| Development of a novel self-microemulsifying drug delivery system for reducing HIV protease inhibitor-induced intestinal epithelial barrier dysfunction. | |
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MedLine Citation:
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PMID: 20349948 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The development of HIV protease inhibitors (PIs) has been one of the most significant advances of the past decade in controlling HIV infection. Unfortunately, the benefits of HIV PIs are compromised by serious side effects. One of the most frequent and deleterious side effects of HIV PIs is severe gastrointestinal (GI) disorders including mucosal erosions, epithelial barrier dysfunction, and leak-flux diarrhea, which occurs in 16-62% of patients on HIV PIs. Although the underlying mechanisms behind HIV PI-associated serious adverse side effects remain to be identified, our recent studies have shown that activation of endoplasmic reticulum (ER) stress response plays a critical role in HIV PI-induced GI complications. The objective of this study was to develop a novel self-microemulsifying drug delivery system (SMEDDS) using various antioxidants as surfactants and cosurfactants to reduce the GI side effects of the most commonly used HIV PI, ritonavir. The biological activities of this SMSDDS of ritonavir were compared with that of Norvir, which is currently used in the clinic. Rat normal intestinal epithelial cells (IEC-6) and mouse Raw 264.7 macrophages were used to examine the effect of new SMEDDS of ritonavir on activation of ER stress and oxidative stress. Sprague-Dawley rats and C57/BL6 mice were used for pharmacokinetic studies and in vivo studies. The intracellular and plasma drug concentrations were determined by HPLC analysis. Activation of ER stress was detected by Western blot analysis and secreted alkaline phosphatase (SEAP) reporter assay. Reactive oxygen species (ROS) was measured using dichlorodihydrofluorescein diacetate as a probe. Cell viability was determined by Roche's cell proliferation reagent WST-1. Protein levels of inflammatory cytokines (TNF-alpha and IL-6) were determined by enzyme-linked immunosorbent assays (ELISA). The intestinal permeability was assessed by luminal enteral administration of fluorescein isothiocyanate conjugated dextran (FITC-dextran, 4 kDa). The pathologic changes in intestine were determined by histological examination. The results indicated that incorporation of antioxidants in this new SMEDDS not only significantly reduced ritonavir-induced ER stress activation, ROS production and apoptosis in intestinal epithelial cells and macrophages, but also improved the solubility, stability and bioavailability of ritonavir, and significantly reduced ritonavir-induced disruption of intestinal barrier function in vivo. In conclusion, this new SMEDDS of ritonavir has less GI side effects compared to Norvir. This new SMEDDS can be used for other HIV PIs and any insoluble antiviral drug with serious GI side effects. |
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Authors:
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Bokai Lei; Weibin Zha; Yun Wang; Cong Wen; Elaine J Studer; Xuan Wang; Fang Jin; Guangji Wang; Luyong Zhang; Huiping Zhou |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Molecular pharmaceutics Volume: 7 ISSN: 1543-8392 ISO Abbreviation: Mol. Pharm. Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-06-07 Completed Date: 2010-09-07 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 101197791 Medline TA: Mol Pharm Country: United States |
Other Details:
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Languages: eng Pagination: 844-53 Citation Subset: IM |
Affiliation:
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Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia 23298, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Alkaline Phosphatase
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metabolism Animals Ascorbic Acid / administration & dosage, chemistry, therapeutic use Blotting, Western Cell Line Cell Survival / drug effects Chromatography, High Pressure Liquid Drug Delivery Systems* Enzyme-Linked Immunosorbent Assay HIV Protease Inhibitors / administration & dosage*, adverse effects*, chemistry Interleukin-6 / metabolism Intestinal Mucosa / drug effects*, metabolism, pathology Linoleic Acids / administration & dosage, chemistry, therapeutic use Male Mice Mice, Inbred C57BL Oleic Acid / administration & dosage, chemistry, therapeutic use Rats Rats, Sprague-Dawley Reactive Oxygen Species / metabolism Ritonavir / administration & dosage*, adverse effects*, chemistry Tumor Necrosis Factor-alpha / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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R01 AT004148-01/AT/NCCAM NIH HHS; R01AI057189/AI/NIAID NIH HHS; R01AT004148/AT/NCCAM NIH HHS; R21 AI068432-01A1/AI/NIAID NIH HHS; R21AI068432/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/HIV Protease Inhibitors; 0/Interleukin-6; 0/Linoleic Acids; 0/Reactive Oxygen Species; 0/Ritonavir; 0/Tumor Necrosis Factor-alpha; 112-80-1/Oleic Acid; 50-81-7/Ascorbic Acid; 544-35-4/ethyl linoleate; EC 3.1.3.1/Alkaline Phosphatase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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