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  • 1
    ISSN: 1573-904X
    Keywords: extent of absorption ; mass balance ; intestinal metabolism ; cefaclor ; cefatrizine ; chymotrypsin ; insulin ; peptides
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A theoretical analysis for estimating the extent of intestinal peptide and peptide analogue absorption was developed on the basis of a mass balance approach that incorporates convection, permeability, and reaction. The macroscopic mass balance analysis (MMBA) was extended to include chemical and enzymatic degradation. A microscopic mass balance analysis, a numerical approach, was also developed and the results compared to the MMBA. The mass balance equations for the fraction of a drug absorbed and reacted in the tube were derived from the general steady state mass balance in a tube: dM/dZ = {[(2/R)(P w + k r)]CV L}/v z, where M is mass, z is the length of the tube, R is the tube radius, P w is the intestinal wall permeability, k r is the reaction rate constant, C is the concentration of drug in the volume element over which the mass balance is taken, V L is the volume of the tube, and v z is the axial velocity of drug. The theory was first applied to the oral absorption of two tripeptide analogues, cefaclor (CCL) and cefatrizine (CZN), which degrade and dimerize in the intestine. Simulations using the mass balance equations, the experimental absorption parameters, and the literature stability rate constants yielded a mean estimated extent of CCL (250-mg dose) and CZN (1000-mg dose) absorption of 89 and 51%, respectively, which was similar to the mean extent of absorption reported in humans (90 and 50%). It was proposed previously that 15% of the CCL dose spontaneously degraded systemically; however, our simulations suggest that significant CCL degradation occurs (8 to 17%) presystemically in the intestinal lumen. Insulin (M r = 5700), which is metabolized in the intestine primarily by α-chymotrypsin, was chosen for the second application of theory. The simulations show that the intestinal absorption of insulin is approximately 1% of the administered dose. Further, the extent of insulin oral absorption may not exceed 2% even if effective enzyme inhibitors are dosed concurrently since simulations show that insulin absorption is permeability limited. The steady-state macroscopic and microscopic simulation results were comparable and, for the antibiotics, were similar to published clinical results. Therefore, both approaches are useful for estimating the extent of oral peptide absorption and intestinal reaction from in vitro and in situ results.
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Pharmaceutical research 12 (1995), S. 1823-1837 
    ISSN: 1573-904X
    Keywords: membrane transporters ; glucose ; peptides ; multidrug resistance ; transporter regulation ; transporter gene families ; genetic transporter defects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Membrane transporter proteins are encoded by numerous genes that can be classified into several superfamilies, on the basis of sequence identity and biological function. Prominent examples include facilitative transporters, the secondary active symporters and antiporters driven by ion gradients, and active ABC (ATP binding cassette) transporters involved in multiple-drug resistance and targeting of antigenic peptides to MHC Class I molecules. Transported substrates range from nutrients and ions to a broad variety of drugs, peptides and proteins. Deleterious mutations of transporter genes may lead to genetic diseases or loss of cell viability. Transporter structure, function and regulation, genetic factors, and pharmaceutical implications are summarized in this review.
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Pharmaceutical research 13 (1996), S. 1631-1634 
    ISSN: 1573-904X
    Keywords: PEPT1 ; H+-coupled transporter ; peptides ; β-lactam antibiotics ; cephalexin ; intestinal absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. A cDNA encoding the H+-coupled peptide transporter, hPEPTl, has previously been cloned from human ileum (8). The objective of this study was to establish a stably transfected cell line expressing hPEPTl in mammalian cell culture. Methods. The hPEPTl cDNA was subcloned into an expression vector carrying the CMV promoter and a neomycin resistance gene. This vector, pCDNA3-PEPT1, was transiently transfected into several cell lines to identify those capable of expressing PEPT1 transport function. CHO cells were selected and stably transfected with PEPT1 (CHO-PEPT1). Dipeptide transport activity was measured with 3H-Gly-Sar, in the presence and absence of inhibitors. Results. The clonal cell line, CHO-PEPT1, displayed high transport activity. Dipeptide transport was sensitive to pH and specific for dipeptides and other small peptides. Peptidomimetic antibiotics, such as cephalexin, were competitors for peptide transport. Conclusions. The stably transfected cell line, CHO-PEPT1 exhibits enhanced transport over that of cell lines with native expression of PEPT1, and therefore, represents a useful tool for rapid screening of drugs that utilize the peptide transporter in the human intestine for absorption.
