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181.
Sven Ulrich Frank Peter Meyer Sabine Neuhof Wolfgang Knorr 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》1995,663(2)
A gas chromatographic method using a HP-5 megabore capillary and nitrogen-phosphorus selective detection for the quantitative analysis of haloperidol (H) and reduced haloperidol (RH) in human serum or plasma is described. A 3-step liquid-liquid extraction is applied. The extraction yield of this procedure is 63% for haloperidol at 20 ng/ml. The limits of detection are 0.4 ng/ml for haloperidol and 1.0 ng/ml for the metabolite if 2 ml of body fluid are applied. At 10 ng/ml the within-day precision is 4.5% for H and 8.3% for RH. Serum levels of eight schizophrenic patients have been monitored weekly over a therapeutic period of six weeks. Seven patients mainly had metabolite ratios RH/H < 1 over the entire period of investigation. They exhibited a linear correlation between dose and serum concentration of haloperidol. In contrast, one patient had metabolite ratios RH/H > 1 over the entire period of the study. Due to considerable increased serum concentrations this patient did not show a linear correlation between the dose and the serum level of haloperidol. 相似文献
182.
Frauke Assmus Richard M. Hoglund Frdric Monnot Sabine Specht Ivan Scandale Joel Tarning 《PLoS neglected tropical diseases》2022,16(3)
BackgroundTo accelerate the progress towards onchocerciasis elimination, a macrofilaricidal drug that kills the adult parasite is urgently needed. Emodepside has shown macrofilaricidal activity against a variety of nematodes and is currently under clinical development for the treatment of onchocerciasis. The aims of this study were i) to characterize the population pharmacokinetic properties of emodepside, ii) to link its exposure to adverse events in healthy volunteers, and iii) to propose an optimized dosing regimen for a planned phase II study in onchocerciasis patients.Methodology / Principal findingsPlasma concentration-time profiles and adverse event data were obtained from 142 subjects enrolled in three phase I studies, including a single-dose, and a multiple-dose, dose-escalation study as well as a relative bioavailability study. Nonlinear mixed-effects modeling was used to evaluate the population pharmacokinetic properties of emodepside. Logistic regression modeling was used to link exposure to drug-related treatment-emergent adverse events (TEAEs). Emodepside pharmacokinetics were well described by a transit-absorption model, followed by a 3-compartment disposition model. Body weight was included as an allometric function and both food and formulation had a significant impact on absorption rate and relative bioavailability. All drug-related TEAEs were transient, and mild or moderate in severity. An increase in peak plasma concentration was associated with an increase in the odds of experiencing a drug-related TEAE of interest.Conclusions/SignificancePharmacokinetic modeling and simulation was used to derive an optimized, body weight-based dosing regimen, which allows for achievement of extended emodepside exposures above target concentrations while maintaining acceptable tolerability margins. 相似文献
183.
We compared the expression of a functional recombinant TMVspecific fullsize antibody (rAb29) in both the apoplast and cytosol of tobacco plants and a single chain antibody fragment (scFv29), derived from rAb29, was expressed in the cytosol. Cloned heavy and light chain cDNAs of fullsize rAb29, which binds to TMV coat protein monomers, were integrated into the plant expression vector pSS. The fullsize rAb29 was expressed in the cytosol and targeted to the apoplast by including the original murine antibody leader sequences. Levels of functional fullsize rAb29 expression were high in the apoplast (up to 8.5g per gram leaf tissue), whereas cytosolic expression was low or at the ELISA detection limit. Sequences of the variable domains of rAb29 light and heavy chain were used to generate the single chain antibody scFv29, which was expressed in the periplasmic space of E.coli and showed the same binding specificity as fullsize rAb29. In addition, scFv29 was functionally expressed in the cytosol of tobacco plants and plant derived scFv29 maintained same binding specificity to TMVcoat protein monomers as rAb29. 相似文献
184.
Functional complementation of human centromere protein A (CENP-A) by Cse4p from Saccharomyces cerevisiae 总被引:4,自引:0,他引:4
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Wieland G Orthaus S Ohndorf S Diekmann S Hemmerich P 《Molecular and cellular biology》2004,24(15):6620-6630
We have employed a novel in vivo approach to study the structure and function of the eukaryotic kinetochore multiprotein complex. RNA interference (RNAi) was used to block the synthesis of centromere protein A (CENP-A) and Clip-170 in human cells. By coexpression, homologous kinetochore proteins from Saccharomyces cerevisiae were then tested for the ability to complement the RNAi-induced phenotypes. Cse4p, the budding yeast CENP-A homolog, was specifically incorporated into kinetochore nucleosomes and was able to complement RNAi-induced cell cycle arrest in CENP-A-depleted human cells. Thus, Cse4p can structurally and functionally substitute for CENP-A, strongly suggesting that the basic features of centromeric chromatin are conserved between yeast and mammals. Bik1p, the budding yeast homolog of human CLIP-170, also specifically localized to kinetochores during mitosis, but Bik1p did not rescue CLIP-170 depletion-induced cell cycle arrest. Generally, the newly developed in vivo complementation assay provides a powerful new tool for studying the function and evolutionary conservation of multiprotein complexes from yeast to humans. 相似文献
185.
