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1
Schick, Brian Adam. "Statin-induced muscle mitochondrial toxicity." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/908.
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Statins are the mainstay of cholesterol-lowering therapy and are taken by millions of people worldwide. These drugs are generally well-tolerated but can cause myopathy ranging from mild muscle pain to fatal rhabdomyolysis. The mechanism of statin-induced myopathy (SIM) is not fully understood and there is currently no convenient and reliable marker of SIM, but mitochondrial dysfunction has been implicated.
We sought to investigate the effect of statins on mitochondrial DNA (mtDNA) levels in order to gain information on the mechanism of SIM and to explore the possibility of utilizing changing mtDNA levels as a marker of SIM.
Several approaches were used. First, mtDNA levels were quantified in skeletal muscle biopsies collected from a previously published 8-week clinical trial of high-dose simvastatin or atorvastatin versus placebo. Forty-eight hypercholesterolemic subjects were randomly assigned to receive placebo (N=16), high dose atorvastatin 40mg/day (N=16), or high dose simvastatin 80mg/day (N=16) for 8 weeks. Muscle mtDNA content was assessed by real-time PCR atbaseline and after 8-weeks on statin treatment and found to be significantly reduced in the groupreceiving simvastatin (P=0.005) but not the other two. In addition, a significant positive correlation was observed between mtDNA and muscle ubiquinone in all groups (R=0.63, P<0.01), with the strongest association found in the simvastatin-treated subjects (R=0.75, P=0.002). Next, in an attempt to determine whether statin-induced muscle pain may be associated with muscle mtDNA depletion, archived muscle biopsies collected from statin users with muscle complaints were sought through a review of a muscle biopsy database and possible study samples were identified; however, this was put on hold as too much information was missing from the pathology reports. Third, a series of cell culture experiments were carried out in which human skeletal muscle myotubes were exposed to various concentrations of simvastatin or atorvastatin, in order to determine an appropriate dose range for subsequent mitochondrial toxicity experiments. Lastly, mtDNA content and expression was quantified in skeletal muscle biopsies collected from 10 patients with statin-induced rhabdomyolysis (SIR) and compared to 8 healthy controls to investigate whether muscle mtDNA is altered in rhabdomyolysis. No differences in mtDNA content or expression were observed between the two study groups, but this may have been be due to the SIR subjects' marked heterogeneity.
Statin therapy can be associated with considerable alterations in mtDNA content, which may play a role in the aetiology of SIM. MtDNA levels alterations with statin exposure should be investigated further to explore the involvement of mitochondrial alterations in the mechanism of SIM, and determine whether these may represent a useful clinical tool for assessing statin-induced muscle toxicity.
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Siddiqui, Moneeza Kalhan. "Genetic factors in statin intolerance." Thesis, University of Dundee, 2016. https://discovery.dundee.ac.uk/en/studentTheses/5852fdf4-5737-4c23-a391-f0bc4e627ebb.
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Background: There are approximately 12 million statin users in the United Kingdom. Reports of statin intolerance occurs between 7 and 29% of users, manifesting as muscle ache, fatigue or more seriously, muscle breakdown leading to myopathy. Creatine phosphokinase (CK) levels are used as a biomarker of statin-induced muscle damage. Non-adherence or discontinuation of therapy is a common result of intolerance and can result in negative cardiovascular disease-related outcomes. Aim: This thesis attempts to identify trends in record-linked medical data in a Scottish Caucasian cohort (GoDARTS) that best represent statin intolerance in order to study associated genetic factors. Methods: Prescribing trends such as switching or discontinuation of statin therapy were examined, and thresholds created to select true cases of intolerance. Information on CK levels was gathered from medical records and appropriate test results were utilized. Genotypic data was gathered for the variants and genetic regions of interest using a variety of methods including chip-based genotyping followed by imputation, TAQMAN genotyping, and exome sequencing. Subsequently hypothesis-based association analyses were conducted, including linear and logistic regressions, followed by meta-analyses, regional GWAS followed by a regional meta –analysis. Results: The phenotypes of statin intolerance were validated both internally and externally. Previously reported missense variants in LILRB5 (Asp247Gly) and CKM (Glu83Gly) were replicated and shown to be associated with CK levels irrespective of statin usage in the GoDARTS cohort and the clinical trial setting (JUPITER). Further, the CKM variant was also associated with inducibility of CK at times of tissue injury. The Asp247 genotype in LILRB5 was associated with increased risk of statin intolerance, and was replicated in associations with non-compliance to statin therapy and the development of myalgia in the JUPITER trial. The association with myalgia showed a stratified effect based on therapy (statin or placebo), with those on placebo showing the genotype effect. Further, the variant was also associated with increased risk of statin-induced myositis, cases of which had been clinically adjudicated and exome sequenced for the PREDICTION-ADR consortium. Further exploration of the LILR gene region showed an association with variants in LILRB2 (His20Arg and Val235Met) which were in strong LD with each other but were not in linkage with the variant in LILRB5. Stratified analysis revealed that the risk for carriers of the LILRB2 variants was increased depending on the genotype carried at the LILRB5 variant. Conclusions: This study characterises novel genetic factors associated with statin intolerance impacting adherence. The findings point to the immunomodulatory effects of statins. The results suggest that true statin-induced myalgia and non-specific myalgia are distinct, with a possible role for the immune system in their development. The findings encourage further investigation into the immune-physiology of statin-induced muscle damage and identifies genetically susceptible groups who are more likely to be statin intolerant.
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Wong, Ho-kwan Hogan, and 黃浩權. "A church and community centre, Statin." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1995. http://hub.hku.hk/bib/B31982608.
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Mack, Deborah Sara. "Statin Pharmacotherapy in U.S. Nursing Homes." eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1104.
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Background: Statins have questionable benefits among older adults with life-limiting illness. Statin use is widespread among U.S. older adults, but little is known about use in nursing homes. This dissertation was designed to identify the prevalence and predictors of statin pharmacotherapy use and discontinuation in U.S. nursing homes.
Methods: Data sources (2011-2016) included: Minimum Data Set 3.0, Medicare administrative claims data, Provider of Service files, and Dartmouth Atlas files. Analyses included: descriptive statistics, multilevel modeling, and proportional change in cluster variations with adjustments to reduce confounding and model misspecification.
Results: Approximately 36% of older adults admitted to U.S. nursing homes between 2015 – 2016 were actively using statins at the time of admission. Among long-stay residents with life-limiting illness, 34% were on statins at one time (2016; aged 65-75 years: 44%, >75 years: 31%). Statin use varied significantly by hospital referral regions, with most variation in the >75 age group. Limiting the sample to statin users, 20% discontinued statins within 30 days of nursing home admission. While discontinuation was positively associated with severity of life-limiting condition, the majority of residents remained on statins 30 days post-admission, including those with a < 6-month prognosis.
Conclusion: Statin use is pervasive across US nursing homes and persists with life-limiting illness. Geographic variation appeared to coincide with clinical uncertainty, especially among adults >75 with few national guidelines. More needs to be done to prioritize statin deprescribing in nursing homes with research that identifies ways to facilitate improved patient-provider awareness and engagement in the discontinuation process.
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Wong, Ho-kwan Hogan. "A church and community centre, Statin." Hong Kong : University of Hong Kong, 1995. http://sunzi.lib.hku.hk/hkuto/record.jsp?B25945865.
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Stringer, Henry. "Mitochondrial DNA alterations and statin-induced myopathy." Thesis, University of British Columbia, 2009. http://hdl.handle.net/2429/9949.
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Background/Objectives: Statins are widely used to treat hyperlipidemia and lower cardiovascular disease risk. While statins are generally well tolerated, ~10-15% of patients experience statin-induced myopathy (SIM), a potentially fatal complication. Statin treatment has been associated with mitochondrial dysfunction. High-dose simvastatin treatment has been associated with skeletal muscle mitochondrial DNA (mtDNA) depletion. The contribution of mitochondrial dysfunction to the development and exacerbation of SIM may be important. The goal of this project was to examine the effects of statins on mtDNA to provide further insight into the etiology and severity of mitochondrial myotoxicity in SIM.
Methods/Results: Two studies were performed. PCR quantification of mtDNA and nuclear DNA was used to measure mtDNA content. Long-template PCR was used to amplify the mitochondrial genome and score mtDNA deletion burden. In an in vitro study, rhabdomyosarcoma cells were exposed to simvastatin and atorvastatin for over 70 days. Both mtDNA content and deletion burden were measured longitudinally and remained unchanged amongst statin treated cells. In an in vivo study, skeletal muscle biopsies from patients diagnosed with SIM (n=24) and comparators showing no pathologic findings (n=23) were retrospectively reviewed from stored clinical samples. The pathologic features and degree of pathology within each biopsy were scored. MtDNA content and deletion score was compared between groups. Two genotypes that are associated with changes in statin response and SIM risk, apolipoprotein E and SLCO1B1, were examined. No difference in genotype frequency between groups was detected.
Controlling for age, gender, biopsy year and apolipoprotein E genotype, SIM subject mtDNA/nDNA (mean±SD, 2036±1146) was significantly lower than the comparators (3220±1594) (p=0.042). No difference was observed in mtDNA deletion score (0-200) between SIM subjects (21.2±19.2) and comparators (19.4±30.0). There was an inverse correlation between mtDNA content and degree of pathology (p=006 r=-0.399).
Conclusions: We found decreased in vivo skeletal muscle mtDNA content in association with SIM. How this relates to the pathogenesis of SIM remains unclear. As the mtDNA deletion score was not associated with SIM, quantitative rather than qualitative mtDNA alterations are suggested. MtDNA content should be further investigated as a potential marker of statin drug myotoxicity.
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Timoney, Maire Christine. "Synthetic and biosynthetic approaches to statin analogues." Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621819.
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Link, Emma. "Genome-wide association of statin-induced myopathy." Thesis, University of Oxford, 2009. http://ora.ox.ac.uk/objects/uuid:ca675486-d678-4200-8bb4-988a923e9c4c.
