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ABC-transporters expressed on endothelial cell membranes efflux anti-HIV drugs
August 27, 2008Researchers at Tulane University Medical Center in New Orleans (USA) have discovered that drug-efflux pumps, belonging to the ATP-binding cassette (ABC) transporter family, are constitutively expressed on vascular endothelial cells. Transcripts for several different ABC-transporters, e.g. MDR-1 (P-gp) and MRPs, were detected in endothelial cells, obtained from brain, aortic artery, pulmonary artery, dermal microvessels and umbilical veins. The ABC-transporter mediated efflux mechanisms decreased intracellular concentrations of the anti-HIV drugs, saquinavir, an HIV protease inhibitor (HPI) and zidovudine, a nucleoside reverse transcriptase inhibitor (NRTI), which are critical components of highly active antiretroviral therapy (HAART) against HIV. Inhibition of ABC-transporters, by using verapamil or MK-571, was shown to increase the intracellular retention of these anti-HIV agents. The MRP transporters were found to play a more dominant role in drug-efflux from endothelial cells. Pre-incubation of cells with the MRP-inhibitor, MK-571 significantly enhanced the intracellular levels of anti-HIV drugs. This study, entitled 'MRP (ABCC) transporters-mediated efflux of anti-HIV drugs, saquinavir and zidovudine, from human endothelial cells,' will be published in the September 2008 issue of Experimental Biology and Medicine.
These investigations led by Dr. Debasis Mondal, an assistant professor of Pharmacology, and co-authored by Mr. Mark Eilers and Dr. Upal Roy, demonstrated the significance of blocking MRP-transporters on endothelial barriers of blood vessels, in order to increase the pharmacokinetic efficacy of both HPIs and NRTIs. Drug-efflux pumps expressed on the blood-brain-barrier (BBB) were previously known to decrease drug entry into the central nervous system (CNS), however, this is the first evidence that endothelial cells from other organs express functional ABC-transporters, as well. The functional expression of MRPs on vascular endothelial barriers implicates their crucial role in facilitating the persistence of sub-endothelial HIV reservoirs.
"Although we have a significant armament of therapeutic agents against HIV, factors that dictate the pharmacokinetics of anti-HIV drugs need to be accounted for in order to have HAART efficacy in sequestered viral reservoirs. Several P-gp inhibitors are currently under clinical trial, however, very little is being done to target the MRP-transporters. Our studies using the anti-HIV drugs, saquinavir and zidovudine, clearly implicated that inhibition of MRPs, rather than P-gp, would be a more beneficial approach to facilitate the entry of HAART drugs into the sub-endothelial reservoirs of HIV, especially within the brain. Unpublished findings from our laboratory suggest that, similar to MK-571, other leukotriene receptor antagonists, e.g. montelukast (SingulairTM) and zafirlukast (AccolateTM) can suppress MRP-mediated efflux of these anti-HIV drugs, as well. We believe that adjunct therapy with these clinically approved MRP inhibitors may improve HAART efficacy in HIV-positive patients, deter the selection of drug resistance and delay the progression of AIDS." Dr. Steve Goodman, Editor-in-Chief of Experimental Biology and Medicine said "this study by Dr. Mondal and colleagues has crucial implications in the persistence of sub-endothelial HIV reservoirs and will be important to the development of future therapies".
Society for Experimental Biology and Medicine
Society for Experimental Biology and Medicine
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Methods in Endothelial Cell Biology (Springer Lab Manuals) by Hellmut G. Augustin (Editor)
Endothelial cell biology has developed into a vibrant discipline and has become a critical instrument to study several disease processes on the cellular and molecular level. It is now widely recognized that dysfunctions of normal endothelial cell homeostasis are involved in some of the most important human diseases, including ischemic heart diseases, hypertension, atherosclerosis, tumors, diabetes, arthritis, and inflammation. Further, the increasing importance and recognition of the field of vascular biology in general requires in vitro and in vivo techniques in order to address the complex questions. |
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Life Extension, ENDOTHELIAL DEFENSE WITH COCOAGOLD - 60 VEGGIE CAPSULES by Life Extension |
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Stick and Ball Model of Vascular Endothelial Growth Factor Photographic Poster Print, 24x24 by Art.com Art.com is the world's largest retailer of art prints, posters, photographs, and framed artwork. With our huge selection of over 400,000 prints, you'll easily find the perfect piece for your home, office, or classroom. Our art is printed on quality paper. When you order framed artwork, the piece is built by our team of in-house professionals. Visit our Amazon store today at www.amazon.com/artdotcom to find Special Offers and search for products based on 'Artist Name' and 'Subject Categories' such as Movie, Music, Vintage, TV, Children, Travel, Kitchen, Museum Art, Animals, Floral, Motivational, and Sports. Art.com is dedicated to providing you with high quality products and service by offering you 100% satisfaction guaranteed. We ship internationally to over 80 countries. Decorate your... |
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Olympian Labs Arginine, 500mg & Ornithine, 250mg by Olympian Labs A balanced combination of amino acids that may increase the release of growth hormone. Growth hormone is required for optimum muscle growth and repair. A reduction in body fat and increases in muscle mass may occur with supplementation of these two amino acids. Warning Signals: Check with your doctor before you take any dietary supplement, including vitamins and minerals. If your doctor starts you on a supplement, watch for warning signals that could indicate problems: stomach discomfort, pain, headache, rashes, or even vague symptoms like tiredness, dizziness, or lethargy. Ingredients: Supplement Facts Serving Size: One (1) Capsule Servings Per Container: 100 Amount Per%Daily Value* Serving: L-Arginine Hydrochloride500 mg L-Ornithine... |
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