An animal model has implicated elevated levels of tissue factor (TF), and resultant hypercoagulability and inflammation, as key factors in recurrent pregnancy loss (RPL) and has demonstrated that pravastatin is effective in treating this condition. In this study, we have re-evaluated the contraindication of statins during pregnancy. Evaluation has shown that while animal testing (at maternally toxic doses) and case reports of birth defects have led to the contraindication of statins during pregnancy, our controlled study, similar to previously published controlled studies, has failed to demonstrate increased fetal risks. As well, we demonstrated that transfer of pravastatin across the placenta is likely limited. While short term suspension of therapy during gestation is considered safe, extended time without therapy is detrimental to cardiovascular health. Coupled with a trend of elevated TF levels in women with RPL, reconsideration of the contraindication of statins is warranted based on appropriate risk: benefit assessment.

An animal model has implicated elevated levels of tissue factor (TF), and resultant hypercoagulability and inflammation, as key factors in recurrent pregnancy loss (RPL) and has demonstrated that pravastatin is effective in treating this condition. In this study, we have re-evaluated the contraindication of statins during pregnancy. Evaluation has shown that while animal testing (at maternally toxic doses) and case reports of birth defects have led to the contraindication of statins during pregnancy, our controlled study, similar to previously published controlled studies, has failed to demonstrate increased fetal risks. As well, we demonstrated that transfer of pravastatin across the placenta is likely limited. While short term suspension of therapy during gestation is considered safe, extended time without therapy is detrimental to cardiovascular health. Coupled with a trend of elevated TF levels in women with RPL, reconsideration of the contraindication of statins is warranted based on appropriate risk: benefit assessment.

Simvastatin is one of the statins, which are a class of drugs originally developed to fight cardiovascular disease by lowering cholesterol. However, it is now clear that they have effects independent of cholesterol. For example, statin therapy, like exercise, induces adaptations within the heart that protect it against I/R injury. Patients are frequently advised to undergo a combination treatment of statins and chronic exercise, although little is known about how this combination treatment affects cardioprotective adaptations. Both treatments appear to exert their cardioprotective effects through different mechanisms, therefore it appears plausible that combining the two treatments would provide added cardioprotection than either treatment alone. Purpose: To investigate the effects of a combination treatment of statins and exercise upon parameters of post-ischemic myocardial function and damage. Methods: Female Sprague-Dawley rats (6 months of age) were separated into 4 groups for a period of 4 weeks: Sedentary (S, n=10), sedentary plus 10 mg simvastatin (Zocor®)/kg body wt/ day (SD, n=9), exercise (R, n=9), and exercise plus simvastatin (RD, n=9). R and RD were exercised identically on a treadmill for 5 days/week at an intensity of about 70% VO2max and for a duration that was gradually increased to 60 min/day. Twenty-four hrs following the last exercise bout, isolated perfused working hearts were subjected to 30 min of global ischemia followed by 30 min of normoxic reperfusion. Coronary effluents were used to determine lactate dehydrogenase (LDH) leakage and prostaglandin generation. Results: Cardiac function was similar in all groups prior to ischemia. Post I/R recovery of cardiac function in S was 17.6 [greater than or equal to]6.6% of pre-ischemic cardiac output times systolic pressure. Recovery was significantly higher in SD (37.7[greater than or equal to]7.7%) and R (40.1[greater than or equal to]7.8%) and tended to be highest in RD (49.7[greater than or equal to]7.1%). SD had significantly higher pre-ischemic coronary flow per g heart weight (CF/g) than all other groups. At 10 min post-ischemia, simvastatin treatment significantly increased CF/g compared to S (p<0.05). Exercise had an effect on increasing post-ischemic myocardial efficiency and RD had significantly higher post-ischemic myocardial efficiency vs. S (p<0.05). Compared to S, LDH leakage during reperfusion was dramatically decreased in SD, R and RD by approximately similar amounts. Simvastatin treatment doubled the basal production of protective prostaglandins, whereas exercise did not significantly alter their production and combining both treatments yielded a lower prostaglandin release than simvastatin treatment. SD had s significantly higher basal prostaglandin release than R (p<0.05). Conclusion: Although the combination treatment of simvastatin and exercise did not result in a statistically significant addition in cardioprotection compared to either treatment alone, there was a trend for improved parameters of post-ischemic cardiac function and damage upon combining both treatments compared to each treatment alone. Specifically, the prostaglandin, CF/g and efficiency data suggest that exercise and statininduced cardioprotection against I/R injury appears to occur by different mechanisms and combining the two treatments may provide greater protection than either alone.