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Lowering LDL-cholesterol with statin therapy produces substantial reductions in cardiovascular events, and larger cholesterol reductions may produce larger benefits. Rarely, myopathy occurs with statins, especially at higher doses and in combination with certain medications. Similarly strong associations might exist between myopathy with high-dose statin regimens and genetic variants, especially those affecting blood statin levels. This study aimed to find genetic variants associated with statin-induced myopathy. A feasibility study was completed to assess whether plausible effect sizes of 5 to10-fold higher risks per genetic variants could be detected among 50-100 cases with statin-induced myopathy and to consider the best study design. A genome-wide association study was then carried out using approximately 300,000 genetic markers (and additional fine-mapping) in 85 people with definite or incipient myopathy and 90 controls, who were all taking 80mg simvastatin daily in a 12,000 participant trial of 80mg vs 20mg simvastatin daily. The cases were also compared to 2,300 additional controls who had not been exposed to intensive-dose statin therapy. Replication of the myopathy result and lipid-lowering associations were tested in a 20,000 participant trial of 40mg simvastatin daily versus placebo. The genome-wide scan yielded a single strong association (p = 4x10-9) of myopathy with the rs4363657 single nucleotide polymorphism (SNP) located within the SLCO1B1 gene on chromosome 12. This non-coding SNP was in nearly complete linkage disequilibrium (r2=0.97) with the non-synonymous rs4149056 SNP. The population prevalence of the rs4149056 C allele was 15%, and the odds ratio for myopathy was 4.5 (95% confidence interval 2.6 to 7.7) for each copy of the C allele and 16.9 (4.7 to 61.1) for CC vs TT homozygotes. Over 60% of these myopathy cases could be attributed to the C variant. The SLCO1B1 gene encodes the organic anion transport polypeptide OATP1B1, which has been shown to regulate hepatic uptake of statins. In literature reports, rs4149056 reduced statin transport and was associated with 37% (31% to 44%) higher systemic statin acid levels per C allele. The association of rs4149056 with myopathy was replicated in the trial of 40mg simvastatin daily, which also showed that it was associated with the cholesterol-lowering effects of simvastatin. No SNPs in any other region were clearly associated with myopathy (although comparison of the myopathy cases with the 2,300 controls identified a region of chromosome 1p12 that warrants further study). This study identified common variants in SLCO1B1 that influence the risks of statin-induced myopathy substantially. Genotyping these variants may be useful for tailoring both the statin dose and safety monitoring. More generally, such studies of the genetic determinants of serious adverse reactions with other drug classes may help to improve the balance between treatment efficacy and safety.
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Boyle, Ashley Kathryn. "Effect of statin treatment on preterm labour." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/29558.
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Preterm labour (PTL) is defined as labour before 37 completed weeks of gestation. Despite advances in medical research, PTL remains a major clinical problem. Preterm birth (PTB) rates range from approximately 5-18% worldwide. Importantly, PTB is the leading cause of childhood morbidity and mortality. PTL is difficult to predict and the aetiology is poorly understood but infection and inflammation are believed to be major factors. It has been suggested that the presence of intrauterine infection or inflammation may initiate the pathological, preterm activation of the inflammatory cascade associated with term labour. Therefore, PTL therapeutics should aim to inhibit these inflammatory pathways. Statins, 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are potent inhibitors of cholesterol biosynthesis, which act on the mevalonate pathway. In addition to their lipid-lowering effects, statins also have anti-inflammatory and anti-contraction properties. The hypothesis of this thesis was that statins will prevent PTB by reducing inflammation. The aims of this thesis were firstly to investigate the effect of the statins, simvastatin and pravastatin, on inflammation and contractility in a pregnant human myometrial cell line. Secondly, to determine whether simvastatin and/or pravastatin can prevent PTB or improve neonatal outcome in a lipopolysaccharide (LPS)-induced mouse model of PTB. Myometrial cells were either co-treated with LPS and simvastatin/pravastatin, pretreated with simvastatin/pravastatin or treated with simvastatin/pravastatin post-LPS stimulation. The effect of statin treatment on the mRNA expression and the release of inflammatory mediators was then investigated. Simvastatin treatment reduced LPS-induced inflammation by both lowering the expression of pro-inflammatory mediators and increasing the expression of anti-inflammatory mediators. Pravastatin treatment did not alter the expression of inflammatory mediators following LPS stimulation. The effect of simvastatin on the contraction of myometrial cells was investigated by embedding the cells in rat tail collagen to form gels. As these are smooth muscle cells, basal contraction was observed causing the gel size to reduce. When LPS was introduced, this caused the gels to contract further than the vehicle treated gels. Simvastatin attenuated the contraction of the myometrial cells, both alone and in the presence of LPS. These effects were reversed by the addition of mevalonate pathway metabolites, mevalonate and geranylgeranyl pyrophosphate (GG-PP) but not by farnesyl pyrophosphate (F-PP). Simvastatin also lowered levels of phosphorylated myosin light chain (pMLC) in the myometrial cells, which is essential for smooth muscle contraction. Again, this effect was abolished by mevalonate and GG-PP but not F-PP. It is hypothesised that simvastatin attenuated myometrial cell contraction by inhibiting Rho isoprenylation by GG-PP, preventing Rho-associated kinase (ROCK) activation, which then prevented the phosphorylation of MLC. A mouse model of intrauterine LPS-induced PTB was utilised to investigate the effect of statin treatment on PTB and fetal survival. Mice received an intraperitoneal injection of pravastatin (10μg) or simvastatin (20μg or 40μg) on gestational day (D)16. This was followed by ultrasound-guided intrauterine injection of LPS (1μg) on D17 and another pravastatin/simvastatin treatment two hours later. When mice were treated with LPS, 77.8% of mice delivered preterm. When mice received LPS and 20μg simvastatin, 50% delivered preterm. However, when mice were treated with LPS and 40μg simvastatin, 40% delivered preterm, more pups were born alive and uterine pro-inflammatory mRNA expression was downregulated. Conversely, pravastatin did not prevent PTB or improve the percentage of live born pups. In summary, simvastatin treatment exerted anti-inflammatory and anti-contraction effects on human myometrial cells in vitro. The anti-contractile properties were likely due to the inhibition of the Rho/ROCK pathway. Furthermore, in our LPS-induced mouse model of PTB, fewer mice delivered preterm with simvastatin treatment, simvastatin attenuated LPS-induced pup mortality and reduced uterine inflammatory gene expression. These results suggest that statin therapy may be a novel treatment for PTL.
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Ostrowski, Stephen M. "Pleiotropic mechanisms of statin action in Alzheimer's Disease." Cleveland, Ohio : Case Western Reserve University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1190669698.
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Turner, R. "Statin-associated muscle toxicity : clinical and genomic perspectives." Thesis, University of Liverpool, 2017. http://livrepository.liverpool.ac.uk/3020572/.
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Ostrowski, Stephen M. "Pleiotropic Mechanisms of Statin Action in Alzheimer's Disease." Case Western Reserve University School of Graduate Studies / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1190669698.
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Peterson, Mikael, and Matthew Martin. "Statin Medication Acquisition Among Medicare Beneficiaries 1992-2002." The University of Arizona, 2007. http://hdl.handle.net/10150/624409.
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Class of 2007 AbstractObjectives: To investigate the relationship of price and prevalence of statins when new mediations enter the market and when old medications are withdrawn from the market. Methods: Patients that received a statin were enrolled in the Medicare Current Beneficiary Survey (MCBS) from 1992 to 2002. The overall prevalence of each statin as well as the prevalence of each statin for a patient’s drug coverage (no coverage, Medicaid, Medigap, employer coverage, or other public coverage) were analyzed. Results: The overall prevalence of statin was statistically significant for 1992 versus 2002 (p<0.001). When atorvastatin came to the market towards the end of 1996, there was no difference between simvastatin (p=0.24) and pravastatin (p=0.12) in 1997 versus 1998. Conclusions: There was a difference in the prevalence of statins when atorvastatin entered the market. When cerivastatin left the market, there was a difference in the prevalence of statin use. Atorvastatin became the most prevalent statin by the end of 2002. The price of statins appeared to decrease over time from $39.01 in 1992 to $31.95 in 2002. Also, the year atorvastatin was released the average price of statins increased to $36.57 in 1997.
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Pietersen, Lauren. "Coenzyme Q10 for statin-induced myopathy : a systematic review." Thesis, Stellenbosch : Stellenbosch University, 2012. http://hdl.handle.net/10019.1/71937.
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Thesis (MNutrition (ITE))--Stellenbosch University, 2012.ENGLISH ABSTRACT: Background Statins are drugs of known efficacy in the treatment of hypercholesterolaemia. However, statin-induced myopathy, an adverse effect of statins in up to 15% of its users, has warranted a reduction in the prescription dose or discontinuation of the drug. The exact mechanism of statin-induced myopathy is unknown, but the potential of Coenzyme Q10 (CoQ10) as treatment has been recognized due to decreased human plasma CoQ10 levels found after statin use and the concomitant role of CoQ10 in muscle function. Objectives This systematic review assessed the effect of CoQ10 supplementation on: the severity of statin-induced myopathic symptoms, levels of plasma creatine kinase, intramuscular and plasma CoQ10, as well as whether any adverse effects of CoQ10 supplementation such as abdominal pain, nausea and vomiting or headaches were experienced. Search methods Two searches for studies were conducted in The Cochrane Central Register of Controlled Trials (inception to March 2011 and inception to November 2011), MEDLINE (inception to March 2011 and inception to November 2011), Web of Science (inception to March 2011 and inception to November 2011), Science Direct (inception to March 2011 and inception to February 2012), Wiley Online Library (inception to March 2011 and inception to February 2012), Springerlink (inception to April 2011 and inception to February 2012), EBSCOhost [Academic Search Premier and CAB abstracts (inception to March 2011 and inception to February 2012), CINAHL (inception to March 2011 and inception to November 2011)], Scopus (inception to March 2011 and inception to November 2011) and Google Scholar (inception to March 2011 and inception to February 2012). Reference lists of articles were hand searched for relevant clinical trials. Only trials with a full text were included in the review. Selection criteria Randomised controlled trials (RCTs) were included with adult participants (mean of 18-64.99 years) of all race/ethnic groups and gender on statin therapy with reported myopathic symptoms from an unknown cause. The intervention was in the form of a pure oral supplement of CoQ10 irrespective of dose, duration and frequency, and the control in the form of a placebo, a similar antioxidant, or no intervention. Outcomes included the severity of myopathic symptoms, levels of plasma creatine kinase (U/L), intramuscular CoQ10 (μmol/kg) and plasma CoQ10 (μmol/L), as well as adverse effects of CoQ10. Data collection and analysis The principle investigator and one independent reviewer selected the studies, extracted data and assessed for risk of bias using the Cochrane Collaboration‘s tool for assessing risk of bias. Authors of relevant clinical trials were contacted for additional information. Results Two RCTs were included in the review, totaling 76 participants. A meta-analysis could not be performed, thus the review is narrative. There were an insufficient number of RCTs to confirm whether routine supplementation of CoQ10 improves statin-induced myopathic symptoms. Conclusions More and larger RCTs are required to determine the efficacy of CoQ10 supplementation in statin-induced myopathy. Consensus needs to be reached regarding the definition and measurement instrument/s of myopathy so that results of future studies can easily be compared and synthesized.
