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      Sucralose, A Synthetic Organochlorine Sweetener: Overview of Biological Issues

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          Abstract

          Sucralose is a synthetic organochlorine sweetener (OC) that is a common ingredient in the world's food supply. Sucralose interacts with chemosensors in the alimentary tract that play a role in sweet taste sensation and hormone secretion. In rats, sucralose ingestion was shown to increase the expression of the efflux transporter P-glycoprotein (P-gp) and two cytochrome P-450 (CYP) isozymes in the intestine. P-gp and CYP are key components of the presystemic detoxification system involved in first-pass drug metabolism. The effect of sucralose on first-pass drug metabolism in humans, however, has not yet been determined. In rats, sucralose alters the microbial composition in the gastrointestinal tract (GIT), with relatively greater reduction in beneficial bacteria. Although early studies asserted that sucralose passes through the GIT unchanged, subsequent analysis suggested that some of the ingested sweetener is metabolized in the GIT, as indicated by multiple peaks found in thin-layer radiochromatographic profiles of methanolic fecal extracts after oral sucralose administration. The identity and safety profile of these putative sucralose metabolites are not known at this time. Sucralose and one of its hydrolysis products were found to be mutagenic at elevated concentrations in several testing methods. Cooking with sucralose at high temperatures was reported to generate chloropropanols, a potentially toxic class of compounds. Both human and rodent studies demonstrated that sucralose may alter glucose, insulin, and glucagon-like peptide 1 (GLP-1) levels. Taken together, these findings indicate that sucralose is not a biologically inert compound.

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          Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides.

          Resistant starch (RS) is starch and products of its small intestinal digestion that enter the large bowel. It occurs for various reasons including chemical structure, cooking of food, chemical modification, and food mastication. Human colonic bacteria ferment RS and nonstarch polysaccharides (NSP; major components of dietary fiber) to short-chain fatty acids (SCFA), mainly acetate, propionate, and butyrate. SCFA stimulate colonic blood flow and fluid and electrolyte uptake. Butyrate is a preferred substrate for colonocytes and appears to promote a normal phenotype in these cells. Fermentation of some RS types favors butyrate production. Measurement of colonic fermentation in humans is difficult, and indirect measures (e.g., fecal samples) or animal models have been used. Of the latter, rodents appear to be of limited value, and pigs or dogs are preferable. RS is less effective than NSP in stool bulking, but epidemiological data suggest that it is more protective against colorectal cancer, possibly via butyrate. RS is a prebiotic, but knowledge of its other interactions with the microflora is limited. The contribution of RS to fermentation and colonic physiology seems to be greater than that of NSP. However, the lack of a generally accepted analytical procedure that accommodates the major influences on RS means this is yet to be established.
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            Membrane transporters in drug development.

            Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.
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              Adherence to long-term therapies: evidence for action.

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                Author and article information

                Journal
                J Toxicol Environ Health B Crit Rev
                J Toxicol Environ Health B Crit Rev
                uteb
                Journal of Toxicology and Environmental Health. Part B, Critical Reviews
                Taylor & Francis
                1093-7404
                1521-6950
                12 November 2013
                September 2013
                : 16
                : 7
                : 399-451
                Affiliations
                [1 ] Department of Electrical and Computer Engineering, College of Engineering, North Carolina State University, Raleigh, North Carolina, USA
                [2 ] Section on Pediatric Diabetes & Metabolism, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, Maryland, USA
                Author notes

                This research was supported in part by the Intramural Research Program of the NIH, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

                Address correspondence to Susan S. Schiffman, PhD, Department of Electrical and Computer Engineering, College of Engineering, North Carolina State University, Raleigh, NC 27695-7911, USA. E-mail: sschiffman@ 123456nc.rr.com
                Article
                10.1080/10937404.2013.842523
                3856475
                24219506
                4b0afd27-fac0-41e3-9c65-1f30faa345b1
                © Susan S. Schiffman and Kristina I. Rother

                This is an open access article distributed under the Supplemental Terms and Conditions for iOpenAccess articles published in Taylor & Francis journals , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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                Research Article

                Toxicology
                Toxicology

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