Kawasaki disease (KD) is a multisystem vasculitis leading to coronary artery aneurysm formation. In a superantigen-mediated murine model of KD, the development of coronary arteritis is mediated by T-cells through the production of TNFα. TNFα localizes to the coronary arteries, where it induces the expression of MMP-9, resulting in the breakdown of elastin and the formation of aneurysms. Statins have been recently shown to have anti-inflammatory and immunomodulatory properties as a result of the inhibition of small GTPases. In our murine model of KD, atorvastatin treatment inhibits superantigen mediated T- cell proliferation and cytokine production, including IL-2 and TNFα. Additionally, statin treatment inhibits TNFα-mediated MMP-9 production by vascular smooth muscle cells, through inhibition of the MEK/ERK pathway. Thus, statins modulate each of the critical steps in the pathogenesis of KD in a disease model, suggesting that statin use could alter the outcome and prognosis of children suffering with this disease.

Kawasaki disease (KD) is a multisystem vasculitis leading to coronary artery aneurysm formation. In a superantigen-mediated murine model of KD, the development of coronary arteritis is mediated by T-cells through the production of TNFα. TNFα localizes to the coronary arteries, where it induces the expression of MMP-9, resulting in the breakdown of elastin and the formation of aneurysms. Statins have been recently shown to have anti-inflammatory and immunomodulatory properties as a result of the inhibition of small GTPases. In our murine model of KD, atorvastatin treatment inhibits superantigen mediated T- cell proliferation and cytokine production, including IL-2 and TNFα. Additionally, statin treatment inhibits TNFα-mediated MMP-9 production by vascular smooth muscle cells, through inhibition of the MEK/ERK pathway. Thus, statins modulate each of the critical steps in the pathogenesis of KD in a disease model, suggesting that statin use could alter the outcome and prognosis of children suffering with this disease.

Thesis (Ph. D.)--University of Iowa, 2008. / Thesis supervisor: Robert B. Wallace. Includes bibliographical references (leaves 300-320).

No description available.

Class of 2012 Abstract / Objectives: 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.

Class of 2007 Abstract / Objectives: 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.

Products of the isoprenoid biosynthetic pathway are involved in diverse biological functions. For example, the isoprenoid diphosphate, farnesyl diphosphate (FPP), is used for synthesis of squalene, a precursor of cholesterol. In addition, FPP and geranylgeranyl diphosphate (GGPP) are used for protein prenylation, which is a post-translational modification of certain proteins required for their proper membrane localization and function. Enzymes within the isoprenoid biosynthetic pathway have been inhibited successfully by drugs that are now used clinically, including statins and nitrogenous bisphosphonates (NBPs). Statins and NBPs are inhibitors of isoprenoid biosynthetic enzymes, due to their structural resemblance to substrates within the pathway. The bisphosphonate core resembles the diphosphate portion of isoprenoid diphosphate intermediates within the isoprenoid biosynthetic pathway. It is hypothesized that distinct isoprenoid biosynthetic enzymes can be inhibited by bisphosphonates in a manner dependent upon the overall bisphosphonate structure. Along with our collaborators, we have developed novel bisphosphonate inhibitors of multiple isoprenoid biosynthetic enzymes. Potent in vitro inhibitors of squalene synthase (SQS) were identified and evaluated in HepG2 liver cells. A lead inhibitor of squalene synthase was combined with a statin and a nitrogenous bisphosphonate, and focus was placed on these combinations as potential novel mechanisms to reduce cholesterol synthesis while minimizing impairment of non-sterol synthesis. Specifically, it was found that the lead SQS inhibitor prevents lovastatin-mediated impairment of protein farnesylation but not geranylgeranylation. Also, the lead SQS inhibitor prevented both zoledronate-induced impairment of protein farnesylation and geranylgeranylation. Novel bisphosphonates were also identified as inhibitors of geranylgeranyl diphosphate synthase (GGDPS) and protein prenylation in K562 leukemia cells. A novel cellular consequence of GGPP depletion was also established. In PC3 cells, zoledronate and digeranyl bisphosphonate (DGBP; a lead inhibitor of GGDPS) were determined to induce autophagy as measured by accumulation of the autophagic marker LC3-II. GGPP depletion was implicated as the cause of autophagic induction in this system. Specifically, results suggest that impairment of proteins geranylgeranylated by geranylgeranyl transferase II is responsible for the induction of autophagy. Mycobacterium isoprenoid biosynthetic enzymes were also evaluated as inhibitory targets for bisphosphonates. Novel inhibitors of Mycobacteria tuberculosis omega-E,Z-FPP synthase and decaprenyl diphosphate synthase were identified. A lead inhibitor of decaprenyl diphosphate synthase was also evaluated in Mycobacterium smegmatis, which was utilized as a surrogate model. The lead inhibitor was found to have no effect on M. smegmatis growth; however it enhanced growth inhibition mediated by ethambutol. This effect was prevented by addition of exogenous decaprenyl diphosphate, suggesting that the growth inhibition was due to decaprenyl diphosphate depletion. Decaprenyl diphosphate was also found to prevent the growth inhibitory effect of SQ109, a novel anti-mycobacterial drug in clinical development with an unknown mechanism of action.