AFRIKAANSE OPSOMMING: Agtergrond Statiene is medikasie bekend vir die effektiewe behandeling van hipercholesterolemie. Statien-geïnduseerde miopatie is egter 'n newe-effek wat voorkom in tot 15% van gebruikers, wat 'n vermindering in die voorgeskrewe dosis of staking van die medikasie tot gevolg het. Die presiese meganisme van statien-geïnduseerde miopatie is onbekend, maar die potensiaal van Koënsiem Q10 (CoQ10) is geïdentifiseer as 'n moontlike behandeling aangesien menslike plasma CoQ10 vlakke verlaag na die gebruik van statiene en as gevolg van die rol van CoQ10 in spierfunksie. Doelwitte Hierdie sistematiese literatuuroorsig het die effek van CoQ10 supplementasie bepaal op: die graad van statien-geïnduseerde miopatiese simptome, plasma kreatien kinase vlakke, intra-muskulêre en plasma CoQ10 vlakke, asook die teenwoordigheid van enige newe-effekte van CoQ10 supplementasie soos abdominale pyn, naarheid en braking of hoofpyne. Soektogstrategie Twee soektogte vir studies is uitgevoer in The Cochrane Central Register of Controlled Trials (ontstaan tot Maart 2011 en ontstaan tot November 2011), MEDLINE (ontstaan tot Maart 2011 en ontstaan tot November 2011), Web of Science (ontstaan tot Maart 2011 en ontstaan tot November 2011), Science Direct (ontstaan tot Maart 2011 en ontstaan tot Februarie 2012), Wiley Online Library (ontstaan tot Maart 2011 en ontstaan tot Februarie 2012), Springerlink (ontstaan tot April 2011 en ontstaan tot Februarie 2012), EBSCOhost [Academic Search Premier en CAB abstracts (ontstaan tot Maart 2011 en ontstaan tot Februarie 2012), CINAHL (ontstaan tot Maart 2011 en ontstaan tot November 2011)], Scopus (ontstaan tot Maart 2011 en ontstaan tot November 2011) en Google Scholar (ontstaan tot Maart 2011 en ontstaan tot Februarie 2012). Verwysingslyste van artikels is ook met die hand nagegaan vir relevante kliniese proewe. Slegs kliniese proewe waarvan die volteks beskikbaar was, is ingesluit in die oorsig. Seleksiekriteria Ewekansige gekontroleerde proewe (EGP) is ingesluit met volwasse deelnemers (gemiddeld 18-64.99 jaar) van alle rasse/etniese groepe en geslag op statien-terapie met gerapporteerde miopatie simptome van onbekende oorsaak. Die intervensie was 'n suiwer orale supplement van CoQ10 ongeag die dosis, duurte en frekwensie, en die kontrole 'n plasebo, soortgelyke antioksidant, of geen intervensie. Uitkomste het ingesluit: die graad van miopatie simptome, vlakke van plasma kreatien kinase (U/L), intra-muskulêre CoQ10 (μmol/kg) en plasma CoQ10 (μmol/L), sowel as newe-effekte van CoQ10. Dataversameling en -analise Die hoof ondersoeker en een onafhanklike hersiener het die seleksie van studies en data-ekstraksie onderneem en die risiko vir sydigheid geassesseer deur gebruik te maak van die Cochrane Collaboration’s tool for assessing risk of bias. Outeurs van relevante kliniese proewe is geraadpleeg vir addisionele inligting Resultate Twee EGP is ingesluit in die oorsig met 'n totaal van 76 deelnemers. 'n Meta-analise kon nie uitgevoer word nie, dus is die oorsig beskrywend. Daar was te min EGP om te bewys dat roetine supplementasie van CoQ10 statien-geïnduseerde miopatiese simptome verbeter. Gevolgtrekkings Meer en groter EGP is nodig om die effektiwiteit van CoQ10 supplementasie in statien-geïnduseerde miopatie te bepaal. Konsensus moet bereik word ten opsigte van die definisie en metingsinstrument/e van miopatie sodat die resultate van toekomstige studies makliker vergelyk en verwerk kan word.
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Clark, Justin. "An evaluation of Warfarin and Statin Drug-Drug Interactions." The University of Arizona, 2012. http://hdl.handle.net/10150/623593.
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Class of 2012 AbstractObjectives: To evaluate the literature with respect to drug-drug interactions of the hydroxymethylglutaryl CoA reductase inhibitors atorvastatin, fluvastatin, lovastatin, pitavastitin, pravastatin, simvastatin, and rosuvastatin with warfarin. Methods: This descriptive retrospective study identified articles reporting on each drug-drug interaction from the online databases PubMed (1970 – February 2012) and the drug compendia Micromedex and Facts & Comparisons. The studies included in this investigation were primary literature reports, written in English with human subjects. All studies included were evaluated using the van Roon 5-point quality of evidence scale developed in the Netherlands to assess drug-drug interactions. This scale rates the study type from lowest to highest quality, from zero to four. Case-reports were evaluated using the Drug Interaction Probability Scale (DIPS). The DIPS tool uses 10 questions to evaluate the probability that an adverse event is caused by a drug-drug interaction. Results: Twenty studies met the inclusion criteria. One study involved atorvastatin, four for fluvastatin, three for lovastatin, 2 for pitavastatin, 1 for pravastatin, 5 for rosuvastatin, and 6 for simvastatin. The mean van Roon quality of evidence score was 2.1+/- 0.74, the mean score for atorvastatin, pitavastatin, and pravastatin was 3, with the mean score of fluvastatin, lovastatin, rosuvastatin, and simvastatin was 2. 70% of the literature reviewed were case-reports or letters. Conclusions: The studies and reports supporting HMG-CoA reductase inhibitors and warfarin drug-drug interactions are most commonly case- reports and are of low quality and quantity.
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Clark, Justin, and Daniel Malone. "An Evaluation of Warfarin and Statin Drug-Drug Interactions." The University of Arizona, 2012. http://hdl.handle.net/10150/614476.
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Class of 2012 AbstractObjectives: To evaluate the literature with respect to drug-drug interactions of the hydroxymethylglutaryl CoA reductase inhibitors atorvastatin, fluvastatin, lovastatin, pitavastitin, pravastatin, simvastatin, and rosuvastatin with warfarin. Methods: This descriptive retrospective study identified articles reporting on each drug-drug interaction from the online databases PubMed (1970 – February 2012) and the drug compendia Micromedex and Facts & Comparisons. The studies included in this investigation were primary literature reports, written in English with human subjects. All studies included were evaluated using the van Roon 5-point quality of evidence scale developed in the Netherlands to assess drug-drug interactions. This scale rates the study type from lowest to highest quality, from zero to four. Case-reports were evaluated using the Drug Interaction Probability Scale (DIPS). The DIPS tool uses 10 questions to evaluate the probability that an adverse event is caused by a drug-drug interaction. Results: Twenty studies met the inclusion criteria. One study involved atorvastatin, four for fluvastatin, three for lovastatin, 2 for pitavastatin, 1 for pravastatin, 5 for rosuvastatin, and 6 for simvastatin. The mean van Roon quality of evidence score was 2.1+/- 0.74, the mean score for atorvastatin, pitavastatin, and pravastatin was 3, with the mean score of fluvastatin, lovastatin, rosuvastatin, and simvastatin was 2. 70% of the literature reviewed were case-reports or letters. Conclusions: The studies and reports supporting HMG-CoA reductase inhibitors and warfarin drug-drug interactions are most commonly case-reports and are of low quality and quantity.
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Hannum, Cameron, Kevin Hawkins, Jenene Spencer, and Elizabeth Hall-Lipsy. "Grapefruit-Statin Interactions: Patient Awareness, Knowledge and Contributing Factors." The University of Arizona, 2016. http://hdl.handle.net/10150/613968.
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Class of 2016 AbstractObjectives: The goals of this study were: to assess patients’ knowledge of grapefruit interactions when taking statin class (dyslipidemia) medications, to identify any pertinent demographic characteristics that may influence knowledge of grapefruit statin interactions, and to identify patient preferred sources of health information. Methods: Questionnaires were administered at community health fairs during the academic school year 2014 through 2015. The survey addressed grapefruit consumption, frequency and amount, for both whole fruit and juice; examined knowledge of the potential for harmful interactions of grapefruit juice with statin medications; and how or where the participant learned this information. Results: A total of 74 participants completed surveys, of which, 72 submitted fully completed surveys, mean age was 64 (SD=+/- 15.6), 71.2% were female (N=52), and 78.1% were white. Of those surveyed, 63.5% (N= 47) reported consuming grapefruit in the past 12 months, and 36.1% (N=26) reported taking a statin. Those taking statins, 50% (N=13) reported consuming grapefruit as well. The majority of people, 61.3% (N=45), reported obtaining health related information from healthcare sources. Those with a college education were more likely to have consumed grapefruit in the last 12 months (X2=4.88, p=0.027) and to have ever consumed grapefruit (X2 =4.40, p=0.036). Conclusions: The majority of the health fair attendees surveyed were highly educated, reported having health insurance, had consumed grapefruit in the past year, and had heard about grapefruit-drug interactions.
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Kurniawan, Dede Indra. "Statin-induced myopathy and the benefit of oral administration of coenzyme Q10." Thesis, Curtin University, 2007. http://hdl.handle.net/20.500.11937/1014.
