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Possible Inhibition (possible + inhibition)
Selected AbstractsGlycerol and Glycerol Glycol GlycodendrimersEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 22 2003Mike M. K. Boysen Abstract Non-covalent interactions between structural parts of complex oligosaccharides and saccharide-recognising proteins are of crucial importance for many cell communication phenomena. Specificity of such interactions and stability of these ligand-receptor complexes are achieved through multivalent interactions between multiple copies of a saccharide ligand and a corresponding number of protein receptors. Substances presenting multiple copies of the saccharide ligand on easily accessible scaffold molecules therefore appear to be promising tools for study of multivalent interactions and their possible inhibition. Such multivalent glycomimetics can be prepared by attachment of saccharide residues to the surface functional groups of dendrimers. In the course of our work, we have prepared novel glycodendrimers with glycerol and glycerol glycol polyether scaffolds. Isopropylidene-protected hydroxyethyl mannoside was chosen as the carbohydrate component, with the construction of the dendritic structures proceeding by a convergent approach featuring iterative Williamson etherification and ozonolysis/hydride reduction steps. Deprotected representatives of such structures are potential inhibitors of mannose-binding lectins of E. coli. Three representative compounds were deprotected and their anti-adhesive properties were examined. The route to these glycodendrimers was also evaluated in terms of synthetic chemistry. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003) [source] In vitro inhibition of CYP3A4 by herbal remedies frequently used by cancer patientsPHYTOTHERAPY RESEARCH, Issue 7 2009Silje Engdal Abstract The herbal remedies Natto K2, Agaricus, mistletoe, noni juice, green tea and garlic, frequently used by cancer patients, were investigated for their in vitro inhibition potential of cytochrome P-450 3A4 (CYP3A4) metabolism. To our knowledge, only garlic and green tea had available data on the possible inhibition of CYP3A4 metabolism. Metabolic studies were performed with human c-DNA baculovirus expressed CYP3A4. Testosterone was used as a substrate and ketoconazole as a positive quantitative inhibition control. The formation of 6- , -OH-testosterone was quantified by a validated HPLC methodology. Green tea was the most potent inhibitor of CYP3A4 metabolism (IC50: 73 µg/mL), followed by Agaricus, mistletoe and noni juice (1324, 3594, >10 000 µg/mL, respectively). All IC50 values were high compared with those determined for crude extracts of other herbal remedies. The IC50/IC25 ratios for the inhibiting herbal remedies ranged from 2.15 to 2.67, indicating similar inhibition profiles of the herbal inhibitors of CYP3A4. Garlic and Natto K2 were classified as non-inhibitors. Although Agaricus, noni juice, mistletoe and green tea inhibited CYP3A4 metabolism in vitro, clinically relevant systemic or intestinal interactions with CYP3A4 were considered unlikely, except for a probable inhibition of intestinal CYP3A4 by the green tea product. Copyright © 2009 John Wiley & Sons, Ltd. [source] Risk of diarrhoea in a long-term cohort of renal transplant patients given mycophenolate mofetil: the significant role of the UGT1A8*2 variant alleleBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2010Jean-Baptiste Woillard WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Mycophenolate mofetil (MMF), the most widely used drug in allograft transplantation, is subject to hepatic and intestinal glucuronidation and entero-hepatic cycling. , Diarrhoea is its most frequent adverse event leading to non-compliance, treatment interruption and ultimately to an increased rate of acute rejection. , Cyclosporin reduces the biliary excretion of mycophenolate metabolites, presumably by inhibiting the efflux transporter MRP2. , When combined with MMF, cyclosporin reduces the incidence of diarrhoea, suggesting the role played by biliary excretion of mycophenolate glucuronides in this adverse event. WHAT THIS STUDY ADDS , In a long-term cohort of renal transplant patients on MMF, the two factors significantly associated with a reduced incidence of diarrhoea were the co-medication with cyclosporin (as opposed to tacrolimus or sirolimus) and the *2 variant allele of the intestinal UGT1A8. , Polymorphisms in the other UDP-glucuronosyl-transferases and MRP2 were not significant. AIM In renal transplant patients given mycophenolate mofetil (MMF), we investigated the relationship between the digestive adverse events and polymorphisms in the UGT genes involved in mycophenolic acid (MPA) intestinal metabolism and biliary excretion of its phase II metabolites. METHODS Clinical data and DNA from 256 patients transplanted between 1996 and 2006 and given MMF with cyclosporin (CsA, n = 185), tacrolimus (TAC, n = 49) or sirolimus (SIR, n = 22), were retrospectively analysed. The relationships between diarrhoea and polymorphisms in UGT1A8 (*2; 518C>G, *3; 830G>A), UGT1A7 (622C>T), UGT1A9 (,275T>A), UGT2B7 (,840G>A) and ABCC2 (,24C>T, 3972C>T) or the co-administered immunosuppressant were investigated using the Cox proportional hazard model. RESULTS Multivariate analysis showed that patients on TAC or SIR had a 2.8 higher risk of diarrhoea than patients on CsA (HR = 2.809; 95%CI (1.730, 4.545); P < 0.0001) and that non-carriers of the UGT1A8*2 allele (CC518 genotype) had a higher risk of diarrhoea than carriers (C518G and 518GG genotypes) (HR = 1.876; 95%CI (1.109, 3.175); P = 0.0192). When patients were divided according to the immunosuppressive co-treatment, a significant effect of UGT1A8*2 was found in those co-treated with CsA (HR = 2.414; 95%CI (1.089, 5.354); P = 0.0301) but not TAC or SIR (P = 0.4331). CONCLUSION These results suggest that a possible inhibition of biliary excretion of MPA metabolites by CsA and a decreased intestinal production of these metabolites in UGT1A8*2 carriers may be protective factors against MMF-induced diarrhoea. [source] Long-chain fatty acyl-coenzyme A-induced inhibition of glucokinase in pancreatic islets from rats depleted in long-chain polyunsaturated ,3 fatty acidsCELL BIOCHEMISTRY AND FUNCTION, Issue 2 2008Ying Zhang Abstract The metabolism of D -glucose was recently reported to be impaired in pancreatic islets from second generation rats depleted in long-chain polyunsaturated ,3 fatty acids. Considering the increased clearance of circulating non-esterified fatty acids prevailing in these rats, a possible inhibition of glucokinase in insulin-producing cells by endogenous long-chain fatty acyl-CoA was considered. The present study was mainly aimed at assessing the validity of the latter proposal. The activity of glucokinase in islet homogenates, as judged from the increase in D -glucose phosphorylation rate in response to a rise in the concentration of the hexose represented, in the ,3-depleted rats, was only 81.8,±,4.8% (n,=,11; p,<,0.005) of the paired value recorded in control animals. This coincided with the fact that the inclusion of D -glucose 6-phosphate (3.0,mM) and D -fructose 1-phosphate (1.0,mM) in the assay medium resulted in a lesser fractional decrease of D -glucose phosphorylation in ,3-depleted rats than in control animals. Moreover, whereas palmitoyl-CoA (50,µM) decreased the activity of glucokinase by 38.0,±,6.0% (n,=,4; p,<,0.01) in islet homogenates from normal rats, the CoA ester failed to affect significantly the activity of glucokinase in islet homogenates from ,3-depleted rats. These findings afford direct support for the view that glucokinase is indeed inhibited by endogenous long-chain fatty acyl-CoA in islets from ,3-depleted rats, such an inhibition probably participating to the alteration of D -glucose catabolism prevailing in these islets. Copyright © 2007 John Wiley & Sons, Ltd. [source] | ||||||||||