP3A4*1G, CYP3AP1*3 and CYP3A5*3 , which are associated with altered enzyme expression and activity. However, no statistically significant relationship was found between these SNPs and a potential phenotypic marker of enzyme activity, the urinary ratio of 6beta-hydroxy-cortisol/cortisol (6beta-OHC/C) concentrations. The analysis of lipid lowering responses in relation to individual SNPs or combinations from gene-gene interactions also revealed no statistically significant findings. In the subgroup of patients with familial hypercholesterolaemia, the CYP3A4*1G, CYP3AP1*3 and CYP3A5*3 polymorphisms appeared to have a small effect on the changes in LDL-C and total cholesterol with the subjects with the CYP3A5*3 and CYP3AP1*3 variants showing less reduction and those with the CYP3A4*1G variant showing more reduction than subjects with the wild-type genotype with a tendency for a gene-dose effect. It is difficult to interpret these findings and the significance may be related to multiple testing. / The statins, or 3-hydroxymethyl-3-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, act on the rate limiting step in endogenous cholesterol synthesis. Their primary action results in reduction of plasma low-density lipoprotein cholesterol (LDL-C) levels and this is thought to be the major mechanism by which they reduce cardiovascular events. There are considerable differences between subjects in both the plasma levels of the statins and in their effects on LDL-C and other lipid parameters and some of this variation appears to be related to genetic differences in the pathways of drug metabolism and distribution and in the pathways involved in lipid metabolism. / The variation in response may be related to variations in systemic or hepatic exposure to the drug, which in turn will be related to the pharmacokinetics. This is also likely to play a role in the adverse effects of myopathy and therapeutic tolerance. In a pharmacokinetic study in healthy male Chinese subjects, the common polymorphism of CYP2D6*10 was analyzed in relation to the pharmacokinetics of lovastatin and simvastatin. There was a tendency for reduced clearance of simvastatin lactone by 30% (P>0.05) in subjects with the CYP2D6*10/*10 genotype. With lovastatin, there were similar findings with 38.5--84.9% decrease in clearance which appeared to be related to enzyme activity according to genotype, with *5 carriers showing a greater decline in clearance than *10 carriers (P&lt;0.05). / These results provide some insights into the pharmacokinetics and pharmacodynamics of statins and the pharamacogenetic relationships to candidate SNPs. Future research in this field should help to facilitate safer and more effective treatment with these commonly used medications, resulting in personalized therapy and optimal clinical benefits for patients with cardiovascular disease. / This thesis describes a study of 270 patients recruited from the outpatient clinics at the Prince of Wales Hospital who were treated with simvastatin 40 mg daily for at least 4 weeks. Their mean (+/-SD) LDL-C baseline level was 5.38+/-1.68 mmol/L and the reduction in LDL-C after simvastatin treatment was 2.81+/-0.99 mmol/L or -47.1+/-12.5%. / Mak, Wah Lun Valiant. / Adviser: Brian Tomlinson. / Source: Dissertation Abstracts International, Volume: 73-06, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 253-289). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Liu, Pi-chu. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 155-173). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.