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Background. Muscle cramps are one of the adverse affects suffered by hypercholesterolemia patients who are treated with statins. Besides reducing cholesterol levels, statins also reduce coenzyme Q10 (CoQ10) blood levels. One of several hypotheses of pathophysiology for statin-induced muscle cramps is reduced level of CoQ10. Besides being a very important antioxidant, CoQ10 also functions as a transmembrane proton conductor and an electron carrier between NADH and succinate dehydrogenases and the cytochrome system, which is needed for phosphorylation of ADP into ATP. Therefore, a decrease in the CoQ10 tissue levels, as reflected in its reduced blood levels, may contribute to the muscle function impairment. Researchers have proven that statins, drugs used to lower cholesterol, are able to reduce CoQ10 blood levels.Null Hypothesis. The administration of CoQ10 will have no effect on the frequency, severity and/or duration of muscle cramps amongst statin users.Aims. This study aimed to assess factors that might influence the development of statininduced myopathy manifested as muscle cramps, including the respondent’s age and sex; the dose and duration of their statin therapy; muscle symptoms (nature, duration and whether or not they have changed with statin use); other medicines consumed; and, other diseases suffered and to investigate the efficacy of oral CoQ10 supplements in reducing muscle cramps in statin users and non-users.Methods. The Study was comprised of two phases: Phase 1 the Muscle Adverse Effect Survey and Phase 2 the Coenzyme Q10 for Muscle Cramps Study. Data collection for Phase 1 took place from January 2006 to April 2006 in 45 community pharmacies throughout Western Australia. The second phase of the study, the clinical trial, took place through School of Pharmacy, Curtin University of Technology, from May 2006 to December 2006.Results. In the first phase of the study, the Muscle Adverse Effect Survey, it was found that the prevalence of myopathy amongst statin users was 22.3% (205/920). Amongst the respondents with muscle symptoms, 73/205 (35.6%) reported their muscle symptoms had worsened on using statins. Assuming non-respondents did not suffer from muscle problems reduced the overall incidence of potential statin-induced myopathy to 73/920 or 7.93%. It was found that atorvastatin was the most commonly prescribed statin (59.3%), followed by simvastatin (29.8%), then pravastatin (10.4%) and fluvastatin (0.6%). Despite the high use of atorvastatin, the incidence rate of myopathy by atorvastatin users was found to be similar with other statins. The most common muscle symptoms were night cramps (54.6%), muscle aching (52.7%), and fatigue (49.3%), while the most commonly affected area of the body was the calves (62%).Statistical analysis with multiple logistic regression showed increasing age, heart failure and the use of cortisone-like drugs increased the risk of muscle symptoms among statin users. It was found that, for every 1-year increase in age, the odds of suffering from muscle symptoms increased 1.039 (95% CI 1.019 – 1.061). Furthermore, taking cortisone-like medication increased the odds of suffering muscle symptoms 16.4 times (95% CI; 2.2 – 124.3), while participants with heart failure were 9.3 times (95% CI 1.2 – 73.2) more likely to develop muscle symptoms when prescribed statins.The second phase of the study, the Coenzyme Q10 for Muscle Cramps Study, was a single blind, placebo-controlled, cross over, 6-week evaluation of the benefits CoQ10 in reducing muscle cramps amongst statin users and non-users. It was found that on average, that statin users experienced a significant reduction in the severity of their muscle cramps, as indicated by lower average pain scores, during the period they were on CoQ10 (6.36 ± 0.75) compared with placebo (7.37 ± 0.85; p = 0.028). Furthermore, patients also experienced significantly shorter cramp duration when they were on CoQ10 (4.88 ± 0.84) than on placebo (5.84 ± 0.84; p = 0.001). In contrast, amongst non-statin users (who were used as controls), there were no significant differences between CoQ10 and placebo efficacy in all assessed variables.Conclusion. This study revealed that muscle symptoms were common among statin users, particularly those suffering from heart failure, taking corticosteroids, and increasing age. Furthermore, the administration of CoQ10 100 mg per day was safe and effective in reducing severity and duration of muscle cramps amongst statin users. However, these later findings need to be confirmed by larger, double blind, placebo controlled studies.
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Keskiväli-Bond, Piia. "Effects of acute early age statin treatment on rat vasculature." Thesis, University of Southampton, 2013. https://eprints.soton.ac.uk/374917/.
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Piecha, Malgorzata Trebše Polonca. "Stability and degradation studies of cholesterol-lowering statin drugs : dissertation /." Nova Gorica : [M. Piecha], 2009. http://www.p-ng.si/~vanesa/doktorati/okolje/12Piecha.pdf.
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Prebreza, Nebih. "Statin-Therapie nach koronarer Stentimplantation und das Überleben nach einem Jahr." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=96959870X.
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Pasha, Rand. "The Role of Coenzyme Q10 in Statin Treated Zebrafish (Danio rerio)." Thesis, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/31427.
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Atorvastatin (ATV) is a member of the statin family of pharmaceuticals sold as Lipitor™ by Pfizer Pharmaceuticals. Statins inhibit HMG-Coenzyme A reductase (HMG-CoAR), thus inhibiting the biosynthesis of cholesterol and other isoprenoid compounds including Coenzyme Q10 (CoQ10). This study evaluated the role of CoQ10 in preventing ATV-induced myotoxicity using the zebrafish Danio rerio as a model organism. ATV reduced spontaneous swimming, response to tactile stimuli, whole body enzyme activities (citrate synthase, cytochrome oxidase and lactate dehydrogenase) as well as increased pericardial sac edema in larvae. Transcript abundance of muscle atrophy markers (atrogen-1, murf) and the mitochondrial biogenesis marker (pgc-1α) were also altered. Additionally, acute toxicity of adult zebrafish resulted in no change in locomotor behaviour; however tissue enzyme activities and transcript abundance were altered. These findings demonstrate the protective effect of CoQ10 against larval ATV-meditated reduction in responses to tactile stimuli and enzyme activities suggesting CoQ10 does play a role in ATV-mediated toxicity.
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Mao, Pei-Lin. "Molecular characterization of statin, a protein marker for non-proliferating cells." Thesis, McGill University, 1989. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=59812.
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One cDNA clone (S1) was isolated from a rat brain expression library by statin-specific monoclonal antibodies. S1 contains a statin-like cDNA insert which on amino acid sequence analysis shows a high homology to human elongation factor-1$ alpha$ (EF-1$ alpha$). S1 gene product, pS1, a statin-like protein fused with $ beta$-galactosidase, was cleaved by an endogenous protease from E. coli; therefore, we reconstructed S1 into a pPL-$ lambda$ vector with a thermo-inducible promoter. To verify that this S1 gene product is distinct from the endogenous E. coli EF-Tu, we used the polyclonal antibody HT7, which specifically recognizes the extreme C-terminal of EF-1$ alpha$ also present in S1, but not in the endogenous EF-Tu. The 3$ sp prime$ and 5$ sp prime$ untranslated regions of S1 were found to be completely different from that of EF-1$ alpha$. The level of EF-1$ alpha$ increased during cell proliferation but dramatically decreased in senescent cells. In contrast, S1 mRNA could only be detected in senescent cells. The presence of three different S1-like mRNAs in the rat brain and four in the liver was demonstrated. While both the statin-like S1 gene and EF-1$ alpha$ may belong to the same multigene family, their expression exhibits inverse patterns in proliferating or non-proliferating cells.
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Loughrey, Brona Veronica. "Effect of statin therapy on monocyte function in the metabolic syndrome." Thesis, Queen's University Belfast, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.534628.
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Taha, Dhiaa A. "Influence of acid-base imbalance and hyperlipidaemia on statin-induced myotoxicity." Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/40222/.
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Disturbances in the acid-base balance, such as acidosis and alkalosis, alone or in the presence of postprandial or pathological hyperlipidaemia can alter the pharmacological and toxicological outcomes of statin therapy. Both acid-base imbalance and hyperlipidaemia are quite common among statin users. Statins are commonly prescribed for elderly patients who have multiple co-morbidities such as diabetes mellitus, cardiovascular and renal diseases. These conditions are risk factors for the development of metabolic acidosis. In addition, patients with abnormal plasma lipoproteins levels are usually treated with statins. There is also a general consensus by clinicians to recommend such patients to use unsaturated fat and fatty acids such as olive oil for prevention of cardiovascular and atherosclerotic diseases. The use of such oils is associated with transient but significant elevation in plasma triglyceride-rich lipoproteins (TRL), mainly chylomicrons. The effect of disturbances in acid-base balance on the inter-conversion of simvastatin and pravastatin between lactone and hydroxy acid forms have been investigated in physiological buffers, human plasma, and cell culture medium over pH ranging from 6.8–7.8. The effects of such inter-conversion on cellular uptake and myotoxicity of statins were assessed in vitro using C2C12 skeletal muscle cells under conditions relevant to acidosis, alkalosis, and physiological pH. Results indicate that the conversion of the lactone forms of simvastatin and pravastatin to the corresponding hydroxy acid is strongly pH-dependent. At physiological and alkaline pH, substantial proportions of simvastatin lactone (~87% and 99%, respectively) and pravastatin lactone (~98% and 99%, respectively) were converted to the active hydroxy acid forms following 24 hours of incubation at 37°C. At acidic pH, conversion occurs to a lower extent, resulting in greater proportion of statin remaining in the more lipophilic lactone form. However, pH alteration did not influence the conversion of the hydroxy acid forms of simvastatin and pravastatin to the corresponding lactones. Furthermore, acidosis has been shown to hinder the metabolism of the lactone form of statins by inhibiting hepatic microsomal enzyme activities. Lipophilic simvastatin lactone was found to be more cytotoxic to undifferentiated and differentiated skeletal muscle cells compared to the more hydrophilic simvastatin hydroxy acid, pravastatin lactone, and pravastatin hydroxy acid. Enhanced cytotoxicity of statins was observed under acidic conditions and is attributed to increased cellular uptake of the more lipophilic lactone or unionised hydroxy acid form. Statins association with plasma lipoproteins was examined using an in silico model, artificial chylomicrons-like lipid particles, rat and human lipoprotein fractions under conditions of physiological and altered pH levels. The effect of statins association with plasma lipoproteins on cellular uptake and myotoxicity of these drugs was also assessed at different pH levels using C2C12 cells that overexpress lipoprotein lipase (LPL). Lipophilic simvastatin displayed considerable association with plasma lipoproteins. The association was more significant with the non-polar lipoprotein fractions (TRL and Low-density lipoprotein [LDL]). This association contributed to increased cellular uptake of statins by C2C12 cells through LPL-mediated process, resulting in a higher intracellular concentration of statins in hyperlipidaemic conditions. These high intracellular concentrations of statins induced significantly higher cytotoxicity in hyperlipidaemic environment comparing to normolipidaemic conditions. Furthermore, a combination of low pH environment (representing acidosis) with hyperlipidaemia enhanced the association of lipophilic statins with plasma lipoproteins and increased cellular uptake and myotoxicity of these drugs. These studies suggest that comorbidities such as hyperlipidaemia, especially when coincident with acidosis, can enhance the statin-associated muscle toxicity, and therefore require extra caution and close monitoring by prescribing clinicians. Hydrophilic rather than lipophilic statins could be a preferable choice in this patient population.
