Local Concentration (local + concentration)

Distribution by Scientific Domains

Kinds of Local Concentration

  • high local concentration


  • Selected Abstracts


    Electrode Reactions of Catechol at Tyrosinase-Immobilized Latex Suspensions

    ELECTROANALYSIS, Issue 8 2004
    Patsamon Rijiravanich
    Abstract Tyrosinase was immobilized on polystyrene latex particles in order to control amounts of the enzyme. The tyrosinase-coated latex particles were composed of the core polystyrene and four successive coating layers: polystyrene sulfonate, polyallylamine, tyrosinase and polyallylamine again, built up by the layer-by-layer technique. They showed catalytic currents for the enzymatic oxidation of catechol to o -quinone. The enzyme activity per particle was evaluated as 2.3×10,7 units from UV absorption of o -quinone. The relation between the catalytic current and the concentration of catechol leads to a Michaelis-Menten type kinetic equation. The layer-by-layer method was found to have a deactivating effect on enzyme catalysis. In spite of this, the catechol oxidation current was larger than the current from free tyrosinase at a common value of enzyme units per volume. This is ascribed to strong adsorption of the latex particles on the electrode, leading to the enhancement of the local concentration of tyrosinase. [source]


    PCNA clamp facilitates action of DNA cytosine methyltransferase 1 on hemimethylated DNA

    GENES TO CELLS, Issue 10 2002
    Tetsuo Iida
    Background: Proliferating cell nuclear antigen (PCNA) is a ring-shaped protein known as a processivity factor of DNA polymerase ,. In addition to this role, PCNA interacts with a number of other proteins to increase their local concentration at replicated DNA sites. DNA cytosine methyltransferase 1 (Dnmt1), which preserves epigenetic signals by completing the methylation of hemimethylated DNA after DNA replication, has been indicated as one of these PCNA binding proteins by a previous work. However, the molecular mechanisms and functional significance of their association have not yet been studied. Results: Dnmt1 can be readily isolated from nuclear extracts by PCNA affinity chromatography. Studies of the interactions between the two proteins demonstrate that the N-terminal region of Dnmt1, which contains a typical PCNA binding motif, has core PCNA binding activity, and that the remaining portion of the protein exerts a negative influence on the interaction of Dnmt1 with PCNA. The affinity of Dnmt1 for DNA is much higher for DNA bound by PCNA than for free DNA. Furthermore, DNA methylation assays with hemimethylated DNA as a substrate revealed that PCNA clamp-bound DNA is methylated more efficiently by Dnmt1 than is free DNA. Conclusion: These results provide the first biochemical evidence that physical interactions between PCNA and Dnmt1 facilitate the methylation of newly neplicated DNA, on which PCNA remains associated as a functional clamp. [source]


    Controlling the mass action of ,-synuclein in Parkinson's disease

    JOURNAL OF NEUROCHEMISTRY, Issue 2 2008
    Changyoun Kim
    Abstract Parkinson's disease (PD) is an age-related neurodegenerative disease with unknown etiology. Growing evidence from genetic, pathologic, animal modeling, and biochemical studies strongly support the theory that abnormal aggregation of ,-synuclein plays a critical role in the pathogenesis of PD. Protein aggregation is an alternative folding process that competes with the native folding pathway. Whether or not a protein is subject to the aggregation process is determined by the concentration of the protein as well as thermodynamic properties inherent to each polypeptide. An increase in cellular concentration of ,-synuclein has been associated with the disease in both familial and sporadic forms of PD. Thus, maintenance of the intraneuronal steady state levels of ,-synuclein below the critical concentration is a key challenge neuronal cells are facing. Expression of the ,-synuclein gene is under the control of environmental factors and aging, the two best-established risk factors for PD. Studies also suggest that the degradation of this protein is mediated by proteasomal and autophagic pathways, which are two mechanisms that are related to the pathogenesis of PD. Recently, vesicle-mediated exocytosis has been suggested as a novel mechanism for disposal of neuronal ,-synuclein. Relocalization of the protein to specific compartments may be another method for increasing its local concentration. Regulation of the neuronal steady state levels of ,-synuclein has significant implications in the development of PD, and understanding the mechanism may disclose potential therapeutic targets for PD and other related diseases. [source]


    Cefazolin embedded biodegradable polypeptide nanofilms promising for infection prevention: A preliminary study on cell responses

