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GST Primary GST Primary Best Strategies for Health Care Quality Im... Best Strategies for Health Care Quality Improvement - Diabetes Quality Improvement Strategies for Antibio... Kathryn McDonald, Stanford-UCSF Evidence-b... Systematic review assessing the effect of ... Quality Improvement Strategies for Antibiotics Management Kathryn McDonald, Stanford-UCSF Evidence-based Practice Center, 117 Encina Commons, Stanford, CA 94305-6019, Kathy.mcdonald@stanford.edu Systematic review assessing the effect of quality improvement strategies on appropriate prescribing of antibiotics and appropriate choice of antibiotics. Adherence Adherence Assistive Devices Assistive Devices Childhood Burn Hanson MacMillan Childhood Burn Hanson MacMillan CLSA_9 CLSA_9 Cyberabuse Cyberabuse Cognitive Behavioural Therapy for Violent ... This review included randomized trials abo... Cognitive Behavioural Therapy for Violent Men who Batter Their Partners This review included randomized trials about the effects of cognitive behavioral therapy on domestic violence. The intervention included programs based on the Duluth Model. The violence had to be committed by a male toward his female partner. The violence also had to be physical. The primary outcomes were new arrests and convictions, and new reports of violence. CABG vs PCI CABG vs PCI Quality Improvement Strategies for Prevent... Quality Improvement Strategies for Preventing Nosocomial Infections (Created 17-Feb-06) Quality Improvement Strategies for Asthma ... Quality Improvement Strategies for Asthma Control Erectile Dysfunction (Created 30-Jan-06) Erectile Dysfunction (Created 30-Jan-06) Inequality - Smoking Cessation to Reduce S... This review was the first part of a projec... Inequality - Smoking Cessation to Reduce Socio-Economic Differences This review was the first part of a project about inequality. It included randomized trials about the effect of smoking cessation interventions on reducing socio-economic differences. The studies had to report data either on persons with low socio-economic groups status or, preferably, on both low and high socio-economic groups. Diet and Physical Activity to Reduce Socio... This review was the second part in a proje... Diet and Physical Activity to Reduce Socio-Economic Differences This review was the second part in a project about inequality. It included randomized trials about the effect of interventions on reducing socio-economic differences in diet and physical activity. The studies had to report data either on persons with low socio-economic groups status or, preferably, on both low and high socio-economic groups. Workfare The data in SRS are not identical to the d... Workfare The data in SRS are not identical to the data in the published report. We used SRS only for an updated search. The review included randomized trials about the effect of welfare-to-work programs. Participants were welfare recipients. There were basically two types of programs. The educational type tried to build knowledge and skills in order to help the welfare recipients acquire jobs that could support them economically. The "work first" approach was more aimed at getting the participants quickly into a job. Exercise interventions for the management ... The objective of this systematic review wa... Exercise interventions for the management of frailty The objective of this systematic review was to examine the effectiveness of current exercise interventions on the management of frailty. A comprehensive search of Medline, Embase, Psycinfo, Cinahl, Scopus, Ageline, Eric, and SportDiscus databases was conducted and produced 1808 citations. So far we have completed 2 levels of “title and abstract” screening and we ended up with 262 articles. We have just started the full text screening. Eligibility criteria included original studies whose participants were identified as frail or prefrail with specific criteria and in which structured physical activity was included as at least one component of the intervention. Create a free account, build a dictionary with saved terms to re-use later! Public Domestic Violence - Using Cognitive Behavior Therapy Smoking Cessation to Reduce Socio-Economic Differences Diet and Physical Activity to Reduce Socio-Economic Differences Workfare Exercise Interventions for the Management of Frailty Search     Simple Advanced Refine (4 coded questions)  Any of these:   Exact Phrase: All of these: None of these: Author: Periodical: Projects: No restrictions   Libraries: Public   Select SRS Projects Show Saved Terms Select Library Show articles that do not have abstracts  Type of Article Clinical Trial Editorial Letter Meta-Analysis Practice Guideline Randomized Controlled Trial Review Addresses Bibliography Biography Case Reports Classical Article Clinical Conference Clinical Trial, Phase I Clinical Trial, Phase II Clinical Trial, Phase III Clinical Trial, Phase IV Comment Comparative Study Consensus Development Conference Consensus Development Conference, NIH Controlled Clinical Trial Corrected and Republished Article Dictionary Directory Duplicate Publication English Abstract Evaluation Studies Festschrift Government Publications Guideline Historical Article Interview In Vitro Journal Article Lectures Legal Cases Legislation Multicenter Study News Newspaper Article Overall Patient Education Handout Periodical Index Published Erratum Retracted Publication Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. 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Retraction of Publication Scientific Integrity Review Support of Research Technical Report Twin Study Validation Studies Not a Primary Study or Review Unknown Primary Study Case Series Case Control Cohort Study Observational Study Qualitative Research CBA or ITS Registry Double Blind Controlled before after study Quasi-randomized trial Simple before after study Cluster-RCT Non-Randomized Study Report Book Book chapter Dissertation Conference procedings Secondary Research Not RCT Humans or Animals Humans Animals Ages All Infant: birth-23 months All Child: 0-18 years All Adult: 19+ years Newborn: birth-1 month Infant: 1-23 months Preschool Child: 2-5 years Child: 6-12 years Adolescent: 13-18 years Adult: 19-44 years Middle Aged: 45-64 years Middle Aged + Aged: 45+ years Aged: 65+ years 80 and over: 80+ years Undetermined Language English French German Italian Japanese Russian Spanish Afrikaans Albanian Unknown Arabic Armenian Azerbaijani Bosnian Bulgarian Catalan Chinese Croatian Czech Danish