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961.
Background
E-52862 is a Sigma-1 receptor antagonist (S1RA) currently under investigation as a potential analgesic medicine. We successfully applied a concentration-effect model retrospectively to a four-way crossover Phase I single ascending dose study and utilized the QTc shortening effects of a meal to demonstrate assay sensitivity by establishing the time course effects from baseline in all four periods, independently from any potential drug effects.Methods
Thirty two healthy male and female subjects were included in four treatment periods to receive single ascending doses of 500 mg, 600 mg or 800 mg of E-52862 or placebo. PK was linear over the dose range investigated and doses up to 600 mg were well tolerated. The baseline electrocardiography (ECG) measurements on Day-1 were time-matched with ECG and pharmacokinetic (PK) samples on Day 1 (dosing day).Results
In this conventional mean change to time-matched placebo analysis, the largest time-matched difference to placebo QTcI was 1.44 ms (90% CI: -4.04, 6.93 ms) for 500 mg; -0.39 ms (90% CI: -3.91, 3.13 ms) for 600 mg and 1.32 ms (90% CI: -1.89, 4.53 ms) for 800 mg of E-52862, thereby showing the absence of any QTc prolonging effect at the doses tested. In addition concentration-effect models, one based on the placebo corrected change from baseline and one for the change of QTcI from average baseline with time as fixed effect were fitted to the data confirming the results of the time course analysis.Conclusion
The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a shortening of QTcF of -8.1 (90% CI: -10.4, -5.9) one hour and -7.2 (90% CI: -9.4, -5.0) three hours after a standardised meal.Trial Registration
EU Clinical Trials Register EudraCT 2010 020343 13 相似文献962.
Matthew F. Buas Lynn Onstad David M. Levine Harvey A. Risch Wong-Ho Chow Geoffrey Liu Rebecca C. Fitzgerald Leslie Bernstein Weimin Ye Nigel C. Bird Yvonne Romero Alan G. Casson Douglas A. Corley Nicholas J. Shaheen Anna H. Wu Marilie D. Gammon Brian J. Reid Laura J. Hardie Ulrike Peters David C. Whiteman Thomas L. Vaughan 《PloS one》2015,10(6)
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Peter Luedike Christos Rammos Julia Pohl Martin Heisler Matthias Totzeck Werner Kleophas Gerd R. Hetzel Malte Kelm Ulrike Hendgen-Cotta Tienush Rassaf 《PloS one》2015,10(10)
BackgroundEnd stage renal disease (ESRD) patients are characterized by increased morbidity and mortality due to highest prevalence of cardiovascular disease. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that controls cellular signaling in human physiology, pathophysiology, and diseases. Increased MIF plasma levels promote vascular inflammation and development of atherosclerosis. We have shown that MIF is associated with vascular dysfunction in ESRD patients. Whether hemodialysis (HD) affects circulating MIF plasma levels is unknown. We here aimed to investigate whether HD influences the circulating MIF pool in ESRD patients.ConclusionMIF is a dialyzable plasma component that is effectively filtrated during HD from the patient blood pool in large amounts. After removal of remarkable amounts of MIF during a single HD session, MIF plasma pool is early reconstituted after termination of HD from unknown sources. 相似文献
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Digestive physiology of the plains viscacha (Lagostomus maximus): A large herbivorous hystricomorph rodent 下载免费PDF全文
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Amal M. Y. Mohsen Eberhard Heller Ulrike Holzgrabe Anders A. Jensen Darius P. Zlotos 《化学与生物多样性》2014,11(8):1256-1262
Nine strychnine derivatives including neostrychnine, strychnidine, isostrychnine, 21,22‐dihydro‐21‐hydroxy‐22‐oxo‐strychnine, and several hydrogenated analogs were synthesized, and their antagonistic activities at human α1 and α1β glycine receptors were evaluated. Isostrychnine has shown the best pharmacological profile exhibiting an IC50 value of 1.6 μM at α1 glycine receptors and 3.7‐fold preference towards the α1 subtype. SAR Analysis indicates that the lactam moiety and the C(21)?C(22) bond in strychnine are essential structural features for its high antagonistic potency at glycine receptors 相似文献
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Susan Hetz Ali Acikgoez Ulrike Voss Karen Nieber Heidrun Holland Cindy Hegewald Holger Till Roman Metzger Marco Metzger 《PloS one》2014,9(4)
Recent advances in the in vitro characterization of human adult enteric neural progenitor cells have opened new possibilities for cell-based therapies in gastrointestinal motility disorders. However, whether these cells are able to integrate within an in vivo gut environment is still unclear. In this study, we transplanted neural progenitor-containing neurosphere-like bodies (NLBs) in a mouse model of hypoganglionosis and analyzed cellular integration of NLB-derived cell types and functional improvement. NLBs were propagated from postnatal and adult human gut tissues. Cells were characterized by immunohistochemistry, quantitative PCR and subtelomere fluorescence in situ hybridization (FISH). For in vivo evaluation, the plexus of murine colon was damaged by the application of cationic surfactant benzalkonium chloride which was followed by the transplantation of NLBs in a fibrin matrix. After 4 weeks, grafted human cells were visualized by combined in situ hybridization (Alu) and immunohistochemistry (PGP9.5, GFAP, SMA). In addition, we determined nitric oxide synthase (NOS)-positive neurons and measured hypertrophic effects in the ENS and musculature. Contractility of treated guts was assessed in organ bath after electrical field stimulation. NLBs could be reproducibly generated without any signs of chromosomal alterations using subtelomere FISH. NLB-derived cells integrated within the host tissue and showed expected differentiated phenotypes i.e. enteric neurons, glia and smooth muscle-like cells following in vivo transplantation. Our data suggest biological effects of the transplanted NLB cells on tissue contractility, although robust statistical results could not be obtained due to the small sample size. Further, it is unclear, which of the NLB cell types including neural progenitors have direct restoring effects or, alternatively may act via ‘bystander’ mechanisms in vivo. Our findings provide further evidence that NLB transplantation can be considered as feasible tool to improve ENS function in a variety of gastrointestinal disorders. 相似文献
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Teresa Coccini Luigi Manzo Frodi Debes Ulrike Steuerwald Pál Weihe Philippe Grandjean 《Biomarkers》2013,18(2):67-76
Experimental evidence suggests that monoamine oxidase B (MAO-B) and muscarinic cholinergic receptors (mAChRs) are involved in the pathogenesis of neurotoxicity caused by methylmercury and polychlorinated biphenyls (PCBs). Blood samples from 7-year-old exposed children were analyzed for platelet MAO-B and lymphocyte mAChRs as potential markers of exposure to these neurotoxicants. The blood neurotoxicity biomarkers were compared with prenatal and current exposures and with neuropsychological test results. Both biomarkers showed homogeneous distributions within this cohort (mAChR, range 0.04–36.78?fmol/million cells; MAO-B, 0.95–14.95?nmol mg?1 protein h?1). No correlation was found between the two biomarkers and either blood neurotoxicant concentrations or clinical findings. MAO-B and mAChR sensitivity may not be sufficiently high to assess early, subclinical responses to low/moderate methylmercury and/or PCB exposure, whereas these markers are significantly altered in sustained exposure scenarios, as shown by clinical studies in drug addicts or patients treated with psychopharmacological agents. 相似文献