    JOURNAL OF ORTHOPAEDIC RESEARCH, Issue 8 2010
    Hongshuai Li
    Abstract Implant-associated infection is a serious complication in orthopedic surgery, and endowing implant surfaces with antibacterial properties could be one of the most promising approaches for preventing such infection. In this study, we developed cefazolin loaded biodegradable polypeptide multilayer nanofilms on orthopedic implants. We found that the amount of cefazolin released could be tuned. A high local concentration of cefazolin was achieved within the first a few hours and therefore may inhibit bacterial colonization in the critical postimplantation period. The developed cefazolin loaded nanofilms showed their in vitro efficacy against Staphylococcus aureus; the more antibiotics loaded, the longer the nanocoated implant had antibacterial properties. More interestingly, antibiotic-loaded polypeptide multilayer nanofilms also improved osteoblast bioactivity including cell viability and proliferation. These findings suggested that biodegradable polypeptide multilayer nanofilms as antibiotic carriers at the implant/tissue interface are compatible with human cells such as osteoblasts and bactericidal to bacteria such as S. aureus. These characteristics could be promising for preventing implant-associated infection and potentially improving bone healing. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:992,999, 2010 [source]


    Interferon-, therapy: Evaluation of routes of administration and delivery systems

    JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2002
    Husam M. Younes
    Abstract Although different routes and delivery systems have been used to deliver interferon-, (IFN-,) for the treatment of a variety of viral and neoplastic diseases, little has been reported regarding the most efficient and least toxic routes and drug delivery modes required to achieve these goals. To have a greater understanding of the best strategies to use to administer this cytokine in an efficient, stable, and safe manner, this review details aspects of IFN-, concerning its mechanism of action, physical properties, and pharmacokinetics. One important conclusion that is drawn from this analysis is that a consistent, local concentration of IFN-, is necessary to achieve an optimal therapeutic response. A critical discussion covering the advantages and limitations of the currently used methodologies to deliver IFN-, in such a fashion is presented. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:2,17, 2002 [source]


    Inherited defects of coagulation factor V: the hemorrhagic side

    JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 1 2006
    R. ASSELTA
    Summary., Coagulation factor V (FV) is the protein cofactor required in vivo for the rapid generation of thrombin catalyzed by the prothrombinase complex. It also represents a central regulator in the early phases of blood clot formation, as it contributes to the anticoagulant pathway by participating in the downregulation of factor VIII activity. Conversion of precursor FV to either a procoagulant or anticoagulant cofactor depends on the local concentration of procoagulant and anticoagulant enzymes, so that FV may be regarded as a daring tight-rope walker gently balancing opposite forces. Given this dual role, genetic defects in the FV gene may result in opposite phenotypes (hemorrhagic or thrombotic). Besides a concise description on the structural, procoagulant and anticoagulant properties of FV, this review will focus on bleeding disorders associated with altered levels of this molecule. Particular attention will be paid to the mutational spectrum of type I FV deficiency, which is characterized by a remarkable genetic heterogeneity and by an uneven distribution of mutations throughout the FV gene. [source]


    Non-invasive monitoring of commonly used intraocular drugs against endophthalmitis by raman spectroscopy

    LASERS IN SURGERY AND MEDICINE, Issue 4 2003
    K. Hosseini MD
    Abstract Purpose To develop a non-contact and non-invasive method for quantification of the local concentration of certain antibiotic and antifungal drugs in the eye. Study Design/Materials and Methods An integrated CCD-based Raman spectroscopic system designed specifically for ophthalmic applications was used to non-invasively detect the presence of ceftazidime and amphotericin B in ocular media. Specific Raman signatures of the above named drugs were determined for various concentrations that were injected through a needle in the aqueous humor of rabbit eyes in vivo. Raman spectra were subsequently acquired by focusing an argon laser beam within the anterior chamber of the eye. Results Compared to ocular tissue, unique spectral features of ceftazidime appeared near 1,028, 1,506, 1,586, and 1,641 cm,1. Amphotericin B exhibited its characteristic peaks at 1,156.5 and 1,556 cm,1. The amplitude of the spectral peak corresponding to these drugs (acquired by 1 second exposure time and 25 mW of laser power) were determined to be linearly dependent on their local concentration in the anterior chamber of the eye. Conclusions Raman spectroscopy may offer an effective tool to non-invasively assess the local concentration of the delivered drugs within the ocular media. This technique potentially could be used to investigate the pharmacokinetics of intraocular drugs in vivo either from a releasing implant or a direct injection. Lasers Surg. Med. 32:265,270, 2003. © 2003 Wiley-Liss, Inc. [source]