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Noal, D., R. L. Gauer, and Rick L. Wallace. "What Patients Without CAD or Equivalents Should be on a Statin?" Digital Commons @ East Tennessee State University, 2010. https://dc.etsu.edu/etsu-works/8691.
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Alsalman, Abdulkhaliq. "Impact of Statin Therapy on Outcomes in Aneurysmal Subarachnoid Hemorrhage Patients." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1994.
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There is conflicting data on the effects of statins on cerebral vasospasm and clinical outcomes in aneurysmal subarachnoid hemorrhage (aSAH) patients. In this retrospective cohort study, patients were divided into those who received pravastatin (PRAV group) 40mg/d and those who did not (NP group). Data were analyzed using multivariate logistic regression. Eighty-one patients met inclusion criteria. There was a statistically significant decreased in the incidence of vasospasm in the PRAV group; however, this association did not retain significance after adjusting for WFNS, race, elevated WBC, and clipping (59% PRAV vs. 88% NP, p=0.08). There was no statistically significant difference in proportion of severe radiological vasospasm or mortality between groups. However, there was a trend towards a decreased mean length of stay (P=0.06) and a significantly higher proportion of survivors discharged to home in the PRAV group (P<0.0001). In conclusion, there was a trend towards a decrease in the incidence of vasospasm in the aSAH receiving pravastatin, but this trend did not achieve statistical significance after adjusting for potential confounders. Pravastatin was associated with other favorable clinical outcomes.
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Zhao, Tong Tong. "Mechanism and Therapeutic Potential of Statin-Mediated Inhibition of Tyrosine Kinase Receptors." Thesis, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/20334.
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Receptor tyrosine kinases (RTK) are key regulators of growth, differentiation and survival of epithelial cells and play a significant role in the development and progression of cancers derived from these tissues. In malignant cells, these receptors and their downstream signalling pathways are often deregulated, leading to cell hyper-proliferation, enhanced cell survival and increased metastatic potential. Furthermore, endothelial expressed RTKs regulate tumor angiogenesis allowing for tumor growth and maintenance by promoting their vascularization. Epithelial malignancies such as squamous cell carcinomas (SCC), non-small cell lung (NSCLC) and malignant mesotheliomas have very limited treatment options when presenting as metastatic disease. RTKs, particularly the epidermal growth factor (EGFR) and the vascular endothelial growth factor (VEGFR) receptors, have been shown to play significant roles in the pathogenesis of these tumor types. Statins are potent inhibitors of HMG-CoA reductase, the rate limiting enzyme of the mevalonate pathway, that are widely used as hypercholesterolemia treatments. The mevalonate pathway produces a variety of end products that are critical for many different cellular pathways, thus, targeting this pathway can affect multiple signalling pathways. Our laboratory has previously shown that lovastatin can induce tumor specific apoptosis especially in SCC and that 23% of recurrent SCC patients treated with lovastatin as a single agent showed disease stabilization in our Phase I clinical trial. Subsequently, our lab was able to demonstrate that lovastatin in combination with gefitinib, a potent inhibitor of the EGFR showed co-operative cytotoxicity when combined (Chapter 2). Furthermore, the pro-apoptotic and cytotoxic effects of these agents were found to be synergistic and to be manifested in several types of tumor cell lines including SCC, NSCLC and glioblastoma. I was able to expand upon these important findings and demonstrated that lovastatin, through its ability to disrupt the actin cytoskeleton, inhibited EGFR dimerization and activation (Chapter 3). This novel mechanism targeting this receptor has clinical implications as lovastatin treatment combined with gefitinib showed co-operative inhibitory effects on EGFR activation and downstream signalling. The RTK family of proteins share similar features with respect to activation, internalization and downstream signalling effectors. I further demonstrated that lovastatin can inhibit the VEGFR-2 in endothelial cells and mesotheliomas, where VEGF and its receptor are co-expressed driving their proliferation, and induces synergistic cytotoxicity in mesothelioma cells in combination with VEGFR-2 tyrosine kinase inhibitors (Chapter 4). These findings suggest that statins may augment the effects of a variety of RTK inhibitors in a similar fashion representing a novel combinational therapeutic approach in a wide repertoire of human cancers. More importantly, based on this work, we initiated a Phase I/II study evaluating high dose rosuvastatin and the EGFR inhibitor tarceva in SCC and NSCLC patients at our institute. This clinical evaluation will provide invaluable data that will play a role in developing this novel therapeutic strategy. Together, the work embodied in this thesis provides a model for the regulation of EGFR/VEGFR-2 activation and signalling by targeting the rho family of proteins that demonstrates a novel mechanism that can be exploited to refine current therapeutic paradigms.
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Mushashi, Fidela. "Impact of British Columbia's reduction in generic drug prices on statin adherence." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/60125.
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Background:
The burden of cost of prescription medications for chronic conditions is substantial. Many patients do not take their medication as prescribed due to cost. In 2010 the government of British Columbia introduced policy changes that reduced generic prices over a period of four years. I studied the impact of five generic price reductions policy on adherence to statin medications.
Methods:
Using data from the British Columbia Ministry of Health through Population Data BC, I analyzed prescription claims of 433,945 residents who were on statins from 2008 to 2014. I measured medication adherence using proportion of days covered (PDC) with brand name statin users as my control group. Interrupted time series analysis was used to compare longitudinal trends before and after policy changes.
Results:
Residents on brand name statins on average had 89.9% (95% CI 0.8924 to 0.9059) proportion of days covered with medication prior to policy interventions. Pre-existing level of adherence to generic statins was 0.89 percentage points (-0.0007 to 0.0184) higher relative to the control. There was a sustained significant decrease of 0.05 percentage points (-0.0009 to -0.00001) per month in trend of brand name use (p=0.0473). Adherence to generics dropped by 0.02 percentage points (-0.0009 to 0.0005) relative to the control over the 24 months preceding policy interventions. After first policy intervention, adherence to brand name statins increased immediately by 1.1 percentage points (-0.0032 to 0.0245) while generics utilization decreased by 0.71 percentage points (-0.0267 to 0.0125) relative to the control. Trend in control decreased by 0.03 percentage points (-0.0026 to 0.0021). After the first policy, there was a rise in trend of generics adherence of 0.27 percentage points (-0.0006-0.0061) per month relative to the control. Further price reductions resulted in moderate improvement in adherence to generic statins.
Conclusion:
Findings indicate that reductions in generic drug prices in BC yielded a modest improvement in pharmaceutical claims for statins. In the future, health policy makers may want to consider fewer but larger drug price reduction interventions for a more effective impact on medication adherence.Medicine, Faculty of
Graduate
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Ooi, Esther M. M. "Regulation of lipoprotein transport in the metabolic syndrome : impact of statin therapy." University of Western Australia. School of Medicine and Pharmacology, 2007. http://theses.library.uwa.edu.au/adt-WU2007.0125.
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[Truncated abstract] The metabolic syndrome is characterized by cardiovascular risk factors including dyslipidemia, insulin resistance, visceral obesity, hypertension and diabetes. The dyslipidemia of the metabolic syndrome includes elevated plasma triglyceride and apolipoprotein (apo) B levels, accumulation of small, dense low-density lipoprotein (LDL) particles and low high-density lipoprotein (HDL) cholesterol concentration. However, the precise mechanisms for this dyslipoproteinemia, specifically low plasma HDL cholesterol, are not well understood. This thesis therefore, focuses on HDL, its structure, function and metabolism. However, lipoprotein metabolism is a complex interconnected system, which includes forward and reverse cholesterol transport pathways. Hence, this thesis also examines and discusses the metabolism of apoB-containing lipoproteins. This thesis tests the general hypothesis that apolipoprotein kinetics are altered in the metabolic syndrome, and that lipid regulating therapies can improve these kinetic abnormalities. The aims were first, to compare and establish the clinical, metabolic and kinetic differences between metabolic syndrome and lean subjects; and second, to determine the regulatory effects of statin therapy, specifically, rosuvastatin on lipoprotein transport in the metabolic syndrome. Five observation statements were derived from the general hypothesis and examined in the studies described below. The findings are presented separately as a series of original publications. Study 1 Twelve men with the metabolic syndrome and ten lean men were studied in a case-control setting. ... These findings explain the HDL raising effects of rosuvastatin in the metabolic syndrome. Collectively, these studies suggest that the dyslipidemia of the metabolic syndrome results from increased production rates of VLDL and LDL particles, reduced fractional catabolic rates of these lipoproteins, together with accelerated catabolism of HDL particles. Treatment with rosuvastatin increases the catabolic rates of all apoB-containing lipoproteins and at a higher dose, decreases LDL apoB production. These effects are consistent with inhibition of cholesterol synthesis leading to an upregulation of LDL receptors. Rosuvastatin decreases the fractional catabolism of HDL particles. The effects of rosuvastatin on HDL kinetics may be related to a reduction in triglyceride concentration and cholesterol ester transfer protein activity. These findings are consistent with the general hypothesis that apolipoprotein kinetics are altered in the metabolic syndrome, and that statin therapy improves these kinetic abnormalities.
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Bailey, Kristian M. "Cytochrome p450 variation and response to statin therapy following acute coronary syndrome." Thesis, University of Leeds, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.578691.