Dutch Esperanto Estonian Finnish Georgian Greek, Modern Hebrew Hindi Hungarian Icelandic Indonesian Kinyarwanda Korean Latin Latvian Lithuanian Macedonian Malay Malayalam Maori Multiple Languages Norwegian Persian Polish Portuguese Pushto Romanian Sanskrit Scottish gaelic Serbian Slovak Slovenian Swedish Thai Turkish Ukrainian Vietnamese Not English Not French Results(1-25 of 40) Sort By: Publication Date Relevance Took: 2.389 seconds to search 17,750,454  Action: Copy Results to new Clipboard Build Search Link Page 1 of 2 1 2 > (40 articles found) Disposition of ezetimibe is influenced by polymorphisms of the hepatic uptake carrier OATP1B1. Jul 2008 Stefan Oswald,Jörg König,Dieter Lütjohann,Thomas Giessmann,Heyo K Kroemer,Christian Rimmbach,Dieter Rosskopf,Martin F Fromm,Werner Siegmund OBJECTIVES: Genetic variability in hepatic uptake was recently shown to influence the disposition and cholesterol-lowering effects of statins. Ezetimibe, an inhibitor of the intestinal cholesterol uptake protein Niemann-Pick C 1 like 1, is another drug for which genetic polymorphisms of hepatic org... ( view more )anic anion transporting polypeptides (OATPs) are expected to be of clinical relevance because ezetimibe undergoes intensive enterohepatic circulation for which hepatic uptake transporters may be rate-limiting determinants. METHODS: Using OATP1B3-, OATP2B1-, and OATP1B1-transfected HEK cells, including the OATP1B1 variants OATP1B1*1b and OATP1B1*5, we measured the uptake of ezetimibe and its glucuronide and we analyzed the competition with the common OATP-substrate bromosulfophthalein. Disposition and sterol-lowering effects of 20-mg ezetimibe were measured in 35 healthy participants genotyped for OATP1B1, ABCB1, ABCC2, and UGT1A1. RESULTS: Ezetimibe glucuronide inhibited bromosulfophthalein uptake in all OATP-transfected cells (50% inhibitory concentration (IC50): 0.14-0.26 mumol/l) whereas ezetimibe was 30-100 times less potent. Only the glucuronide was accumulated significantly in cells expressing OATP1B1 and OATP2B1. Its uptake in cells expressing OATP1B1*1b and *5 was reduced. In-vivo studies showed there was a gene-dose-dependent decrease in the area under the curve of ezetimibe in participants with the OATP1B1*1b protein (*1a/*1a, N=12, 112+/-66 ngxh/ml vs. *1a/*1b, N=8, 88+/-39 ngxh/ml vs. *1b/*1b, N=5, 55+/-18 ngxh/ml; Jonkheere-Terpstra, P=0.041) and a tendency for increased glucuronide exposure (704+/-296 vs. 878+/-369 vs. 1059+/-363 ngxh/ml; P=0.092). Fecal ezetimibe excretion was significantly decreased whereas renal glucuronide excretion was increased in carriers of *1b/*1b. Fecal excretion was also diminished in carriers of OATP1B1*5 and *15. The sterol-lowering effect of ezetimibe was not influenced by OATP1B1 polymorphisms. CONCLUSION: Pharmacokinetics of ezetimibe is influenced by OATP1B1 polymorphisms in healthy participants after single dose administration. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Disposition and antimuscarinic effects of the urinary bladder spasmolytics propiverine: influence of dosage forms and circadian-time rhythms. May 2008 Karen May,Kristin Westphal,Thomas Giessmann,Danilo Wegner,Ulrike Adam,Markus M Lerch,Reinhard Oertel,Rolf W Warzok,Werner Weitschies,Manfred Braeter,Werner Siegmund Propiverine extended release is expected to be better tolerated compared to immediate release tablets because of slower drug release and reduced formation of active metabolites in the colon. CYP3A4 and ABCC2, the major variables in pharmacokinetics of propiverine, are less expressed in the colon. T... ( view more )herefore, disposition and pharmacodynamics of propiverine were measured in a double-blind, double-dummy, crossover study with administration of 15 mg immediate release 3 times daily for 7 days compared to 45 mg extended release once daily for 7 days in 24 healthy subjects. Twelve subjects also received 15 mg propiverine intravenously. Serum and urine propiverine levels were measured repeatedly following oral administration on day 7 for up to 72 hours and correlated to duodenal expression of CYP3A4, ABCB1, and ABCC2. Propiverine immediate release 3 times daily was not different to extended release once daily in areas under the serum concentration-time curve (0-24 hours) and peak-trough fluctuation. The areas under the serum concentration-time curve of propiverine immediate release was circadian-time-dependent, with the lowest values during the night. Disposition of intravenous propiverine and propiverine immediate release administered in the night was influenced by intestinal expression of ABCC2. We concluded that oral absorption of propiverine is site-dependent and influenced by dosage form and circadian-time-dependent elimination processes. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Towards new antimalarial drugs: synthesis of non-hydrolyzable phosphate mimics as feed for a predictive QSAR study on 1-deoxy-D-xylulose-5-phosphate reductoisomerase inhibitors. Apr 2008 Dirk Giessmann,Philipp Heidler,Timothy Haemers,Serge Van Calenbergh,Armin Reichenberg,Hassan Jomaa,Claus Weidemeyer,Silke Sanderbrand,Jochen Wiesner,Andreas Link The conversion of 1-deoxy-D-xylulose-5-phosphate (DOXP) to 2-C-methyl-D-erythritol-4-phosphate (MEP) is effectively blocked by 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr) inhibitors such as the natural antibiotic fosmidomycin. Prediction of binding affinities for closely related Dxr ligan... ( view more )ds as well as estimation of the affinities of structurally more distinct inhibitors within this class of non-hydrolyzable phosphate mimics relies on the synthesis of fosmidomycin derivatives with a broad range of target affinity. Maintaining the phosphonic acid moiety, linear modifications of the lead structure were carried out in an effort to expand the SAR of this physicochemically challenging class of compounds. Synthetic access to a set of phosphonic acids with inhibitory activity (IC(50)) in the range from 1 to >30 microM vs. E. coli Dxr and 0.4 to 20 microM against P. falciparum Dxr is reported. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Synthesis of beta- and gamma-oxa isosteres of fosmidomycin and FR900098 as antimalarial candidates. Mar 15, 2008 Timothy Haemers,Jochen Wiesner,Dirk Giessmann,Thomas Verbrugghen,Ulrik Hillaert,Regina Ortmann,Hassan Jomaa,Andreas Link,Martin Schlitzer,Serge Van Calenbergh To expand the structure-activity relationships of fosmidomycin and FR900098, two potent antimalarials interfering with the MEP-pathway, we decided to replace a methylene group in beta-position of the phosphonate moiety of these leads by an oxygen atom. beta-oxa-FR900098 (11) proved equally active a... ( view more )s the parent compound. When applied to 4-[hydroxyl(methyl)amino]-4-oxobutyl phosphonic acid, featuring a hydroxamate instead of the retrohydroxamate moiety, a beta-oxa modification yielded a derivative (13) with superior activity against the Plasmodium falciparum 3D7 strain than fosmidomycin, while a gamma-oxa modification resulted in less active derivatives. A bis(pivaloyloxymethyl)ester of phosphonate 13 proved twice as active in inhibiting cultured parasites as a similar prodrug of FR900098. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Inflammatory-activated microvascular endothelial cells regulate interleukin-8 and monocyte chemoattractant protein-1 expression of A549 cells in a paracrine fashion. Feb 2008 Martina Wendel,Ute Giessmann,Patrick Behrend,Antje Augstein,Roland Koslowski,Dirk Haufe,Michael Kasper,Thea Koch Increased levels of interleukin (IL)-8 and monocyte chemoattractant protein (MCP)-1 have been found in bronchoalveolar lavage fluid of acute respiratory distress syndrome (ARDS) patients. The authors investigated whether inflammatory-activated microvascular pulmonary endothelial cells (HMVECL) regu... ( view more )late expression of IL-8 and MCP-1 in the alveolar epithelial cell line A549 and studied the effects of hypoxia (5% O(2)) and hyperoxia (85% O(2)). The authors observed significant up-regulation of IL-8 and MCP-1 expression in A549 cells that was independent from the IL-1 receptor pathway but was modified by oxygen tension. These data show that the pulmonary microvascular endothelium is able to regulate epithelial cell chemokine expression in a paracrine fashion. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Unusual inorganic ring systems of scandium and yttrium containing group 13 Metals: coordination of monomeric Me(2)InOMe to yttrium. Dec 24, 2007 Stephan Giessmann,Steffen Blaurock,Volker Lorenz,Frank T Edelmann Novel transformations of lanthanide(III) disiloxanediolates with group 13 metal trialkyls are reported. Treatment of the scandium metallacrown complex [{(Ph2SiO)2O}2{Li(DME)}2]ScCl.THF (1) with AlMe3 resulted in an Li-Al exchange reaction and the formation of the heterotrimetallic inorganic ring sy... ( view more )stem [{(Ph2SiO)2O}2{Li(THF)2}AlMe2]ScCl.THF (2). The related yttrium metallacrown [{(Ph2SiO)2O}2{Li(THF)2}2]YCl.THF (3) reacts with InMe3 under the formation of the heterobimetallic Y/In disiloxanediolate complex [{(Ph2SiO)2O}2{InMe2(OMe)}2InMe2]Y (4). In the latter, two monomeric Me2InOMe ligands are stabilized through coordination to yttrium. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Structural varieties in heterobimetallic lanthanide disiloxanediolates: "inorganic metallocenes" versus in-plane metallacrowns. Nov 26, 2007 Stephan Giessmann,Steffen Blaurock,Volker Lorenz,Frank T Edelmann The previously proposed concept of "inorganic metallocenes" of group 3 and rare-earth elements has been tested by preparing a series of novel disiloxanediolates with metals displaying different ionic radii. For the smaller scandium and yttrium, approximately planar arrangements of the disiloxanedio... ( view more )late frameworks with solvent and chloride ligands in trans positions were found. Thus, the compounds [{(Ph2SiO)2O}2{Li(DME)}2]ScCl(THF/DME) (2; DME=1,2-dimethoxyethane and THF=tetrahydrofuran) and [{(Ph2SiO)2O}2{Li(THF)2}2]YCl(THF) (3) can be described as heterobimetallic inorganic ring systems or metallacrown complexes with "in-plane" coordination of the metal. In contrast, "out-of-plane" geometries with cis coordination of additional ligands were identified in the praseodymium derivatives [{(Ph2SiO)2O}2{Li(THF)2}{Li(THF)}]Pr(micro-Cl)2Li(THF)2 (4) and [{(Ph2SiO)2O}2{Li(DME)}2]PrCl(DME) (5). These compounds can be viewed as analogues of the known metallocene derivatives (C5Me5)2Pr(micro-Cl)2Li(THF)2 and (C5Me5)2PrCl(THF). The molecular structures of 2-5 have been determined by X-ray diffraction. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Unprecedented examples of heterobimetallic cerium(IV) disiloxanediolates. Oct 1, 2007 Stephan Giessmann,Steffen Blaurock,Volker Lorenz,Frank T Edelmann The first disiloxanediolate complexes of cerium(IV) are reported. Starting from the readily available precursor ((t)BuO)(3)Ce(IV)(NO(3))(THF)(2) (1), we prepared the novel heterobimetallic compounds [{(Ph(2)SiO)(2)O}{K(THF)(2)}](2)Ce(O(t)Bu)(2) (2) and [{(Ph(2)SiO)(2)O}(2){(DME)-KO(t)Bu}{(Ph(2)SiO(... ( view more )2))K}Ce](2) (3) and structurally characterized them by X-ray diffraction. ( view less ) View Full Abstract View Article Details   Related Articles The oral, once-daily phosphodiesterase 4 inhibitor roflumilast lacks relevant pharmacokinetic interactions with inhaled budesonide. Aug 2007 Robert Hermann,Werner Siegmund,Thomas Giessmann,Kristin Westphal,Anita Weinbrenner,Bernhard Hauns,Felix Reutter,Gezim Lahu,Karl Zech,Thomas D Bethke This open-label, randomized, 3-period crossover study evaluated the pharmacokinetic interaction potential of roflumilast and budesonide following repeated coadministration to healthy male subjects (N = 12). Treatments consisted of oral roflumilast 500 mug, once daily, orally inhaled budesonide 800 ... ( view more )mug, twice daily, and concomitant administration of both treatments for 7 days each. Roflumilast and roflumilast N-oxide in plasma and budesonide serum levels were measured by specific assays. Geometric mean test/reference ratios of steady-state pharmacokinetic parameters were evaluated by analysis of variance. Safety and tolerability were monitored. Pharmacokinetic parameters of roflumilast, roflumilast N-oxide, and budesonide after coadministration of roflumilast and budesonide were similar to those after mono-treatment. Compared with budesonide and roflumilast mono-treatments, slightly lower maximum serum/plasma concentration (C(max)) and area under the curve (AUC) values of roflumilast N-oxide and budesonide (ranging from -8% to -16%) were observed with combined treatment. All test/reference ratios were within predefined equivalence acceptance ranges for roflumilast AUC (0.80, 1.25) and C(max) (0.70, 1.43) and for roflumilast N-oxide and budesonide AUC and C(max) (all 0.67, 1.50). Coadministration of roflumilast and budesonide did not alter the steady-state disposition of each other and did not affect safety and tolerability of either drug. ( view less ) View Full Abstract View Article Details   