    Binding of Methylene Blue to Polyelectrolytes Containing Sulfonate Groups

    MACROMOLECULAR CHEMISTRY AND PHYSICS, Issue 13-14 2009
    Ignacio Moreno-Villoslada
    Abstract The interaction between methylene blue (MB) and poly(sodium 4-styrenesulfonate) (PSS), poly(sodium vinylsulfonate) (PVS), and the more hydrophobic poly[sodium 2-(N -acrylamido)-2-methyl-propanesulfonate] (PAMPS), is investigated. The main driving forces for the interaction with PSS are supposed to be short-range aromatic/aromatic interactions, which explain the smaller dissociation constant, the resistance to the cleaving effect of NaCl, and the prevention of MB self-aggregation around the macromolecules under a moderate excess of the polymer. On the contrary, as a consequence of long-range interactions, a higher local concentration of MB around PAMPS and, more significantly, around PVS results in MB self-aggregation that can be quenched in the presence of NaCl. [source]


    A SeqA hyperstructure and its interactions direct the replication and sequestration of DNA

    MOLECULAR MICROBIOLOGY, Issue 4 2000
    V. Norris
    A level of explanation in biology intermediate between macromolecules and cells has recently been proposed. This level is that of hyperstructures. One class of hyperstructures comprises the genes, mRNA, proteins and lipids that assemble to fulfil a particular function and disassemble when no longer required. To reason in terms of hyperstructures, it is essential to understand the factors responsible for their formation. These include the local concentration of sites on DNA and their cognate DNA-binding proteins. In Escherichia coli, the formation of a SeqA hyperstructure via the phenomenon of local concentration may explain how the binding of SeqA to hemimethylated GATC sequences leads to the sequestration of newly replicated origins of replication. [source]


    Liposome-bound APO2L/TRAIL is an effective treatment in a rabbit model of rheumatoid arthritis

    ARTHRITIS & RHEUMATISM, Issue 8 2010
    Luis Martinez-Lostao
    Objective We previously observed that T lymphocytes present in synovial fluid (SF) from patients with rheumatoid arthritis (RA) were sensitive to APO2L/TRAIL. In addition, there was a drastic decrease in the amount of bioactive APO2L/TRAIL associated with exosomes in SF from RA patients. This study was undertaken to evaluate the effectiveness of bioactive APO2L/TRAIL conjugated with artificial lipid vesicles resembling natural exosomes as a treatment in a rabbit model of antigen-induced arthritis (AIA). Methods We used a novel Ni2+ -(N -5-amino-1-carboxypentyl)-iminodiacetic acid),containing liposomal system. APO2L/TRAIL bound to liposomes was intraarticularly injected into the knees of animals with AIA. One week after treatment, rabbits were killed, and arthritic synovial tissue was analyzed. Results Tethering APO2L/TRAIL to the liposome membrane increased its bioactivity and resulted in more effective treatment of AIA compared with soluble, unconjugated APO2L/TRAIL, with substantially reduced synovial hyperplasia and inflammation in rabbit knee joints. The results of biophysical studies suggested that the increased bioactivity of APO2L/TRAIL associated with liposomes was due to the increase in the local concentration of the recombinant protein, augmenting its receptor crosslinking potential, and not to conformational changes in the protein. In spite of this increase in bioactivity, the treatment lacked systemic toxicity and was not hepatotoxic. Conclusion Our findings indicate that binding APO2L/TRAIL to the liposome membrane increases its bioactivity and results in effective treatment of AIA. [source]


    Delivery of a Growth Factor Fusion Protein Having Collagen-Binding Activity to Wound Tissues