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Background - Pharmacogenetics aims to maximize benefits and minimize risks of drug treatment. Our objectives were to examine the influence of common variants of hepatic metabolism and transporter genes on the lipid-lowering response to statin therapy . . Methods and Results - The Secondary Prevention of Acute Coronary Events - Reduction of Cholesterol to Key European Targets (SPACE ROCKET) Trial was a rnulticentre, randomized, controlled trial assessing the proportion of patients, at 3 months, achieving European Society of Cardiology 2003 (ESC-03) lipid targets. Of 1263 patients randornized, 77.6% simvastatin versus 79.9% rosuvastatin achieved ESC- 03 targets [OR: 1.16; 95% Cl: 0.88-1.53; P = 0.29]. A post-hoc analysis showed higher achievement of the new ESC, American Heart Association and American College of Cardiology optimal lipid target of LDLc less than 1.81 mmo1/1 (70 mg/dl with rosuvastatin (45.0%) compared with simvastatin (37.8%; OR: 1.37; 95% Cl: 1.09-1.72; p=0.007). We genotyped 601 patients for functional single nucleotide polymorphisms in the genes coding for the cytochrome P450 (CYP) metabolic enzymes, CYP2C9*2 (430C>T), CYP2C9*3 (l075A~C), CYP2C19*2 (681G>A), CYP3AS*1 (6986A>G), and hepatic influx and efflux transporters SLCOIBl (S21T>C) and BCRP (421C>A). An enhanced response to rosuvastatin was seen for patients with variant genotypes of either CYP3A5 (p=O.006) or BCRP (p=O.OlO). Multivariate logistic-regression analysis revealed that patients with at least 1 variant CYP3A5 and/or BCRP allele (n=186) were more likely to achieve the ESC/AHAJACC LDL cholesterol target (OR: 2.29; 95% Cl: 1.16-4.53; P=0.017; rosuvastatin 54.0% to target vs simvastatin 33.7%). Gene variants of CYP2C9, CYP2C19, or SLC01Bl did not affect lipid-lowering response, nor were differential effects on statin response seen for patients with the most common genotypes for CYP3A5 and BCRP (n=415; OR: 1.21' 95% Cl: 0.77-1.90: p=0.415). Conclusion - Rosuvastatin lOmg lowered mean cholesterol more effectively than simvastatin 40mgand achieved better results for the latest, more stringent, ESC targets. This difference is more apparent in patients with CYP3A5 and/or BCRP variant genotypes.
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Kilias, Antonios [Verfasser]. "Experimentelle Untersuchungen zu Wirkmechanismen der Statin-bedingten Modulation der Angiogenese / Antonios Kilias." Gießen : Universitätsbibliothek, 2012. http://d-nb.info/1064096905/34.
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Noonan, Katherine. "Do anti-inflammatory agents promote linear ablation lesion discontinuities? : an electrophysiological examination." Thesis, Queensland University of Technology, 2011. https://eprints.qut.edu.au/49852/1/Katherine_Noonan_Thesis.pdf.
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Background: Catheter ablation for atrial fibrillation (AF) is more efficacious than antiarrhythmic therapy. Post ablation recurrences reduce ablation effectiveness and are contributed by lesion discontinuity in the fibrotic linear ablation lesions.
The anti-fibrotic role of statins in reducing AF is being assessed in current trials. By reducing the chronic pathological fibrosis that occurs in AF they may reduce AF. However if statins also have an effect on the acute therapeutic fibrosis of an ablation, this could exacerbate lesion discontinuity and AF recurrence. We tested the hypothesis that statins attenuate ablation lesion continuity in a recognised pig atrial linear ablation model.
Aims: To assess whether Atorvastatin diminishes the bi-directional conduction block produced by a linear atrial ablation lesion.
Methods: Sixteen pigs were randomised to statin (n=8) or placebo (n=8) with drug pre-treatment for 3 days and a further 4 weeks. At initial electrophysiological study (EPS1) 3D right atrium (RA) mapping and a vertical ablation linear lesion in the posterior RA with bidirectional conduction block were completed (Gepstein Circ 1999). Follow-up electrophysiological assessment (EPS2) at 28 days assessed bidirectional conduction block maintenance.
Results: Data of 15/16 (statin=7) pigs were analysed. Mean lesion length was 3.7 ± 0.8cm with a mean of 17.9 ± 5.7 lesion applications. Bi-directional conduction block was confirmed in 15/15 pigs (100%) at EPS1 and EPS2.
Conclusions: Atorvastatin did not affect ablation lesion continuity in this pig atrial linear ablation model. If patients are on long-term statins for AF reduction, periablation cessation is probably not necessary.
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Bakar, Nur Salwani. "Investigation of the association between genetics, drug exposure and statin-induced muscle toxicity." Thesis, University of Newcastle upon Tyne, 2015. http://hdl.handle.net/10443/3083.
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Statins are generally well-tolerated, although statin-related myotoxicity (SRM) has been reported in a considerable number of patients. The risk factors underlying SRM have yet to be fully characterised. This study aimed to further elucidate the risk factors that increase the likelihood of SRM using data generated from cellular and clinical settings. The data from the cellular studies would provide information regarding candidate single nucleotide polymorphisms (SNPs) which could be tested in the clinical setting. In the cellular studies, three model cell lines were used; human proximal tubule (HK-2), rat skeletal muscle (L6) and human muscle cells. Lipophilic statins, simvastatin and atorvastatin, inhibited monocarboxylate transporter 1 (MCT1)-mediated DL-lactate uptake at the same magnitude as phloretin, a well-known MCT1 inhibitor. No significant lactate uptake inhibition was observed with up to 1 mM of hydrophilic statins (pravastatin and rosuvastatin). The magnitudes of inhibition of multidrug resistance-associated protein (MRP)-mediated CMFDA efflux and MDR1-mediated Hoeschst 33342 efflux by the lipophilic statins were lower than that caused by MK571 and cyclosporine A, which are typical inhibitors of MRP and MDR1, respectively. Both hydrophilic statins showed no significant effect on MRPs and MDR1 functions. In the clinical setting, a case-control study (116 cases and 314 controls) of unrelated dyslipidaemic patients was performed to determine the association between 12 SNPs from nine focus genes [i.e., SLCO1B1, ABCC2, ABCG2, CYP3A4 (*22 allele), COQ2, GATM, GPx, SLC16A1, SLC16A3] and SRM. Of the 12 SNPs genotyped, only SNP in SLCO1B1 (rs4149056) appeared to be the most important genetic predictor of SRM (P = 0.059, P = 0.047 in univariate and multivariate analysis, respectively), thus confirming previous findings. The association between rs4149056 and SRM was demonstrated to be independent to the type of administered statins and was likely to be influenced by the patient gender. Further patient recruitment is ongoing to increase study power and to confirm the assumption of the abovementioned association.
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Donnelly, Louise. "Genetic and clinical determinants of lipid-lowering response to statin therapy in diabetes." Thesis, University of Dundee, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.505632.
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Aldujaily, Esraa Abdulaal. "An investigation of tumour-associated macrophages and statin therapy in human pulmonary adenocarcinoma." Thesis, University of Leicester, 2017. http://hdl.handle.net/2381/43086.
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Introduction: Pulmonary adenocarcinoma represents a major area of unmet clinical need in cancer treatment. Recent advances in immunotherapy which target the PD-L1 immune checkpoint promise great improvements in outcomes for some patients. The immune system offers several other possible targets. Tumour associated macrophages (TAMs) are a common feature of lung tumour stroma. Epidemiological data have indicated a possible role of statins in reducing cancer mortality via their anti-inflammatory effects, but the mechanisms underpinning this are not clear. The possible roles of pro-tumour versus anti-tumour macrophages were investigated in lung adenocarcinomas, and the possibility of influencing this axis with statin drugs. Methods: Immunohistochemical evaluation was used with phenotyping of TAMs using multiplex immunohistochemistry in tissue microarray sections of about 300 lung adenocarcinomas with matched clinicopathological data. Quantitative digital pathology, using Hamamatsu scanner images and Visiopharm software to count and phenotype TAMs in TMA sections. Results: It has been found that the pro-tumourigenic (CD68+CD163+) TAM numbers are elevated in invasive versus in situ tumour regions. Interestingly, statin users have significantly lower protumourigenic macrophage numbers than non-statin users, significantly in areas of in situ tumour growth in comparison to invasive lesions. Tumours in statin users were also of significantly lower histological grade, showing a higher percentage of in situ components than non-statin users. Conclusion: Automated image analysis methods efficiently count and classify macrophages in tumour tissue. Statin therapy is related to macrophage class, specifically within in situ lesions. These data support a model whereby statins target protumourigenic TAMs in early disease, highlighting their potential as cancer-preventive agents.
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Kelley, Leslie K. "Effectiveness of Statin and Bisphosphonate Treatment in a 3NP model of Huntington’s Disease." ScholarWorks@UNO, 2015. http://scholarworks.uno.edu/td/1993.
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Nelson, DeAnn Lynn, and DeAnn Lynn Nelson. "Promoting the Use of Statin Therapy in Navajo Patients with Type 2 Diabetes." Diss., The University of Arizona, 2017. http://hdl.handle.net/10150/625670.
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Background: Type 2 diabetes mellitus (T2DM) is a major health concern among Navajo Indians. Native Americans and Alaskan Natives (NA/AN) currently have the highest rates of T2DM in the United States (Indian Health Service, 2016). The rate of diabetes on the Navajo Indian reservation is 22% (Partnersinhealth.org, 2009). Major health concerns for patients with T2DM include cardiovascular complications. Treatment is essential to prevent high-risk complications such as, cardiovascular disease (CVD).
Purpose: The purpose of this quality improvement project was to implement a clinical decision support tool (CDST) to increase primary care provider awareness of current American Diabetes Association (ADA) statin therapy guidelines. The first objective was to increase the prescription rates of statin medications by 10%. The second objective of this project was to increase the performance target rate by 10%.
Setting: This project was implemented at the Gallup Indian Medical Center (GIMC) Family Medicine Clinic. GIMC is located in Gallup, New Mexico.
Participants: Participants included primary care providers, six Medical Doctors, two Nurse Practitioners, and one Physician Assistant.
Methods: An evidence based clinical support decision tool (CDST) was generated the ADA statin therapy guidelines. Participants were educated on these practice guidelines and the CDST. The CDST was implemented into the electronic health record (EHR) over a four-week period. The provider used the CDST as a point-of-care guide when prescribing statin therapy to those with T2DM.
Results: There was a 0.5% increase in the GPRA performance rating at GIMC as well as a 10% increase in prescribed statin therapy medications. There were 253 newly prescribed statin medications during data collection.
Conclusion: While this project did not result in significant improvement of statin therapy GPRA performance ratings, a new EHR tool that providers can use to improve patient care was implemented. One outcome was met, there was a 10% increase in statin medication prescriptions. Further studies and future PDSA cycles will be required for testing the effectiveness of CDSTs.
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Coker, Joyce Feyisitan. "Statin-use and the adoption of healthy lifestyle choices : a cross-national comparison." Thesis, University of Leeds, 2015. http://etheses.whiterose.ac.uk/13195/.
