1,758 research outputs found
Modeling the response of water and carbon fluxes to atmospheric dryness in the land surface scheme : JSBACH: Evaluating alternative process representations using multi-biome eddy covariance data
Simply So Different : The Uniquely Expressive Character of the Openly Gay Individual After Boy Scouts of America v. Dale
The Paradox of Corporate Giving: Tax Expenditures, the Nature of the Corporation, and the Social Construction of Charity
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
Calcitonin receptor-like receptor is expressed on gastrointestinal immune cells
Background/Aims: Pharmacological and morphological studies suggest that the gut mucosal immune system and local neuropeptide-containing neurones interact. We aimed to determine whether gut immune cells are targets for calcitonin gene-related peptide (CGRP), which has potent immune regulatory properties. Methods: Using density gradient centrifugation, rat lamina propria mononuclear cells (LP-MNCs) and intra-epithelial lymphocytes (IELs) were isolated. RT-PCR was employed for the detection of mRNA of rat calcitonin receptor-like receptor (CRLR), which is considered to represent the pharmacologically defined CGRP receptor-1 subtype, as well as mRNA of the receptor activity-modifying proteins, which are essential for CRLR function and determine ligand specificity. A radioreceptor assay was employed for the detection of specific CGRP binding sites. Results: RT-PCR and DNA sequencing showed that LP-MNCs and IELs express CRLR. Incubation of isolated LP-MNCs with radiolabelled alphaCGRP revealed the existence of specific binding sites for CGRP. Conclusion: These novel data indicate that mucosal immune cells of the rat gut are a target for CGRP and provide significant evidence that CGRP functions as an immune regulator in the gut mucosa. Copyright (C) 2002 S. Karger AG, Basel
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