    ARTIFICIAL ORGANS, Issue 2 2003
    Tetsuya Ishikawa
    Abstract: Recently, we established a collagen-binding growth factor consisting of epidermal growth factor and the fibronectin collagen-binding domain (FNCBD-EGF). FNCBD-EGF is a biologically active fusion protein that could stably bind to collagen materials, and exert its growth factor activity even after collagen binding. In this study, we investigated the concept that FNCBD moiety with high collagen affinity may enhance the effective local concentration of EGF at the site of administration in the following tissues: skin wounds, catheter-injured arteries, and hind limb muscles. In an animal model of impaired wound healing, application of FNCBD-EGF in combination with collagen gel induced granulation tissue formation in the wounds due to its sustained retention. In the injured artery, infused FNCBD-EGF remained bound to collagen exposed on the injured tissues even after blood circulation was restored. Injection of the fusion protein into the hind limbs revealed that our delivery system was effective for direct administration to muscular tissue. [source]


    Crystallization of selenomethionyl exo-,-1,3-galactanase from the basidiomycete Phanerochaete chrysosporium

    ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 12 2009
    Takuya Ishida
    Exo-,-1,3-galactanase from Phanerochaete chrysosporium (Pc1,3Gal43A) consists of a glycoside hydrolase family 43 catalytic domain and a substrate-binding domain that belongs to carbohydrate-binding module family 35. It catalyzes the hydrolysis of ,-1,3-galactan, which is the backbone of the arabinogalactan proteins; the C-terminal carbohydrate-binding module family 35 domain increases the local concentration of the enzyme around ,-1,3-galactan by its high affinity for the substrate. To enable phase determination using the multiwavelength anomalous dispersion method, selenomethionyl Pc1,3Gal43A was crystallized at 298,K using the hanging-drop vapour-diffusion method. The presence of selenium in the crystals was confirmed from the X-ray absorption spectrum. The crystals belonged to space group P21 and diffracted to 1.8,Å resolution. [source]


    Application of microdialysis to study the in vivo release of pingyangmycin from in situ gels in rabbits

    BIOMEDICAL CHROMATOGRAPHY, Issue 11 2006
    Zi-bin Gao
    Abstract Microdialysis was used together with HPLC to monitor the local concentration of pingyangmycin hydrochloride (PYM) after embolizing rabbit ear-veins with an injectable sustained release formulation, PYM-Zein/PYM-Zein-sucrose acetate isobutyrate (SAIB), in situ gel. The dialysis probe was perfused at 2 µL/min. The in vivo recovery was 46.6 3.1% (n = 4). The samples were injected directly into HPLC. PYM was detected using UV detector at 291 nm. Separation from other components in the dialysate was performed using a Discovery® RP-Amide C16 column within 12 min. The response for PYM in the dialysate was linear (r2 > 0.996) over the range of 2.5,212 µg/mL. The limit of detection and limit of quantitation of PYM in the dialysate were 0.4 and 1.5 µg/mL, respectively. The results demonstrated that the in situ gel of PYM-Zein-SAIB could extend the release of PYM to 4 days. SAIB could significantly cut down the initial burst of PYM from the in situ gels (p < 0.05). Copyright © 2006 John Wiley & Sons, Ltd. [source]


    Gauged harmonic maps, Born-Infeld electromagnetism, and magnetic vortices

    COMMUNICATIONS ON PURE & APPLIED MATHEMATICS, Issue 11 2003
    Fanghua Lin
    We study maps from a 2-surface into the standard 2-sphere coupled with Born-Infeld geometric electromagnetism through an Abelian gauge field. Such a formalism extends the classical harmonic map model, known as the ,-model, governing the spin vector orientation in a ferromagnet allows us to obtain the coexistence of vortices and antivortices characterized by opposite, self-excited, magnetic flux lines. We show that the Born-Infeld free parameter may be used to achieve arbitrarily high local concentration of magnetic flux lines that the total minimum energy is an additive function of these quantized flux lines realized as the numbers of vortices antivortices. In the case where the underlying surface, or the domain, is compact, we obtain a necessary sufficient condition for the existence of a unique solution representing a prescribed distribution of vortices antivortices. In the case where the domain is the full plane, we prove the existence of a unique solution representing an arbitrary distribution of vortices and antivortices. Furthermore, we also consider the Einstein gravitation induced by these vortices, known as cosmic strings, establish the existence of a solution representing a prescribed distribution of cosmic strings cosmic antistrings under a necessary sufficient condition that makes the underlying surface a complete surface with respect to the induced gravitational metric. © 2003 Wiley Periodicals, Inc. [source]


    Extracellular matrix molecules and synaptic plasticity: immunomapping of intracellular and secreted Reelin in the adult rat brain

    EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2006
    Tania Ramos-Moreno
    Abstract Reelin, a large extracellular matrix glycoprotein, is secreted by several neuron populations in the developing and adult rodent brain. Secreted Reelin triggers a complex signaling pathway by binding lipoprotein and integrin membrane receptors in target cells. Reelin signaling regulates migration and dendritic growth in developing neurons, while it can modulate synaptic plasticity in adult neurons. To identify which adult neural circuits can be modulated by Reelin-mediated signaling, we systematically mapped the distribution of Reelin in adult rat brain using sensitive immunolabeling techniques. Results show that the distribution of intracellular and secreted Reelin is both very widespread and specific. Some interneuron and projection neuron populations in the cerebral cortex contain Reelin. Numerous striatal neurons are weakly immunoreactive for Reelin and these cells are preferentially located in striosomes. Some thalamic nuclei contain Reelin-immunoreactive cells. Double-immunolabeling for GABA and Reelin reveals that the Reelin-immunoreactive cells in the visual thalamus are the intrinsic thalamic interneurons. High local concentrations of extracellular Reelin selectively outline several dendrite spine-rich neuropils. Together with previous mRNA data, our observations suggest abundant axoplasmic transport and secretion in pathways such as the retino-collicular tract, the entorhino-hippocampal (,perforant') path, the lateral olfactory tract or the parallel fiber system of the cerebellum. A preferential secretion of Reelin in these neuropils is consistent with reports of rapid, activity-induced structural changes in adult brain circuits. [source]


    Bioceramic Bone Graft Substitutes: Influence of Porosity and Chemistry

    INTERNATIONAL JOURNAL OF APPLIED CERAMIC TECHNOLOGY, Issue 3 2005
    Karin A. Hing
    Bioceramics have been considered for use as synthetic bone graft substitutes (BGSs) for over 30 years, throughout which there have been two primary areas of research: (i) optimization of the physical pore structure and (ii) formulation of an appropriate bioceramic chemistry. While it is well recognized that both the rate of integration and the final volume of regenerated bone are primarily dependent on the macroporosity, there still seems to be some dispute regarding the optimum "type" of porosity. The rate and quality of bone integration have, in turn, been related to a dependence on pore size, porosity volume fraction, and interconnection size and interconnection density, both as a function of structural permeability and mechano-transduction. Moreover, the role of strut microstructure and pore geometry have been considered with respect to their influence on entrapment and recruitment of growth factors (GFs) in addition to its influence on scaffold mechanics. Deconvoluting the relative affects of these parameters is complicated by the use of both resorbable and nonresorbable bioactive bioceramics, which are believed to mediate bioactivity in the osseous environment through two principal mechanisms: (i) directly through dissolution and release of ionic products in vivo, elevating local concentrations of soluble species that interact directly with local cells or influence cell behavior by their effect on local pH, (ii) indirectly through the influence that surface chemistry will have on protein adsorption, GF entrapment, and subsequent cell attachment and function. This article aims to review some of the recent developments in bioceramic BGSs, with a view to understanding how the various physiochemical parameters may be optimized to promote bone healing. [source]


    Efficacy and Safety of Drug-Eluting Stents: Current Best Available Evidence

    JOURNAL OF CARDIAC SURGERY, Issue 6 2006
    Shahzad G. Raja M.R.C.S.
    Drug-eluting coronary stents deliver effective local concentrations of antiproliferative drugs (thus avoiding systemic toxicities), without substantially modifying the technique of percutaneous coronary intervention. Studies involving several different stent platforms and antiproliferative drug coatings have recently demonstrated dramatic reductions in restenosis rates, compared to conventional bare metal stents. Although the clinical benefits of drug-eluting stents are increasingly evident, important concerns about their long-term safety and costs have been raised. Furthermore, drug-eluting stents are being claimed to replace coronary artery bypass surgery in the near future. This review article evaluates the current best available evidence on the efficacy and safety of drug-eluting stents with a focus on the impact of this "revolutionary" new technology on the practice of coronary artery bypass surgery. [source]


    Low-dose prostacyclin in treatment of severe brain trauma evaluated with microdialysis and jugular bulb oxygen measurements

    ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 7 2000
    P.-O. Grände
    Background: The endogenous substance prostacyclin is a substance with the potential to improve microcirculation and oxygenation around contusions in the brain following a head trauma by its vasodilatory, antiaggregatory and antiadhesive effects. Microdialysis measurements of local concentrations of selected interstitial substances in the brain, and measurements of venous jugular bulb oxygenation reflecting overall brain oxygenation, might be useful to evaluate possible therapeutic effects of a specific therapy, such as treatment with prostacyclin. Methods: This case report study on six patients, of whom five were given prostacyclin, includes cerebral microdialysis measurements of interstitial lactate (n=5), pyruvate (n=3), glycerol (n=5) and glucose (n=4), and is combined with measurements of venous jugular bulb oxygenation in three of the patients. One microdialysis catheter was placed adjacent to a contusion, and in four of the patients another catheter was also placed in the contralateral less injured side for comparison. Low-dose prostacyclin infusion (0.5,1.0 ng kg,1 min,1) was started when lactate concentrations in the more injured side was raised at a constant level for more than 10 h. The study also includes one patient used as control to whom no prostacyclin was given. Results: Lactate was markedly lower in the less injured than in the more injured area of the brain. During the prostacyclin infusion elevated lactate and lactate/pyruvate ratio were reduced. Elevated glycerol decreased, a low glucose increased and jugular bulb blood oxygenation increased following start of prostacyclin. The control patient showed an increase in lactate and lactate/pyruvate ratio. Conclusion: The microdialysis data combined with the jugular bulb oxygenation data indicated that low-dose prostacyclin exerts effects compatible with improved oxygenation and reduced cell damage in the severely traumatised brain. [source]


    Real-time measurement of serotonin release and motility in guinea pig ileum

    THE JOURNAL OF PHYSIOLOGY, Issue 2 2006
    Paul P. Bertrand
    Enterochromaffin (EC) cells are sensors that detect chemical or mechanical stimuli and respond with release of serotonin (5-HT). 5-HT activates local motor reflexes, but whether local motor reflexes also evoke 5-HT release is unknown. The aim of the present study was to establish the relationship between the release of 5-HT and the enteric neural circuits controlling the movements of the intestine. Recordings were made from full-thickness preparations of guinea pig ileum using electrochemical techniques with carbon fibre electrodes to measure local concentrations of 5-HT. The tension in the circular muscle (CM) and longitudinal muscle (LM) was recorded with force transducers. The release of 5-HT from the EC cells was detected selectively and the timing of the events quantified. Pressure-evoked peristalsis caused detectable 5-HT release only when the recording site was invaded by a ring of CM contraction. Spontaneous and stretch-evoked reflex contraction of the CM and LM occurred simultaneously with 5-HT release. Paralysis of the smooth muscle significantly reduced the stretch-evoked release. Muscarinic agonists evoked reflexes that were associated with increases in tension in CM and LM simultaneous with 5-HT release. Tetrodotoxin abolished the coordination between the CM contraction and 5-HT release but not the direct activation of the CM and EC cells by the agonists. In conclusion, the correlation between local motor reflexes and 5-HT release observed in the present study is caused primarily by the contraction of the smooth muscle and subsequent deformation of the mucosa. The EC cell is, thus, a site of convergence for mechanical forces that contribute to the release of 5-HT during motor reflexes. [source]


    Pharmacokinetics, immunogenicity and bioactivity of the therapeutic antibody catumaxomab intraperitoneally administered to cancer patients

    BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2010
    Peter Ruf
    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The trifunctional antibody catumaxomab is a highly effective anti-cancer therapeutic that is administered to patients suffering from malignant ascites intraperitoneally (i.p.) in microgram (µg) doses. So far, no clinical pharmacokinetic data are available. WHAT THIS STUDY ADDS , Catumaxomab attains effective local concentrations in the ascites fluid and shows low systemic exposure with an acceptable safety profile confirming the appropriateness of the i.p. application scheme. AIMS Catumaxomab is the first EMEA approved trifunctional anti-EpCAM×anti-CD3 antibody for the treatment of cancer patients with malignant ascites. A phase II pharmacokinetic study was conducted to determine local and systemic antibody concentrations and anti-drug antibody (ADA) development. METHODS Thirteen cancer patients with symptomatic malignant ascites were treated with four ascending doses of 10, 20, 50, and 150 µg catumaxomab intraperitoneally (i.p.) infused on days 0, 3, 6 or 7 and 10. The pharmacokinetics of catumaxomab were studied by implementation of supportive data from a non clinical mouse tumour model. Additionally, ADA development was monitored. RESULTS Ten out of 13 patients were evaluable for pharmacokinetic analysis. Catumaxomab became increasingly concentrated in ascites during the course of treatment, attaining effective concentrations in the ng ml,1 range. Catumaxomab remained immunologically active even after several days in the circulation. The observed systemic catumaxomab exposure was low (<1%), with a maximal median plasma concentration (Cmax) of 403 pg ml,1. The mean elimination half-life in the plasma was 2.13 days. All patients developed ADA, but not before the last infusion. High observed inter-individual variability and low systemic exposure may be explained by the inverse correlation between tumour burden, effector cell numbers and systemic antibody bioavailability as demonstrated in a defined mouse tumour model. CONCLUSIONS Based on the high and effective local concentrations, low systemic exposure and acceptable safety profile, we confirmed that the i.p. application scheme of catumaxomab for the treatment of malignant ascites is appropriate. [source]


    Consideration of the Effect of Irregular Catalytic Active Component Distributions in Mesopores , Extension of a Model for Wall Catalyzed Reactions in Microchannel Reactors

    CHEMICAL ENGINEERING & TECHNOLOGY (CET), Issue 7 2003
    B. Platzer
    Abstract Data available from the literature and experimental results have shown that the distribution of the catalytic active components can be irregular already for fresh catalysts. The determination of the local concentrations of the catalytic active components using wavelength dispersive X-ray spectroscopy confirms this for microstructured wafers used in microchannel reactors. Considering this nonuniform distribution, the used model gives the relation between the local concentration profiles of the reactants inside the pores and the product yield in the entire pore. These results were used in an equation for the diffusion flux at the pore mouth, which is useful for a microchannel model developed in a recent paper [1]. The theoretical considerations deal with cylindrical pores with known reactant concentrations at the pore mouth and known distribution of the catalytic active component within the pore. Beside numerical results, some analytical solutions with low mathematical expense, applicable to special cases, are discussed. The nonconsideration of the irregular distribution of the catalytic active component can be the reason for difficulties during the extrapolation of experimental results to slightly different conditions and can have a great influence on the reaction results. The regarded examples are typical of wall-catalyzed reactions in microchannel reactors with mesopores. [source]


    Toxicity testing of the VEGF inhibitors bevacizumab, ranibizumab and pegaptanib in rats both with and without prior retinal ganglion cell damage

    ACTA OPHTHALMOLOGICA, Issue 5 2010
    Sebastian Thaler
    Abstract. Purpose:, To evaluate the effects of intravitreally introduced vascular endothelial growth factor (VEGF) inhibitors in rat eyes with healthy retinal ganglion cells (RGC) and into others with N-methyl-D-aspartate (NMDA)-induced RGC damage. Methods:, Bevacizumab, ranibizumab and pegaptanib were intravitreally injected each at two different concentrations. Respective vehicles of the three substances served as controls. In a different group, additionally a rat anti-VEGF antibody was injected after NMDA treatment. Retrogradely labelled RGC were counted on retinal wholemounts 1 week or 2 months after intravitreal introduction of the VEGF inhibitors. Electron microscopy (EM) was performed on normal rat eyes 2 months after introduction of the VEGF inhibitors. Results:, RGC counts in healthy rat eyes were essentially unchanged from those of the control animals after the administration of both low and high concentrations of bevacizumab, ranibizumab or pegaptanib. Compared to the other two substances, however, high doses of pegaptanib and its respective vehicle significantly decreased RGC after 1 week and led to a marked increase of mitochondrial swelling in EM. In eyes with NMDA-induced RGC damage, no changes of RGC numbers were detected after rat anti-VEGF antibody or bevacizumab, ranibizumab and pegaptanib at both tested concentrations. Conclusions:, Even at higher doses, bevacizumab and ranibizumab showed no toxic effects on RGC in vivo in either untreated rats or in the NMDA-induced RGC damage model. Also a rat anti-VEGF antibody showed no adverse effects after NMDA. Anti-VEGF therapy therefore appears safe even for eyes with additional excitotoxic RGC damage. Potential harm from the pegaptanib carrier solution at very high local concentrations cannot be excluded. [source]