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

Class of 2012 Abstract / Specific Aims: To evaluate the quality of evidence in the literature substantiating major drug-drug interactions of the HMG-CoA reductase inhibitors (statins) atorvastatin, lovastatin, and simvastatin with the azole anti-fungals fluconazole, itraconazole, and ketoconazole. Methods: In this descriptive retrospective analysis, a list of articles reporting on each drug-drug interaction was compiled from the online databases Medline and International Pharmaceutical Abstracts, and the drug compendia Micromedex and Facts & Comparisons. The studies included in this analysis were primary literature reports, written in English, and consisted of human subjects. All studies included were evaluated using a 5-point quality of evidence scale developed to assess drug-drug interactions (van Roon scale). This scale rates the study type from lowest to highest quality, from zero to four. Case reports were additionally analyzed 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. Main Results: Twenty-one studies met the selection criteria. There were three studies involving atorvastatin, four studies involving lovastatin, and fourteen studies involving simvastatin. The mean quality of evidence score on the van Roon scale was 2.0 + 0.77, where atorvastatin studies had a score of 2.3 + 1.15, lovastatin had a score of 2.25 + 0.95 and simvastatin had a score of 1.86 + 0.66. Seventy-one percent of the studies reviewed were case reports. Conclusions: The reports substantiating some drug-drug interactions may be of little and low quality evidence.

HMG-CoA reductase inhibitors, known commonly as statins are one of the most widely prescribed medications worldwide. Statins reduce circulating cholesterol levels and are very effective at reducing one’s risk for all-cause and cardiovascular mortality. Though generally well tolerated, statin-associated muscle symptoms (SAMS) present in more than a quarter of statin users. The most common SAMS is myalgia or muscle pain. Statin myalgia often presents in the absence of myofibre damage, making its origin and treatment ambiguous. There are numerous rodent models for statin myopathy in the literature, but surprisingly there is no representation of statin myalgia that we are aware of. This is shocking given the high prevalence of statin myalgia compared to statin myopathy. Recently, our lab published an in vitro model of statin myalgia that focused on elevated xCT transporter activity and interstitial glutamate. This model explains that pain perceived in statin myalgia is the result of statins’ downstream ability to elevate skeletal muscle interstitial glutamate concentrations, thereby activating peripheral nociceptors. The studies herein aimed to create an in vivo rodent model of statin myalgia based on the aforementioned in vitro model. We hypothesized that glutamate, sampled by way of skeletal muscle microdialysis, would be elevated in the skeletal muscle interstitium of rats following statin treatment. Drawing conclusions on the role of glutamate in statin myalgia was not a straightforward process and required multiple model adjustments due to confounding variables. Additionally, many of the recognized effects of statins that were assumed from human and in vitro studies did not translate well to our rodent model. This was the first attempt at creating an in vivo model of statin myalgia and evidence suggests that a rodent model may not be an appropriate representation of what occurs in humans. While these studies also raised doubt on the efficacy of rodent models for SAMS investigations in general and highlighted the importance of having standardized models, certain limitations and assumptions of our model must be addressed before concrete conclusions can be drawn. / Thesis / Master of Science in Medical Sciences (MSMS) / Statins, a class of cholesterol-lowering medications, are one of the most widely prescribed medications worldwide. They have been demonstrated to be very effective at reducing one’s risk of cardiovascular-related death. Statins are generally very well tolerated, however, the most common negative side effects of their use are muscle related and include muscle pain, muscle inflammation and muscle damage. Muscle pain is the most common of these symptoms to present and interestingly, often presents without any clinical indication of muscle damage. The lack of a physical explanation for what is causing this pain makes treating statin-associated muscle pain quite difficult. A lot of effort has gone into determining the mechanism(s) for statin-associated muscle damage, however, there is a gap when it comes to investigating the mechanism(s) for statin-associated muscle pain. The studies herein, therefore, aimed to bridge this gap and investigated a potential mechanism for statin-associated muscle pain in a rodent model. The foundation for this model was built on a cell culture model that was previously developed in our lab. Our data suggest that a rodent model for statin-associated muscle pain may not be an appropriate representation of what occurs in humans. In particular, reduced blood cholesterol and substantial skeletal muscle oxidative stress were not demonstrated in our model as they have been in humans and in cell culture studies. This raised concern around the efficacy of rodent models for statin associated muscle symptoms in general and highlighted the importance of having standardized models. The differences between human/cell culture studies and rodent models also made it difficult to draw firm conclusions on whether the mechanism for statin myalgia investigated herein is supported.