Related Articles Quantitative determination of nystatin in human plasma using LC-MS after inhalative administration in healthy subjects. Nov 21, 2006 Eberhard Scheuch,Thomas Giessmann,Werner Siegmund The antifungal polyene antibiotics nystatin was tested in a clinical trial to describe pharmacokinetics and safety after repeated administration of Nystatin "Lederle" sterile powder in healthy volunteers. To monitor the nystatin concentration-time profile in plasma we developed a sensitive method i... ( view more )n the range of 1-100ng/ml based on liquid chromatography coupled with tandem mass spectrometry. The target substance was separated from the biological matrix on C(18) solid-phase extraction cartridges with methanol. The Chromatography was performed isocratically using a reversed phase Caltrex Resorcinearene column. The mobile phase consisted of 5mM ammonium formate buffer and acetonitrile (40:60, v/v). The mass spectrometer works with electrospray ionization in its positive selected ion monitoring (SIM) mode using the respective MH(+) ions, m/z 926.6 for nystatin and m/z 924.4 for amphotericin B as internal standard. The method validation was performed according to the demands and international criteria for validation of bioanalytical methods and was successfully applied to the quantification of nystatin in human plasma in the pharmacokinetic trial. ( view less ) View Full Abstract View Article Details   Related Articles Roflumilast, a once-daily oral phosphodiesterase 4 inhibitor, lacks relevant pharmacokinetic interactions with inhaled salbutamol when co-administered in healthy subjects. Nov 2006 T D Bethke,T Giessmann,K Westphal,A Weinbrenner,B Hauns,D Hauschke,M David,G Lahu,K Zech,R Hermann,W Siegmund OBJECTIVE: Roflumilast is an oral, once-daily phosphodiesterase 4 inhibitor under investigation for the treatment of chronic obstructive pulmonary disease and asthma. In clinical practice, the drug is likely to be co-administered with inhaled bronchodilating beta2-adrenoceptor agonists. Therefore, ... ( view more )this study investigated the pharmacokinetic characteristics of roflumilast and its pharmacodynamically active metabolite roflumilast N-oxide when co-administered with orally inhaled salbutamol in healthy subjects. METHODS: In this open, randomized clinical study, 12 healthy male subjects received repeated doses of oral roflumilast 500 microg once daily, orally inhaled salbutamol 200 microg 3 times daily, and a combination of both drugs over 7 days according to a 3-period, changeover design with 14 days washout between treatments. RESULTS: Co-administration of roflumilast and salbutamol did not markedly change roflumilast or roflumilast N-oxide disposition. Point estimates (90% confidence intervals) of area under the curve from 0-24 h (AUC 0-24) and maximum plasma concentration in steady state (Cmax,ss) for roflumilast with salbutamol versus roflumilast alone were 1.05 (0.94, 1.17) and 0.97 (0.84, 1.10); the respective point estimates (90% confidence intervals) for AUC 0-24 and Cmax,ss of roflumilast N-oxide were 0.98 (0.91, 1.06) and 0.98 (0.92, 1.03). Roflumilast co-administration did not alter the pharmacokinetics of steady state salbutamol. The respective point estimates (90% confidence intervals) for AUC 0-6 and Cmax,ss of salbutamol with roflumilast versus salbutamol alone were 1.10 (0.99, 1.21), 1.08 (0.91, 1.28). The combination of both drugs was well tolerated. CONCLUSION: There were no relevant pharmacokinetic interactions between roflumilast and salbutamol at therapeutically effective doses. ( view less ) View Full Abstract View Article Details   Related Articles Disposition and sterol-lowering effect of ezetimibe are influenced by single-dose coadministration of rifampin, an inhibitor of multidrug transport proteins. Nov 2006 Stefan Oswald,Thomas Giessmann,Dieter Luetjohann,Danilo Wegner,Dieter Rosskopf,Werner Weitschies,Werner Siegmund BACKGROUND AND AIMS: The disposition and sterol-lowering effect of ezetimibe are associated with long-lasting enterosystemic circulation, which is initiated by secretion of ezetimibe and its glucuronide via intestinal P-glycoprotein (P-gp) (ABCB1) and the multidrug resistance-associated protein 2 (... ( view more )MRP2) (ABCC2) into gut lumen. Hepatic uptake and secretion may contribute to recycling. To obtain deeper insight into the intestinal and hepatic processes, the disposition of ezetimibe was studied in the presence of rifampin (INN, rifampicin), a modulator of P-gp, MRP2, and hepatic organic anion (uptake) transporting polypeptides (OATPs) (SLCOs). METHODS: The disposition of ezetimibe (20 mg orally) alone and after coadministration of rifampin (600 mg orally) was measured in a crossover study of 8 healthy subjects with the SLCO1B1 *1a/*1a genotype. Concentrations of ezetimibe and its glucuronide in serum, urine, and feces, as well as cholesterol, lathosterol, and the plant sterols campesterol and sitosterol in serum, were quantified by use of liquid chromatography and gas chromatography with mass spectrometric detection. RESULTS: After rifampin administration, the maximum serum concentrations of ezetimibe and its glucuronide were significantly elevated (12.0+/-4.20 ng/mL versus 4.67+/-2.72 ng/mL, P=.017, and 282+/-73.8 ng/mL versus 107+/-35.3 ng/mL, P=.012, respectively). The area under the curve of ezetimibe was not affected (102+/-37.6 ng.h/mL versus 140+/-86.3 ng.h/mL, P=not significant), whereas that of the glucuronide was markedly increased (2150+/-687 ng.h/mL versus 1030+/-373 ng.h/mL, P=.012). Renal clearance remained unchanged. Fecal excretion of ezetimibe was markedly decreased (7.6+/-2.2 mg versus 10.4+/-1.8 mg, P=.036), whereas renal excretion of the glucuronide was strongly elevated (4.8+/-1.9 mg versus 2.0+/-1.2 mg, P=.049) after coadministration. The onset of a significant sterol-lowering effect of ezetimibe was significantly shortened by rifampin coadministration. CONCLUSIONS: Coadministration of rifampin increases the maximum serum concentrations of ezetimibe but reduces its enterosystemic recycling, most likely by inhibition of the secretion of ezetimibe and its glucuronide via P-gp and MRP2. ( view less ) View Full Abstract View Article Details   Related Articles Simvastatin does not influence the intestinal P-glycoprotein and MPR2, and the disposition of talinolol after chronic medication in healthy subjects genotyped for the ABCB1, ABCC2 and SLCO1B1 polymorphisms. Apr 2006 Annika Bernsdorf,Thomas Giessmann,Christiane Modess,Danilo Wegner,Stefanie Igelbrink,Ute Hecker,Sierk