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187.
Genome size variation in plants is thought to be correlatedwith cytological, physiological, or ecological characters. However,conclusions drawn in several studies were often contradictory.To analyze nuclear genome size evolution in a phylogenetic framework,DNA contents of 134 accessions, representing all but one speciesof the barley genus Hordeum L., were measured by flow cytometry.The 2C DNA contents were in a range from 6.85 to 10.67 pg indiploids (2n = 14) and reached up to 29.85 pg in hexaploid species(2n = 42). The smallest genomes were found in taxa from theNew World, which became secondarily annual, whereas the largestdiploid genomes occur in Eurasian annuals. Genome sizes of polyploidtaxa equaled mostly the added sizes of their proposed progenitorsor were slightly (1% to 5%) smaller. The analysis of ancestralgenome sizes on the base of the phylogeny of the genus revealedlineages with decreasing and with increasing genome sizes. Correlationsof intraspecific genome size variation with the length of vegetationperiod were found in H. marinum populations from Western Europebut were not significant within two species from South America.On a higher taxonomical level (i.e., for species groups or theentire genus), environmental correlations were absent. Thiscould mostly be attributed to the superimposition of life-formchanges and phylogenetic constraints, which conceal ecogeographicalcorrelations. 相似文献
188.
Remodeling of the actin cytoskeleton is crucial for a multitude of cellular functions including cell movement, intracellular transport as well as signal transduction and gene expression processes. Cofilin has been identified as a key mediator of actin reorganization. Its activity is regulated via reversible phosphorylation of ser-3. In a variety of cell types stimulation through particular surface receptors fastly induces the dephosphorylation/activation of cofilin. Yet, the signal transduction cascades linking receptor stimulation with cofilin activation have not been identified so far. Here we show that the GTPase Ras acts as a central regulator of the cofilin dephosphorylation pathway. Thus, stimulation of Ras through platelet-derived growth factor (PDGF) or transient expression of activated Ras-proteins induces the dephosphorylation of cofilin. Importantly, the cooperation of two Ras-initiated signaling pathways is required to induce cofilin dephosphorylation: a Ras-Raf-MAPkinase/Erk-kinase (MEK)- and a Ras-phosphatidylinositol-3-kinase (PI3K)-effector cascade. 相似文献
189.
Sherif Louis Katalin Benedek Michael Mowat George Klein Sabine Mai 《Cytotechnology》2004,44(3):143-149
Characterization of genetic disorders in humans and animal models requires identification of chromosomal aberrations. However, identifying fine deletions or insertion in metaphase chromosomes has been always a challenge due to limitations of resolution. In this study we developed a rapid method for chromosome elongation using two different intercalating agents: ethidium bromide and 5-bromo-2′-deoxyuridine (BrdU), together with a short-term mitotic block using colcemid. About 70% of the chromosomes from cells that underwent this elongation procedure reached three times longer than those prepared from control cells. FISH experiments using elongated chromosomes revealed a duplicated region of chromosome 11 that was not visible in cells prepared with conventional methods. 相似文献
190.
Jan S Guillou H D'Andrea S Daval S Bouriel M Rioux V Legrand P 《Reproduction, nutrition, development》2004,44(2):131-140
In order to study the effects of saturated fatty acids on delta6-desaturase activity, rat hepatocytes in primary culture were incubated with lauric (C12:0), myristic (C14:0) or palmitic (C16:0) acids. After optimization, the standard in vitro conditions for the measurement of delta6-desaturase activity were as follows: 60 micromol x L(-1) alpha-linolenic acid (C18:3n-3), reaction time of 20 min and protein content of 0.4 mg. Data showed that cell treatment with 0.5 mmol x L(-1) myristic acid during 43 h specifically increased delta6-desaturase activity. This improvement, reproducible for three substrates of delta6-desaturase, i.e. oleic acid (C18:1n-9), linoleic acid (C18:2n-6) and alpha-linoleic acid (C18:3n-3) was dose-dependent in the range 0.1-0.5 mmol x L(-1) myristic acid concentration. 相似文献