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Background: Statin-use and the adoption of healthy lifestyle choices are important components of cardiovascular disease prevention. The nature of the relationship between the former and the latter, and the influence of personal and social factors on this relationship remains unclear. Aim: This research aimed to examine whether statin-use influences the adoption of healthy dietary and exercise choices by changing the way people think of high cholesterol as a risk factor for cardiovascular disease in the context of their social world. Methods: Questionnaires were used to compare the dietary and exercise behaviours; perceptions of high cholesterol; and perceived future risk of cardiovascular disease of statin users and non-statin users recruited in Nigeria and in the UK. In-depth interviews were conducted in each country to explore between group differences and the influence of social factors on statin-use, adoption of a healthy lifestyle choices; perceptions of high cholesterol, future cardiovascular disease risk and availability of social support. Results: A similar proportion of the 148 participants recruited from Nigeria and the 89 participants recruited from the UK reportedly adopted a low-fat diet, 69% and 70% respectively. Reported adoption of healthy exercise behaviours was much lower and notably different between the country samples, 16% and 32% respectively. Statin-use was found to influence the adoption of healthy lifestyle choices in 3 ways: it was found to encourage, hinder, and work alongside the adoption of healthy lifestyle choices. The adoption of healthy lifestyle choices was also influenced by cause-control perceptions, gender, and social factors such as location, preferences and demands of other people, and societal norms such as body image ideals. Conclusion: Statin-use influenced the adoption of healthy lifestyle choices in 3 different ways. Dietary changes were preferred to exercise changes. Illness perceptions and preferences of the individual and their social world influenced statin-use and the adoption of healthy lifestyle choices.
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Morioka, Travis Y. "The association of serum 25-hydroxyvitamin D status and statin-associated musculoskeletal symptoms." Thesis, Boston University, 2012. https://hdl.handle.net/2144/12534.
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Thesis (M.A.)--Boston University
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.Objectives: In this study, we investigated the relationship between serum vitamin D status and the prevalence of musculoskeletal pain among individuals on statin therapy. We hypothesized that lower serum vitamin D concentration would be associated with a higher odds of self-reported musculoskeletal pain among statin users. Background: HMG-CoA reductase inhibitors, or statins, are widely used lipid-lowering drugs that significantly reduce morbidity and mortality associated with heart disease. Statin use is associated with a higher prevalence of self-reported musculoskeletal pain in the general population. Non-blinded studies have shown improvement in statin-associated myalgia symptoms and increased tolerance to statin therapy after treatment of vitamin D deficiency. Methods: We performed secondary data analyses using the National Health and Nutrition Examination Survey (NHANES) 2001-2004. Employing SAS and SUDAAN, we carried out logistic regression to evaluate whether vitamin D deficiency modified the relationship between statin use and musculoskeletal pain. Based on a priori assumptions, we adjusted for the effects of demographics, selected disease states, and health habits in the logistic regression model. We also explored concentration-related trends of the effect of vitamin D on musculoskeletal pain. Results: Among 5941 participants age 40 years and older, the mean serum vitamin D concentration was 23.5 ng/mL [95% Confidence Interval (CI) 22.4, 24.2]. There was no significant difference in the mean serum vitamin D concentration between statin users (23.3 ng/mL, 95% CI 22.3, 24.3) and non-statin users (23.5 ng/mL, 95% CI 22.8, 24.2). Statin users had higher odds [adjusted odds ratio (aOR) 1.57, 95% CI 1.15, 2.13)] of self-reported musculoskeletal pain in any area (specifically including the lower extremities, lower back, upper extremities, and upper back) compared with non-users. Vitamin D deficiency was not a predictor of musculoskeletal pain (aOR 0.95, 95% CI 0.70, 1.28) in the overall sample. However, we found vitamin D deficiency to have a significant interaction with statin use for the outcome of musculoskeletal pain (p for interaction = 0.01). After stratifying the sample according to statin use, we found that compared to statin users with a vitamin D concentration of 15 ng/mL or higher, those using statins with vitamin D concentration less than 15 ng/mL demonstrated substantially higher odds of musculoskeletal pain (aOR 2.56, 95% CI 1.25, 5.25). Assessment of vitamin D as a continuous variable did not reveal a concentration-related trend between increasing vitamin D concentrations and musculoskeletal pain (p for trend = 0.4). Conclusions: After controlling for multiple confounders, our analyses showed that serum vitamin D concentration less than 15 ng/mL was associated with musculoskeletal pain among statin users. However, among those not using statins, no association between serum vitamin D levels and self-reported musculoskeletal pain was demonstrated. We showed that vitamin D deficiency modifies the relationship between statio use and musculoskeletal pain. Treating vitamin D deficiency has other proven benefits including, bone health and skeletal muscle function. Our data suggests it may be reasonable to identify and treat vitamin D deficiency in patients who report musculoskeletal pain, using statins.
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Onyirimba, Esther. "Standardized Clinical Guideline for Assessment, Documentation, and Treatment of Statins." ScholarWorks, 2019. https://scholarworks.waldenu.edu/dissertations/7499.
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The purpose of this project was to develop a practice guideline for screening patients at risk for cardiovascular disease, educate the staff at the site about the guideline, and implement the guideline at a primary care clinic. The intention was to identify and treat patients at risk for cardiovascular disease to prevent occurrence of heart disease. Cardiovascular disease includes hypertension, coronary heart disease, heart failure, and stroke. Coronary heart disease is one of the leading causes of death in the Western world. The local practice problem and focus of this project was underprescribed statin therapy for patients at risk for developing heart disease at a clinic in the southern United States. The practice-focused question that guided this project explored whether an evidence-based clinical guideline that might impact the prescription of statins for the prevention of cardiovascular disease would be approved for implementation in a primary care clinic serving adult and geriatric patients. The appraisal of guidelines for research and evaluation and the Fineout-Overholt model were used to guide this project. Sources of evidence to meet the purpose of this project were obtained from the literature and scholarly articles. The results of the presentation to the expert panel indicated that this clinical practice guideline would be implemented at the project site and would be used by nurse practitioners and physicians. The implications of this project for positive social change might include improved management of patients who are at risk for heart disease and a decrease in premature deaths related to cardiovascular disease.
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Lowrie, Richard. "A cluster randomised controlled trial of Pharmacist-led Statin Outreach Support in Primary Care." Thesis, University of Glasgow, 2012. http://theses.gla.ac.uk/3352/.
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Summary Background Elevated blood lipids (particularly cholesterol and sub-fractions) contribute to the risk of developing cerebral, peripheral and cardiovascular disease and associated complications which are leading causes of morbidity and death. Statins reduce the risk of suffering vascular events, with or without decreasing cholesterol levels. Statin prescribing continues to increase but there is scope to improve prescribing and dosing, particularly in primary care. However, there is insufficient empirical evidence to inform approaches to quality improvement. Methods Following pilot work, we designed a new model of primary care based pharmacist-led intervention for General Practitioners (GPs) and nurses. The aim of the intervention (called Statin Outreach Support, SOS) was to improve statin prescribing by GPs, in line with recent evidence, targeting patients at highest risk of suffering a vascular event. Eleven trained pharmacists worked in SOS allocated practices one day per week for a year. During this period, the pharmacist met three times with all GPs, all nurses and other practice staff. Between meetings, pharmacists used patient level clinical and prescribing data to identify eligible patients and help practices initiate, up-titrate the dose or switch to simvastatin 40mg where indicated. The effectiveness of SOS was tested in a prospective single blind cluster randomised controlled trial. Usual care (UC) practices received no pharmacist support during the study. With a mean of 1.7 years follow up, the study had over 90% power (at 5% significance) to detect a difference of 12% in the proportion of patients with controlled cholesterol after practices had received the SOS intervention. Results Thirty one practices were recruited from the UK’s largest Health Board area. At randomisation, 16 practices were allocated to the SOS intervention and 15 to UC with 4,040 patients included at baseline. Recruited practices showed few differences compared with invited, non participating practices. Practices and patients randomised to each arm of the study had similar distributions with respect to age, complications, cholesterol levels and statin prescribing. The mean age was 68 years; 53% male, 45% ischaemic aetiology. Fifty nine percent had no statin prescribed at baseline; only 51% had cholesterol controlled. Follow up included 7586 patients in 29 practices (one practice had disbanded between recruitment and randomisation and another practice dropped out). Compared with UC, the SOS intervention achieved the primary endpoint of increasing the proportion of patients prescribed Simvastatin 40mg with controlled cholesterol (SOS 44.9% vs. UC 27.9%; odds ratio 1.79 (95% CI: 1.61, 1.98), p< 0.001). Secondary endpoints were also improved in the SOS arm practices. The intervention effect was strong and consistent across most subgroups including a positive impact on patients from practices in areas of greater socioeconomic deprivation. Conclusion A pragmatic, new, complex intervention was developed, tested and shown to be effective in a cluster randomised controlled trial with good internal and external validity. If implemented on a wider scale, in practices with comparable characteristics and baseline prescribing, the SOS intervention has the potential to reduce the burden of vascular events for patients with vascular disease. This work provides a convincing evidence base for the role of pharmacists collaborating with primary care practices, to improve statin prescribing and drug based cholesterol management, for patients at highest risk of suffering vascular events.
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Montazerolghaem, Maryam. "Additives Increasing the Bone-Forming Potential around Calcium Phosphate Cements : Statin, Strontium and Silicon." Doctoral thesis, Uppsala universitet, Tillämpad materialvetenskap, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-246289.