Background: In the United States, 30-60% of older adults fall each year; 10-20% of these falls result in injury, hospitalization, or even death. Better prevention of falls in this population may be facilitated by broader identification of risk factors. The use of statins has emerged as a potential risk factor, but the data provide conflicted results. Purpose: To examine the relationship between statin use and falls among community-dwelling older adults. Methods: We evaluated the patient registry of a Level 1 trauma center. All patients aged > 50 years who were admitted for falls in 2015 were included (n=615). Many of these patients had been previously admitted for falls and many were later readmitted for falls. We analyzed predictors of both prior admission and readmission with linear regressions. Independent variables were self-reported balance problems, diagnosis of dementia, and the use of statins. Results: On average, patients admitted for falls were 79.9 + 9.3 years old and 28% (n=173) were taking statins. Our collection of predictors explained 14.2% of the variance in the number of prior admissions (p<0.001). In this model, the use of statins significantly predicted the number of previous fall-related admissions (95% CI: 0.07–0.50, p=0.010). This same model maintained its significance when predicting admissions for future falls (p<0.001) and the use of statins continued to predict a greater number of readmissions (95% CI: 0.04–0.36, p=0.015). Conclusion: More than 25% of all Americans age > 40 years are taking cholesterol-lowering medication; 93% of those medications are statins. Although evidence is conflicted, these data support the finding that statin therapy increases the risk of falls in older adults. Incorporating exercise training as a prophylactic measure: enhancing lipid profiles and decreasing the need for statins while also improving balance, coordination, and mobility, may reduce fall-related injuries.

Lipoprotein(a) (Lp(a)) consists of an LDL-like particle and the specific protein apo(a), which is very similar to plasminogen. Apo(a) contains repeated kringle structures and a serine protease domain, which cannot be activated by t-PA. Lp(a) is considered to be a predictor for atherosclerotic disease. It has been found incorporated in atherosclerotic plaques and inhibits in vitro fibrinolysis. Lp(a) was determined in 1527 randomly selected individuals participating in the Northern Sweden WHO-MONICA project. A weak but significant relation between Lp(a) and increasing age was found. Menopausal status was the strongest independent predictor of Lp(a) level in women. Fibrinogen was independently related to Lp(a) in both sexes. Only a minor fraction of Lp(a) variance could be explained for in a multiple regression model, which is in agreement with the contention that Lp(a) is highly genetically determined. Lp(a) was determined in 1571 patients investigated with coronary angiography because of suspected severe coronary artery disease (CAD). Patients with proven CAD at elective angiography had significantly higher Lp(a) than patients without significant CAD or healthy controls. Lp(a) was found to be an independent discriminator of CAD in both sexes. HLA-DR genotype 13 or 17 was found more frequently in 30 male patients with angiographic CAD at young age (&lt; 50 years) than in 30 age matched controls. These genotypes were common in patients with high Lp(a) levels, which indicates that Lp(a) may be related to immunological processes. The reaction of Lp(a) was investigated in 32 patients with acute myocardial infarction (AMI). Lp(a) increased during the first week, but the response was comparatively weak. Individual Lp(a) responses were heterogeneous and no correlations to infarct size or changes in the acute phase proteins were found. In a randomized cross-over study on 36 hypercholesterolaemic patients treated with simvastatin/placebo during 12+12 weeks Lp(a) did not change significantly, but patients with high Lp(a) levels at baseline tended to develop further increased Lp(a). To conclude, Lp(a) was found to be an independent predictor of angiographic CAD in both men and women. Lp(a) levels are primarily genetically determined and only a small fraction of Lp(a) variance could be explained by other factors in this study. Lp(a) may be related to HLA DR types and immunological processes involved in atherosclerotic disease. Lp(a) increased slightly during the first week of AMI, but was not related to changes in the acute-phase proteins. The effective LDL-lowering agent simvastatin did not influence Lp(a) significantly. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1993, härtill 5 uppsatser.</p> / digitalisering@umu

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