Haenisch,Ingolf Cascorbi,Bernd Terhaag,Werner Siegmund AIMS: To evaluate whether simvastatin influences (i) the intestinal expression of P-glycoprotein (P-gp) and MRP2, and (ii) the disposition of the beta(1)-selective blocker talinolol, a substrate of these transporter proteins. METHODS: The disposition of talinolol after intravenous (30 mg) and singl... ( view more )e or repeated oral administration (100 mg daily) was monitored before and after chronic treatment with simvastatin (40 mg daily) in 18 healthy subjects (10 males, eight females, body mass index 19.0-27.0 kg m(-2)) genotyped for ABCB1, ABCC2 and SLCO1B1 polymorphisms. The steady-state pharmacokinetics of simvastatin was evaluated before and after repeated oral talinolol administration. The duodenal expression of ABCB1 and ABCC2 mRNA before and after simvastatin treatment was quantified using real-time reverse transcriptase-polymerase chain reaction (TaqMan. RESULTS: Simvastatin did not influence the expression of duodenal ABCB1 and ABCC2. There was no significant pharmacokinetic interaction between simvastatin and talinolol. Duodenal ABCB1 mRNA content was significantly correlated with the AUC(0-infinity) (r = 0.627, P = 0.039) and C(max) (r = 0.718, P = 0.013) of oral talinolol. The ABCB1 and ABCC2 gene polymorphisms did not influence simvastatin and talinolol disposition. The half-life of the latter was significantly shorter in the nine carriers with a SLCO1B1*1b allele compared with the seven subjects with the wild-type SLCO1B1*1a/*1a genotype (12.2 +/- 1.6 h vs. 14.5 +/- 1.4 h, P = 0.01). CONCLUSIONS: Simvastatin does not influence the intestinal expression of P-gp and MRP2 in man. There was no pharmacokinetic interaction between talinolol and simvastatin during their chronic co-administration to healthy subjects. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Intestinal expression of P-glycoprotein (ABCB1), multidrug resistance associated protein 2 (ABCC2), and uridine diphosphate-glucuronosyltransferase 1A1 predicts the disposition and modulates the effects of the cholesterol absorption inhibitor ezetimibe in humans. Mar 2006 Stefan Oswald,Sierk Haenisch,Christiane Fricke,Thomas Sudhop,Cornelia Remmler,Thomas Giessmann,Gabriele Jedlitschky,Ulrike Adam,Eike Dazert,Rolf Warzok,Wolfram Wacke,Ingolf Cascorbi,Heyo K Kroemer,Werner Weitschies,Klaus von Bergmann,Werner Siegmund BACKGROUND AND AIMS: Ezetimibe is an inhibitor of the cholesterol uptake transporter Niemann-Pick C1-like protein (NPC1L1). Target concentrations can be influenced by intestinal uridine diphosphate-glucuronosyltransferases (UGTs) and the efflux transporters P-glycoprotein (P-gp) (ABCB1) and multidr... ( view more )ug resistance associated protein 2 (MRP2) (ABCC2). This study evaluates the contribution of these factors to the disposition and cholesterol-lowering effect of ezetimibe before and after induction of UGT1A1, P-gp, and MRP2 with rifampin (INN, rifampicin). METHODS: Serum concentrations of ezetimibe, as well as its glucuronide, and the plant sterols campesterol and sitosterol (surrogate for cholesterol absorption) were studied in 12 healthy subjects before and after rifampin comedication. In parallel, duodenal expression of UGT1A1, P-gp, MRP2, and NPC1L1 was quantified by use of real-time reverse transcriptase-polymerase chain reaction and quantitative immunohistochemical evaluation. The affinity of ezetimibe and its glucuronide to P-gp and MRP2 was assessed in P-gp- overexpressing Madin-Darby canine kidney II cells and P-gp-containing or MRP2-containing inside-out vesicles. RESULTS: Up-regulation of intestinal P-gp, MRP2, and UGT1A1 (but not of NPC1L1) by rifampin was associated with markedly decreased areas under the curve of ezetimibe and its glucuronide (116 +/- 78.1 ng.h/mL versus 49.9 +/- 31.0 ng.h/mL and 635 +/- 302 ng.h/mL versus 225 +/- 86.4 ng.h/mL, respectively; both P = .002) and increased intestinal clearances (2400 +/- 1560 mL/min versus 5500 +/- 4610 mL/min [P = .003] and 76.6 +/- 113 mL/min versus 316 +/- 457 mL/min [P = .010], respectively) and nearly abolished sterol-lowering effects. Intestinal expression of UGT1A1, ABCB1, and ABCC2 was inversely correlated with the effects of ezetimibe on plant sterol serum concentrations. Parallel in vitro studies confirmed that ezetimibe glucuronide is a high-affinity substrate of MRP2 and has a low affinity to P-gp whereas ezetimibe interacts with P-gp and MRP2. CONCLUSIONS: The disposition and sterol-lowering effects of ezetimibe are modified by metabolic degradation of the drug via intestinal UGT1A1 and either intestinal or hepatic secretion (or both) via P-gp and MRP2. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging. Nov 15, 2005 C Schiller,C-P Fröhlich,T Giessmann,W Siegmund,H Mönnikes,N Hosten,W Weitschies AIM: The gastrointestinal transit of sequentially administered capsules was investigated in relation to the availability of fluid along the intestinal lumen by magnetic resonance imaging. METHODS: Water-sensitive magnetic resonance imaging was performed on 12 healthy subjects during fasting and 1 h... ( view more ) after a meal. Specifiable non-disintegrating capsules were administered at 7, 4 and 1 h prior to imaging. RESULTS: While food intake reduced the mean fluid volumes in the small intestine (105 +/- 72 mL vs. 54 +/- 41 mL, P < 0.01) it had no significant effect on the mean fluid volumes in the colon (13 +/- 12 mL vs. 18 +/- 26 mL). The mean number of separated fluid pockets increased in both organs after meal (small intestine: 4 vs. 6, P < 0.05; large intestine: 4 vs. 6, P < 0.05). The distribution of capsules between the small and large intestine was strongly influenced by food (colon: 3 vs. 17 capsules, P < 0.01). CONCLUSIONS: The results show that fluid is not homogeneously distributed along the gut, which likely contributes to the individual variability of drug absorption. Furthermore, transport of fluid and solids through the ileocaecal valve is obviously initiated by a meal-induced gastro-ileocaecal reflex. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Decreased gap junctional communication in neurobiotin microinjected lens epithelial cells after taxol treatment. Jun 2005 Daniel Giessmann,Carsten Theiss,Winrich Breipohl,Karl Meller The aim of the study was to examine gap-junction-mediated intercellular communication after experimentally induced aggregations of microtubules in cultured bovine lens epithelial cells. Intercellular communication between lens cells appears to be crucial for normal lens homeostasis. However, invest... ( view more )igations on the maintenance of direct ion and metabolite exchange via gap junctions and its quantified dependency of cytoskeletal microtubules have not been available under conditions leading to bundling of microtubules. Thus, metabolic coupling of neighboring lens epithelial cells was quantified following microinjections of neurobiotin into single cells under various conditions. In controls, intensive gap-junction-mediated intercellular communication could be documented by dye-spreading of microinjected neurobiotin. In contrast, taxol treatment for 1-3 days impaired, but did not completely block gap-junction-mediated intercellular communication. After depletion of taxol, a complete recovery of intercellular communication was achieved. In addition, confocal laser scanning microscopy and rapid-freeze deep-etch electron microscopy revealed a displacement of actin-filaments from the perinuclear cytoplasm, accompanied by an abnormal aggregation of microtubules after taxol treatment, including impeded translocation of connexin 43 from the cytoplasm into the plasma membrane. Incubation of cells with nocodazole destroyed the microtubule network, accompanied by a clear reduction of plasma-membrane-integrated connexin 43 and significant impairment of dye spreading. Thus, in lens epithelial cells intercellular communication at gap junctions made by connexin 43 depends on the integrity of the microtubule network through the translocation of connexins to the plasma membrane. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles The talinolol double-peak phenomenon is likely caused by presystemic processing after uptake from gut lumen. May 2005 Werner Weitschies,Annika Bernsdorf,Thomas Giessmann,Michael Zschiesche,Christiane Modess,Vera Hartmann,Claudia Mrazek,Danilo Wegner,Stefan Nagel,Werner Siegmund PURPOSE: Evaluation of the double-peak phenomenon during absorption of the beta(1)-selective blocker talinolol relative to paracetamol, which is well absorbed from all parts of the gut, and relative to vitamin A, which is absorbed via the lymphatic pathway. METHODS: Talinolol was given with paracet... ( view more )amol and retinyl palmitate in fast-disintegrating, enteric-coated, and rectal soft capsules to 8 fasting male healthy subjects (21-29 years, 68-86 kg). To evaluate whether the talinolol double-peak is associated with processes of food absorption, a breakfast was served 1 h after administration of a fast disintegrating capsule. RESULTS: Bioavailability of talinolol in enteric-coated and rectal capsules was significantly reduced by about 50% and 80%, respectively, despite unchanged bioavailability of paracetamol. Double-peaks appeared after 2-3 h and 4-6 h with talinolol given as fast-liberating capsules. Food increased the maximum concentrations significantly (223 +/- 76 microg/ml vs. 315 +/- 122 microg/ml, p < 0.05) and shifted the second peak of talinolol to shorter t(max) values (3.8 +/- 1.2 h vs. 2.1 +/- 0.6 h, p < 0.05), which was associated with faster absorption of retinyl palmitate. Pharmacokinetic model fits showed that about half of the oral talinolol dose given with and without meal is drained from the intestine via a presystemic storage compartment. CONCLUSIONS: The double-peak phenomenon of talinolol is likely caused by a presystemic storage compartment, which represents the complex interplay of heterogeneous uptake and kick-back transport processes along the intestinal-hepatic absorption pathway. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles The anticholinergic drug propiverine inhibits the protein kinase C activity in the rat urinary bladder. Jan 2005 K U Möritz,R Walter,K May,T Giessmann,W Siegmund There is ample evidence that non-cholinergic protein kinase C (PKC) mediated signal transduction pathways are involved into regulation of bladder smooth muscle contractions. To evaluate whether the anticholinergic and calcium modulating drug propiverine exerts intracellular effects by inhibition of... ( view more ) the PKC, male inbred LEW 1A rats were pretreated with 0.6, 2, 6 and 60 mg/kg body weight for 5 days. Furthermore, competition assays with partially purified PKC were performed with propiverine in vitro. The activities of the membrane-bound and soluble PKC were assessed by 32P enrichment of lysine-rich histone. Results: The active, membrane-bound PKC decreased by about 60% accompanied by increase of the soluble form after propiverine in doses above 0.6 mg/kg. 100 nM of the drug inhibited the PKC also in vitro whereas the propiverine metabolites M5 and M6 and atropine were without any effect. CONCLUSIONS: Propiverine was identified to be an inhibitor of the protein kinase C. Its contribution to the noncholinergic control of hyperactive detrusor smooth muscle cells needs further investigation. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Expression of vascular endothelial growth factor during healing of the meniscus in a rabbit model. Sep 2004 R Becker,T Pufe,S Kulow,N Giessmann,W Neumann,R Mentlein,W Petersen Our aim was to investigate vascular endothelial growth factor (VEGF) expression after lacerations of a meniscus in a rabbit model. Specimens of meniscus were examined using immunohistochemistry, enzyme-linked immunoassay and the reverse transcription polymerase chain reaction after one, two, five o... ( view more )r ten weeks. In the periphery of the meniscus 90% of the lacerations had healed after five and ten weeks, but no healing was observed in the avascular area. Expression of VEGF protein and VEGF mRNA was found in the meniscus of both the operated and the contralateral sites but both were absent in control rabbits which had not undergone operation. The highest expression of VEGF was found in the avascular area after one week (p < 0.001). It then lessened at both the vascular and avascular areas, but still remained greater in comparison with the control meniscus (p < 0.05). Despite greater expression of VEGF, angiogenesis failed at the inner portion. These findings demonstrated the poor healing response in the avascular area which may not be caused by an intrinsic cellular insufficiency to stimulate angiogenesis. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Carbamazepine regulates intestinal P-glycoprotein and multidrug resistance protein MRP2 and influences disposition of talinolol in humans. Sep 2004 Thomas Giessmann,Karen May,Christiane Modess,Danilo Wegner,Ute Hecker,Michael Zschiesche,Peter Dazert,Markus Grube,Eike Schroeder,Rolf Warzok,Ingolf Cascorbi,Heyo K Kroemer,Werner Siegmund BACKGROUND AND METHODS: The antiepileptic drug carbamazepine is known to be an inducer of cytochrome P450 (CYP) 3A4 after binding to the nuclear pregnane X receptor. To evaluate whether it also regulates the multidrug transporter proteins P-glycoprotein (P-gp) and multidrug resistance protein MRP2 ... ( view more )in humans, duodenal expression of multidrug resistance gene MDR1 messenger ribonucleic acid (mRNA) and MRP2 mRNA, content of P-gp and MRP2, and disposition of the nonmetabolized P-gp substrate talinolol after intravenous (30 mg) and long-term oral administration (100 mg for 19 days) were assessed in 7 healthy subjects (age, 23-35 years; body weight, 64-93 kg) before and after comedication of carbamazepine (600 mg for 14-18 days). RESULTS: Carbamazepine medication was associated with increased urinary excretion of D-glucaric acid and induction of carbamazepine elimination. Creatinine clearance was not affected. Duodenal expression of both MDR1 mRNA and MRP2 mRNA and the MPR2 protein was significantly induced, whereas the P-gp content was not affected. MDR1 mRNA expression and MPR2 mRNA expression were correlated ( r = 0.873, P <.001). After carbamazepine, metabolic clearance of intravenous talinolol was significantly increased. Residual clearance was significantly decreased in dependence on MDR1 mRNA expression ( r = -0.647, P =.012) and MRP2 mRNA expression ( r = -0.613, P =.020). Oral absorption of talinolol was significantly lower after carbamazepine comedication (53.2% +/- 15.5% versus 62.1% +/- 13.0%, P =.018), and renal clearance and metabolic clearance were significantly increased, correlated in each case with MDR1 mRNA ( r = 0.612, P =.020, and r = 0.554, P =.040, respectively) and MRP2 mRNA ( r = 0.596, P =.025, and r = 0.565, P =.035, respectively). CONCLUSIONS: Aside from induction of CYP3A4, carbamazepine acts as an inducer of intestinal MDR1 mRNA, MRP2 mRNA, and MRP2 protein content. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Replacement therapy with levothyroxine plus triiodothyronine (bioavailable molar ratio 14 : 1) is not superior to thyroxine alone to improve well-being and cognitive performance in hypothyroidism. Jun 2004 W Siegmund,K Spieker,A I Weike,T Giessmann,C Modess,T Dabers,G Kirsch,E Sänger,G Engel,A O Hamm,M Nauck,W Meng OBJECTIVES: There is evidence from recent controlled clinical studies that replacement therapy of hypothyroidism with T4 in combination with a small amount of T3 may improve the well-being of the patients. As the issue is still the subject of controversial discussion, our study was assigned to conf... ( view more )irm the superiority of a physiological combination of thyroid hormones (absorbed molar ratio 14 : 1) over T4 alone with regard to mood states and cognitive functioning. DESIGN AND PATIENTS: After a run-in period with the T4 study medication for 4 weeks, a controlled, randomized, double-blind, two-period (each 12 weeks), cross-over study without washout between the treatment periods was performed in 23 hypothyroid patients (three males, 20 females, age 23-69 years, 21 subjects after surgery/radioiodine, two with autoimmune thyroiditis) to compare the effects of the previous individual T4 dose (100-175 micro g) with a treatment in which 5% of the respective T4 dose was substituted by T3. MEASUREMENTS: Standard hormonal characteristics and standardized psychological tests to quantify mood and cognitive performance were measured after the run-in period and at the end of each treatment period. In 12 subjects, the concentration-time profiles of fT3 and fT4 were compared after the last administration of the respective study medication. TSH, fT3 and fT4 were measured with immunological assays. CLINICAL RESULTS: Replacement therapy with T4 and T4/T3 was not different in all steady-state hormonal, metabolic and cardiovascular characteristics except for TSH, which was more suppressed after T4/T3. The efficacy of replacement therapy with the T4/T3 combination was not different from the T4 monotherapy with regard to all psychological test scores describing mood and cognitive functioning of the patients. Mood was even significantly impaired by the T4/T3 combination in eight subjects, with TSH < 0.02 mU/l, compared to patients with normal TSH (Beck Depression Inventory: 8.25 +/- 5.01 vs. 4.07 +/- 5.60, P = 0.026). PHARMACOKINETIC RESULTS: The area under the concentration-time curve (AUC(0-8h)) of fT3 was significantly higher after T4/T3 compared to the T4 monotherapy (42.8 +/- 9.03 pmol x h/l vs. 36.3 +/- 8.50 pmol x h/l, P < 0.05) and was significantly correlated to serum TSH (r(s) = -0.609, P < 0.05). After T4/T3, patients with a history of Graves' disease or autoimmune thyroiditis had significantly higher serum trough levels of fT3 whereas the fT4 concentrations were significantly lower in patients with a nonautoimmune background. CONCLUSION: Replacement therapy of hypothyroidism with T4 plus T3 does not improve mood and cognitive performance compared to the standard T4 monotherapy. There is even a higher risk of signs of subclinical hyperthyroidism associated with impaired well-being of the patients, which is clearly caused by significant fluctuations in the steady-state fT3 serum concentrations. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Linker peptide and affinity tag for detection and purification of single-chain Fv fragments. May 2004 Gabriele Küttner,Elke Giessmann,Helga Wessner,Christa Scholz,Dina Reinhardt,Karsten Winkler,Uwe Marx,Wolfgang Höhne The peptide tag GATPQDLNTML, corresponding to amino acids 46-56 of the human immunodeficiency virus type 1 (HIV-1) capsid protein p24, is the linear epitope of the murine monoclonal antibody CB4-1. This antibody shows high affinity (KD = 1.8 x 10(-8) M) to the free epitope peptide in solution. The ... ( view more )original p24 peptide tag and mutant derivatives were fused to the C terminus of a single-chain antibody (scFv) and characterized with respect to sensitivity in Western blot analyses and behavior in purification procedures using affinity chromatography. The p24 tag also proved to be a suitable alternative to the (Gly4Ser)3 linker commonly used to connect single-chain antibody variable regions derived from a heavy (VH) and light chain (VL). Binding of CB4-1 antibody to the p24 tag was not hampered when the tag was located internally in the protein sequence, and the specific antigen affinity of the scFv was only slightly reduced. All scFv variants were solubly expressed in Escherichia coli and could be purified from the periplasm. Our results highlight the p24 tag as a useful tool for purifying and detecting recombinantly expressed scFvs. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles CYP2D6 genotype and induction of intestinal drug transporters by rifampin predict presystemic clearance of carvedilol in healthy subjects. Mar 2004 Thomas Giessmann,Christiane Modess,Ute Hecker,Michael Zschiesche,Peter Dazert,Christiane Kunert-Keil,Rolf Warzok,Georg Engel,Werner Weitschies,Ingolf Cascorbi,Heyo K Kroemer,Werner Siegmund BACKGROUND: Clinical trials have indicated that the combined beta- and alpha-adrenergic receptor blocker carvedilol improves the survival rate in patients with advanced chronic heart failure. The objective of our study was the identification and quantification of factors that modulate steady-state ... ( view more )serum concentrations of carvedilol and its enantiomers and that may influence therapeutic efficacy and safety. METHODS: The influence of genetic variants of cytochrome P450 (CYP) 2D6 and CYP2C9 and of transporter proteins (P-glycoprotein, multidrug resistance protein 2 [MRP2]) on the disposition of carvedilol and its enantiomers after intravenous (5 mg) and long-term oral administration (25 mg for 7 days) was assessed in 12 healthy subjects. The intestinal expression of P-glycoprotein and MRP2 was analyzed by quantitative real-time polymerase chain reaction and immunohistochemical techniques. RESULTS: The area under the serum concentration-time curve (AUC) values of carvedilol were significantly (P <.05) increased in 6 subjects with CYP2D6 deficiency, with effects being more pronounced for R(+)-carvedilol (230 +/- 72.6 ng. h/mL versus 93.9 +/- 64.6 ng. h/mL in extensive metabolizers) than for S(-)-carvedilol (62.9 +/- 21.1 ng. h/mL versus 32.7 +/- 14.5 ng. h/mL). The AUC and fecal excretion of intravenous carvedilol were correlated with the intestinal expression of MDR1 messenger ribonucleic acid (mRNA) (r = -0.67, P =.001; r = 0.83, P =.002) and MRP2 mRNA (r = -0.74, P <.001; r = 0.70, P =.025). Furthermore, we measured the disposition of long-term oral carvedilol after comedication of the pregnane X receptor ligand rifampin (INN, rifampicin) (600 mg, 9 days), which up-regulates both P-glycoprotein and MRP2 but not CYP2D6. Rifampin decreased the AUC of carvedilol to an extent independent of the CYP2D6 genotype (poor metabolizers, 341 +/- 147 ng. h/mL versus 126 +/- 41.7 ng. h/mL; extensive metabolizers, 173 +/- 102 ng. h/mL versus 74 +/- 41.4 ng. h/mL; both P <.05). The AUC was significantly correlated with intestinal expression of MDR1 mRNA (r = -0.671, P =.001) and MRP2 mRNA (r = -0.595, P <.006). CONCLUSIONS: Variable plasma concentrations of carvedilol during long-term administration are predicted by CYP2D6 genotype and intestinal expression of P-glycoprotein and MRP2. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Microinjection of actin antibodies impaired gap junctional intercellular communication in lens epithelial cells in vitro. Sep 2003 Daniel Giessmann,Carsten Theiss,Winrich Breipohl,Karl Meller PURPOSE: The aim of this study was to check the importance of cytoskeletal actin for gap junction mediated intercellular communication (GJIC) in cultured lens epithelial cells (LEC). METHODS: Bovine LEC were cultured until confluency on cover-slides of a collocate-system. In order to study the cyto... ( view more )skeletal influence on cell communication microcinjection of gap junction permeable neurobiotin into a single cell was preceded by microinjection of actin antibodies. Confocal laser scanning microscopy of specimens treated with actin antibodies and/or subsequent phalloidin labelling, and electron microscopy, were applied to check for cytoskeleton cell membrane links. Specificity of actin antibodies was proved by immoblotting techniques. RESULTS: Immunohistochemistry and phalloidin-rhodamine staining displayed bundles of actin-filaments extending through the entire LEC. Quantitative analysis of GJIC showed intensive dye-spreading of neurobiotin between adjacent LEC. Injection of actin antibodies thirty minutes prior to microinjection of neurobiotin significantly reduced GJIC. Microinjection of irrelevant antibodies had no effect on GJIC. CONCLUSION: Integrity of the actin-cytoskeleton is fundamental for unimpaired GJIC in LEC. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles The effects of the human MDR1 genotype on the expression of duodenal P-glycoprotein and disposition of the probe drug talinolol. Nov 2002 Werner Siegmund,Karen Ludwig,Thomas Giessmann,Peter Dazert,Eike Schroeder,Bernhard Sperker,Rolf Warzok,Heyo K Kroemer,Ingolf Cascorbi BACKGROUND AND OBJECTIVES: A single-nucleotide polymorphism (SNP) of the human multidrug-resistance gene in wobble position of exon 26 reportedly predicts expression and function of P-glycoprotein in human enterocytes and lymphocytes. Several other allelic variants of MDR1 have been identified, som... ( view more )e of which lead to amino acid exchange with as yet unknown functional relevance. METHODS: In healthy white volunteers, we investigated the influence of the hereditary variants C3435T in exon 26 and G2677T/A (Ala893Ser/Thr) in exon 21 and the influence of 7 frequent or putative functional SNPs on duodenal MDR1 messenger ribonucleic acid (n = 32) and immunoreactive P-glycoprotein (n = 37) expression. Moreover, the disposition of the probe drug talinolol was evaluated in 55 subjects after oral administration (100 mg) and in 23 subjects after intravenous administration(30 mg). RESULTS: Duodenal MDR1 messenger ribonucleic acid and P-glycoprotein, as assessed by real-time polymerase chain reaction (TaqMan) and immunostaining, were not influenced by any MDR1 polymorphism studied. Talinolol disposition was not affected by the exon 26 mutation C3435T. In carriers of the TT/TA variants of G2677T/A, the area under the serum concentration-time curve values of oral talinolol were slightly but significantly elevated compared with those in carriers of at least 1 wild-type allele (P <.05, Kruskal-Wallis test; P =.014, Mann-Whitney U test). However, multiple comparisons with combinations of putative functional SNPs did not confirm a significant influence of the MDR1 genotype on talinolol disposition. CONCLUSIONS: We did not identify any influence of MDR1 genotypes on duodenal expression of P-glycoprotein and disposition of talinolol in humans. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Page 1 of 2 1 2 > (40 articles found)

      
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