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More than one million people worldwide receive some kind of bone graft each year. Grafts are often needed following bone tumour removal or traumatic fractures to fill voids in the bone and to aid in the healing process. The most common method involves bone transplantation, in which bone tissue is taken from one site to fill the defect in another site. The procedure thus involves two surgeries, which leads to an increased risk of complications. New, synthetic graft materials that can be used to fill defects and minimise the complications associated with bone tissue harvesting are therefore necessary. The synthetic materials available today lack the inherent biological factors of bone that stimulate the bone regeneration process. Much of today’s research concerning synthetic bone graft materials aims to solve this issue and researchers have suggested several different strategies. The purpose of this thesis is to improve the performance of acidic calcium phosphate cements, which are materials used as synthetic bone grafts. By combining these cements with drugs or ion additives, local delivery could be achieved with the potential to stimulate bone formation. Two different combinations were attempted in this thesis: cement in combination with simvastatin, or cement in combination with strontium halide salts. Both simvastatin and strontium are known to positively affect bone formation. The efficacy of the cements with the additives was evaluated using different bone cell cultures. The results regarding simvastatin showed that the cement’s mechanical property was not affected upon drug loading, and that the drug was released by a diffusion-controlled mechanism. Moreover, results showed that simvastatin stimulated the bone-forming cells (osteoblasts) to produce more bone tissue, while it inhibited bone-degrading cells (osteoclasts) from degrading the cement. These findings suggest that simvastatin could aid in the bone regeneration process in the local area surrounding the cement. The main purpose of the study using strontium halide salts was to increase the cement’s X-ray contrast, which is a property used to monitor cement during injection. In addition, strontium is believed to positively affect bone cells. The X-ray contrast did increase after the addition of 10 wt% strontium bromide or strontium iodide, while the cell study results did not indicate any significant effects on the bone-forming cells. In the last section of this thesis, zebrafish were used as a model to evaluate bone formation upon treatment with degradation products from synthetic bone grafts. The zebrafish is a small organism with 70 % gene homology to humans; due to its transparency, fast development and ease of handling, it is an interesting model for high-throughput studies. Silicate, which is an ionic degradation product of many different bone substitute materials, was used as a proof-of-concept to visualise bone formation in these fish. The results showed an increased bone formation upon treatment with 0.625 μM silicate ions. The results suggest that this model could be used as a complement to bone cell culture studies in pre-clinical evaluations of the degradation products of bone substitute materials, thus helping researchers to design materials with degradation products that could stimulate bone formation.
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Liu, Xiaoling. "Determination of whether the effects of statin drugs are mediated by phosphoinostide 3-kinase." Virtual Press, 2004. http://liblink.bsu.edu/uhtbin/catkey/1306853.
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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
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Fulcher, Jordan Ronald. "Studies of Statins, Cholesterol and the Risk of Cardiovascular Disease." Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/18205.
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Statins have been shown to substantially reduce the risk of cardiovascular disease and mortality over the past two decades. However there remain questions around their initiation, biological mechanisms, efficacy and safety, particularly in certain population subgroups. The aim of this thesis was to investigate some of the major uncertainties. Patient level meta-analyses were performed using data from 27 randomised statin trials to explore the effects of statins by gender and by age. The accuracy of common cardiovascular risk calculators used to guide the initiation of statin therapy was also investigated. A meta-analysis of trials with extended follow-up examined whether earlier statin treatment confers long-term legacy benefits. And an approach to serial aortic plaque imaging using optical coherence tomography (OCT) in a cholesterol fed rabbit model +/- statin therapy was developed, to explore plaque changes and guide methods for ongoing anti-atherosclerotic research. We found statins have similar, significant proportional vascular and mortality benefits in women compared to men, and are effective across all risk levels. Efficacy and safety in those age >75 years without heart failure or dialysis is also similar to younger adults, but there remains insufficient evidence in the primary prevention setting. Newer UK and US risk calculators perform better than the Framingham calculator, but persisting inaccuracies require clinical consideration. In long term trial follow up, there appear to be legacy effects from prior statin therapy for at least five years which would support an earlier approach to lipid lowering. Serial OCT imaging of rabbit atherosclerotic plaque is feasible, with preliminary findings that statins significantly slow plaque progression. More accurately characterising which individuals should commence statin, or potentially newer lipid lowering therapies, based on risk/benefit profiles will be the major ongoing focus in this area.
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Al-Foraih, Meisa. "Dietary, Physical Activity and Other Lifestyle Habits and their Associations with Medication Adherence in a Group of Hypercholesterolemic Patients Prescribed Statin Therapy in Kuwait." Thesis, Griffith University, 2014. http://hdl.handle.net/10072/366088.
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The growing epidemic of coronary heart disease (CHD) is evident worldwide, accounting for global mortality rates of approximately 7.2 million per year. Coronary heart disease causes are multi-factorial encompassing both intrinsic and extrinsic factors; including age, gender, genetics, diet, physical activity, obesity, psychology, smoking and alcohol intake. Serum low density lipoprotein (LDL), an underlying consequence mainly of poor dietary habits, is strongly associated with increased risk of developing CHD and therefore a major target for CHD risk reduction strategies. Although intrinsic factors such as age, gender and genetics cannot be controlled or corrected, modifiable factors (extrinsic) can be managed and thus CHD risk may be reduced. Prescription of lipid-lowering drugs such as statins (3-hydroxy-3-methyl-glutaryl-CoA reductase or HMG-CoA inhibitors) has significantly increased due to their LDL-cholesterol lowering properties, where subsequently CHD risk may be reduced. There is little doubt in the efficacy of these drugs; the effectiveness however, is the issue in question. Various studies have reported up to 55% non-adherence to statin medications, after 6 months of treatment. It is important to recognize that once statin adherence subsides in these patients, risk reduction is dependent on the alternative concomitant therapies (diet, physical activity, maintenance of weight and smoking cessation), which may or may not have been implemented by the patient. Therefore the goal of this study was investigate the degree of adherence to statin medication, and alternative concomitant behaviours and examine whether an association exists between these various coronary risk reduction factors and overall CHD risk profile.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Public Health
Griffith Health
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Proestou, Gregory. "Molecular characterization of clone S44-I, that encodes for a protein antigenically related to statin." Thesis, McGill University, 2000. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=33441.
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Is a nuclear phosphoprotein synthesized as a 57 kDa protein that is primarily found in the proximity of the nuclear envelope. It is expressed in growth-arrested cells, such as quiescent and senescent human fibroblasts but not in their replicating counterparts (Wang, 1985a), and in terminally differentiated cells (Muggleton-Harris et al., 1989). Hence, statin is a useful marker for nonproliferation and suppressed growth. On the other hand, transformed cells are statin negative.A WI-38 cDNA library was screened for potential statin clones using the antistatin antibody S44. Clone S44-I was obtained and sequence analysis demonstrated that it shows 99.9% homology to the human C-terminal peroxisomal targeting signal (hPTS1). Northern blot analysis revealed that it is expressed not only in quiescent and senescent, but also in replicating WI-38 as well as in transformed cells. These results suggest that the expression of S44-I is not cell-cycle-arrested-specific.
In vitro translation of S44-I using 35S labeled L-methionine demonstrated that it encodes for a 71 kDa protein which is consistent with the size of the open reading frame (ORF). Moreover, S44-I was transiently transfected and Western blot analysis revealed that S44-I encodes for the expected 71 kDa protein in addition to an 80 kDa polypeptide. Mutation of potential initiation methionines of S44-I for possible alternate initiation of translation mechanism did not eliminate any of the two proteins.
In conclusion, these findings are not consistent with previous studies that have analyzed statin at the protein level. This implies that S44-I does not encode for statin but for the hPTS1 or a related member which may possess a shared antigenic epitope recognizable by the anti-statin antibody.
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Wu, Jun. "Statin Medication Adherence and Associated Outcomes in Type 2 Diabetes Medicaid Enrollees with Comorbid Hyperlipidemia." The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1276258784.
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Cirillo, Dominic J. "The effect of statin use on incident immune-mediated and infectious conditions among U.S. veterans." Diss., University of Iowa, 2008. http://ir.uiowa.edu/etd/9.
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Tissier, Florine. "Effets à long terme de l'atorvastatine à faible dose sur l'athérosclérose : une étude pluridisciplinaire chez un modèle animal, le lapin Watanabe." Thesis, Brest, 2015. http://www.theses.fr/2015BRES0076/document.
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Les maladies cardiovasculaires sont la première cause de mortalité dans le monde, en lien notamment avec la présence et la rupture de plaques d’athérome. Afin d’éviter la survenue d’évènements aigus, un traitement par statines peut être proposé. Cependant, leur utilisation engendre un risque d’effets délétères. Afin de réduire ce risque, une réduction des doses utilisées pourrait être envisagée. Ce travail de thèse étudie les effets potentiels d’un traitement à très faible dose d’atorvastatine et à long terme sur un modèle animal : le lapin Watanabe. Des mesures ont été menées sur des individus contrôles et traités de 3 à 12 mois. Le suivi de la lipidémie et des principaux facteurs biochimiques, de l’adhésion et de l’inflammation a été fait au niveau sanguin. Le développement de l’athérosclérose a été évalué en tomographie par cohérence optique (OCT). Des mesures en histologie ont permis de valider un classement proposé avec l’OCT et de quantifier les macrophages intra plaques. L’élasticité artérielle a été testée in vivo par la mesure de la vitesse de l’onde de pouls et in vitro par un test de traction statique. La fonction vasculaire a été appréhendée en vasoréactivité sur différents territoires (aorte, carotide, mésentérique). Le contenu en élastine et collagène de la paroi des vaisseaux a été effectué en microscopie à deux photons et génération de seconde harmonique. Enfin la respiration mitochondriale du myocarde et sa susceptibilité aux ROS a été évaluée sur fibres cardiaques perméabilisées, l’activité de systèmes antioxydants enzymatiques mesuré, ainsi que la peroxydation lipidique. Les résultats montrent des effets bénéfiques de ce traitement à très faible dose d’atorvastatine sur la fonction cardiovasculaire indépendamment d’un effet hypolipidémiantCardiovascular diseases are the first worldwide causes of death, associated to the presence and rupture of atherosclerotic plaques. To limit acute events, statins may be prescribed. However, its use leads to deleterious effects risk. To reduce this risk, a dose reduction could be considered. The work of this thesis is to study potential effects of a very low dose of atorvastatin, taken in the long term, in an animal model: the Watanabe rabbit. Measurements are made on control and treated animals from the age of 3 to 12 months. Circulating lipids, biochemical parameters and parameters of adhesion and inflammation were studied. Atherosclerosis evolution was evaluated by optical coherence tomography (OCT). Histological measurements allowed to validate a ranking proposed with OCT observations and to quantify intra-plaque macrophage content. Arterial stiffness was tested in vivo with pulse wave velocity and in vitro with a static tensile test. Vascular function was approached with vasoreactivity in different territories (aorta, carotid, mesenteric). Elastin and collagen contents of the artery wall were determined with two-photon and second harmonic generation microscopy. Finally, mitochondrial respiration and its susceptibility to ROS were evaluated in permeabilized cardiac fibers, any enzymatic antioxidant systems and lipid peroxidation were measured. Results show beneficial effects of this very low dose atorvastatin treatment in cardiovascular function, independently of a lipid-lowering effect.Keywords: atherosclerosis