The Role of Drug Transporters in Statin-Induced Myopathy

Statins are the first line therapy for treatment and prevention of cardiovascular disease. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, or statins, reduce plasma cholesterol levels by inhibiting the rate-limiting step in cholesterol biosynthesis. While statins are well tolerated, up to 15% of patients develop myopathy, manifesting as muscle aches and pain and in rare cases, potentially life-threatening statin-induced rhabdomyolysis. Given that approximately 3 to 4 million Canadians are treated with statins, an estimated 500,000 patients experience associated skeletal muscle side effects that may prevent the continued treatment of hypercholesterolemia. Despite the prevalence of this side effect, little is known regarding the molecular determinants of statin myopathy. Increased systemic statin exposure is linked to risk of developing myopathy, but the role of skeletal muscle exposure and its relevance to muscle toxicity remains to be determined. Drug transporter proteins are important determinants of drug absorption, tissue exposure and drug elimination. Statins are substrates of multiple drug transporters and require hepatic uptake to exert their cholesterol lowering effect. However, little is known about the role drug transporters have in the skeletal muscle distribution of statins and their toxicity. We aimed to identify drug transporters in skeletal muscle involved in controlling muscle exposure. We found that the uptake transporter OATP2B1 and three novel statin efflux transporters, MRP1, MRP4 and MRP5, are expressed in skeletal muscle. We demonstrate that OATP2B1 sensitizes muscle to toxicity and MRP1 attenuates toxicity of atorvastatin and rosuvastatin in an in vitro skeletal muscle model. We studied the regulation and function of two transcriptional variants of OATP2B1, demonstrating that these variants had similar function but differential regulation, resulting in ubiquitous expression for OATP2B1 full length form and primarily hepatic expression for the truncated variant. We employed a novel Oatp2b1 knockout mouse model to examine the in vivo role of Oatp2b1 in rosuvastatin disposition. We found that Oatp2b1 does not have a significant effect on rosuvastatin pharmacokinetics but the hepatic exposure was increased in Oatp2b1 knockout mice. Taken together, these studies further our understanding of the in vitro and in vivo involvement of drug transporters in the context of statin myopathy

Discharge chamber studies for mercury bombardment ion thrusters

Discharge chamber performance optimization for mercury bombardment ion thruster

High voltage solar array study Final report

High voltage solar array stud

The Recognition of Same-Sex Relationships: Comparative Institutional Analysis, Contested Social Goals, and Strategic Institutional Choice

The emerging field of comparative institutional analysis (CIA) has much to offer public policy analysts. However, the failure of CIA to address the dynamic process through which social goals are articulated limits the scope of its application to the largely prescriptive pronouncements of legal scholars. By examining the movement for equal recognition of same-sex relationships, this Essay builds on the basic observations of CIA and introduces a new dimension, namely the dynamic process through which social goals are articulated and social change is pursued. The acknowledgment that the production of social goals involves institutional behavior, as well as multiple sites of contestation, can enhance the analytic power of CIA and offer a comparative institutional method of analysis to social movement theory. When CIA encounters contested social goals, the result is a program of “strategic institutional choice” which evaluates not simply an institution’s competency to supply the desired rights or status, but also its responsiveness to demands for such rights or status and its resilience against attempts by opponents to subvert the process or to reverse gains. This three-part “strategic” analysis does not identify the optimal institution, but instead informs the allocation of resources among institutions as advocates simultaneously pursue their goal in a variety of complementary institutional settings. The debate over same-sex relationships has been conducted through a creative and combative program of institutional one-upmanship where gains secured by pro-recognition advocates through the market or courts are frequently reversed by the traditional values movement through the political process, with increasing emphasis on the constitutional amendment process. After a brief Introduction, Part II of the Essay examines CIA’s failure to consider the production of social goals, the single institutionalism practiced by social movement theory, and the nature of strategic institutional choice. Part III describes the forces aligned on either side of the struggle over the recognition of same-sex relationships and outlines the costs and benefits associated with participation. Part IV evaluates the pro-recognition gains made in various institutional settings in terms of the three core components of strategic institutional choice: competency, responsiveness, and resilience. Part V discusses the constitutional amendment process, as the ultimate majoritarian prerogative. It offers some final thoughts on the potential transitory nature of minority gains that take place within a democratic frame where a motivated majority can choose to rewrite the rules that define institutions and their decision-making authority

The Effect of CV-1 Cell Geometry on the Ultraviolet Radiation Sensitivity of Mammalian Cells In Vitro

The effect of cell geometry on the radiosensitivity to ultraviolet (UV) light has been studied in the CV-1 host cell-capacity system. In this system the macromolecular damage incurred by monolayers of cells cultures as the result of exposure to UV radiation is monitored by testing the ability of irradiated cells to support the replication of Herpes simplex virus. The target molecule has been shown to be DNA and is centrally located Mammalian cells have an absolute requirement for Mg++ and Ca++ in order to remain attached to artificial substrata. To test the effect of cell geometry on UV radiation sensitivity. Monolayer cultires were exposed to a Mg++ and Ca++ free UV transparent buffer solution. Cultures containing from 0% to 100% spherical cells were irradiated Cultures containing 40% or more spherical cells were less sensitive to UV exposures by as much as a factor of five. The decrease in sensitivity was proportional to the percentage of spherical cells in cultures from 0% to 40%. An experiment was conducted in which the UV dose to the surface of spherical cells was modified by 24%, 27%, and 44%. The results of this experiment showed that 27% less energy ultimately reached an DNA target in a spherical cell than in an umbonate cell. It was concluded that protoplasmic shielding of the centrally located target molecule was probably responsible for the decreased UV radiation sensitivity of spherical cell

A Laboratory Investigation of Supersonic Clumpy Flows: Experimental Design and Theoretical Analysis

We present a design for high energy density laboratory experiments studying the interaction of hypersonic shocks with a large number of inhomogeneities. These ``clumpy'' flows are relevant to a wide variety of astrophysical environments including the evolution of molecular clouds, outflows from young stars, Planetary Nebulae and Active Galactic Nuclei. The experiment consists of a strong shock (driven by a pulsed power machine or a high intensity laser) impinging on a region of randomly placed plastic rods. We discuss the goals of the specific design and how they are met by specific choices of target components. An adaptive mesh refinement hydrodynamic code is used to analyze the design and establish a predictive baseline for the experiments. The simulations confirm the effectiveness of the design in terms of articulating the differences between shocks propagating through smooth and clumpy environments. In particular, we find significant differences between the shock propagation speeds in a clumpy medium compared to a smooth one with the same average density. The simulation results are of general interest for foams in both inertial confinement fusion and laboratory astrophysics studies. Our results highlight the danger of using average properties of inhomogeneous astrophysical environments when comparing timescales for critical processes such as shock crossing and gravitational collapse times.Comment: 7 pages, 6 figures. Submitted to the Astrophysical Journal. For additional information, including simulation animations and the pdf and ps files of the paper with embedded high-quality images, see http://pas.rochester.edu/~wm