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  • 4
    Electronic Resource
    Electronic Resource
    Bognor Regis [u.a.] : Wiley-Blackwell
    Journal of Polymer Science Part A: Polymer Chemistry 32 (1994), S. 1847-1865 
    ISSN: 0887-624X
    Keywords: polyurethanes ; siloxanes ; copolymers ; phase segregation ; flame retardancy ; segmented polyurethanes ; Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Siloxane urethane block copolymers were prepared with siloxanes as the soft segment. Films were cast from a variety of solvents. Solvent has an effect on the segregation of soft and hard segments. Surface studies, including ESCA, EDS, and FT-IR, show well segregated block copolymers with enhanced siloxane on the surface. DSC studies show a low mp (-44°C) for the soft segment and a Tg for the hard segment above room temperature. These materials show higher thermal stability compared to polyether urethane block copolymers. These copolymers also show relatively good resistance to exposure to oxygen plasma and show improved flame retardancy compared to nonsiliconated, polyether polyurethane block copolymers. © 1994 John Wiley & Sons, Inc.
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  • 5
    Electronic Resource
    Electronic Resource
    Bognor Regis [u.a.] : Wiley-Blackwell
    Journal of Polymer Science Part A: Polymer Chemistry 30 (1992), S. 1525-1533 
    ISSN: 0887-624X
    Keywords: polycarbonate ; photo-Fries ; photolysis ; fluorescence ; diphenylcarbonate ; Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The effect of polymer matrices on a photoinduced rearrangement process has been shown to be dependent upon whether the photoreactive group is attached to a polymer backbone, or free. If diphenylcarbonate is simply embedded in a polymer matrix, the rearrangement process is independent of whether the host film is above or below its glass transition. However, if the diphenylcarbonate group is incorporated as part of a polycarbonate backbone, the Fries rearrangement process is significantly reduced for photolyses conducted at temperatures well below the glass transition of polycarbonate. The utility of fluorescence spectroscopy in identification of the initial salicylate type photo-Fries type rearrangement product of polycarbonate is also demonstrated. The broad, structureless fluorescence spectrum with peak maximum at 470 nm produced by photolysis of polycarbonate films for short time periods is assigned to emission from phenyl salicylate type photoproducts. © 1992 John Wiley & Sons, Inc.
    Additional Material: 10 Ill.
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  • 6
    Electronic Resource
    Electronic Resource
    Bognor Regis [u.a.] : Wiley-Blackwell
    Journal of Polymer Science Part A: Polymer Chemistry 36 (1998), S. 1317-1328 
    ISSN: 0887-624X
    Keywords: vapor phase deposition ; polybenzoxazoles ; poly(phenylenebenzoxazole) ; thermal depolymerization ; Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Vapor phase deposition was carried out on multifunctional aliphatic and aromatic benzoxazoles to yield powdered samples of poly(dimethylenebenzoxazoles). Representative aliphatic and aromatic poly(dimethylenebenzoxazoles) were also synthesized through solution methods using 4-amino-3-hydroxyhydrocinnamic acid and 2-(4-(bromomethyl)phenyl)-6-(bromomethyl)benzoxazole, respectively, as monomers. Both aromatic and aliphatic polybenzoxazoles containing —CH2CH2— units in the polymer backbone displayed catastrophic weight loss over a very narrow temperature range. This is in contrast with other polybenzoxazoles which show a gradual weight loss over 500-1000°C. Vapor phase deposition carried out under vacuum on the polymers gave similar polymers in the collection zone suggesting the catastrophic weight loss is attributed to thermal depolymerization of the polymer through a diradical intermediate similar to the thermolysis and polymerization of [2.2]paracyclophane. © 1998 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 36: 1317-1328, 1998
    Additional Material: 20 Ill.
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  • 7
    ISSN: 1573-904X
    Keywords: absorption ; peptides ; metkephamid ; bioavailability ; degradation ; permeability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In this study the intestinal degradation and absorption of a synthetic pentapeptide, metkephamid, were investigated in the rat by determination of its wall permeabilities in the small and large intestine and the extent and mechanism of its intestinal degradation. The peptide was metabolized in the gut wall through contact with membrane-bound enzymes in the brush border membrane. The extent of metabolic inactivation depended on the intestinal segment investigated and decreased in the axial direction. No metabolism was found in the colon. The dimensionless wall permeabilities (P w*), determined by single-pass perfusion, were also site dependent. P w* was highest in the ileum [1.91 ± 0.24, (SE); n = 4], followed by the jejunum (1.64 ± 0.34; n = 4) and the colon (0.67 ± 0.38; n = 4). Based on the permeability data alone and under the assumption of no presystemic metabolism, complete bioavailability would be predicted for metkephamid. However, following oral administration, the mean absolute bioavailability was only 0.22 ± 0.065% (n = 3), indicating the overall dominance of degradation in the absorption process. Thus future strategies in oral peptide delivery should focus on increasing the stability of the peptide in the intestine by modifying the peptide structure and/or delivering the compound to an intestinal segment showing little or no enzymatic degradation.
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  • 8
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Biotechnology and Bioengineering 28 (1986), S. 646-658 
    ISSN: 0006-3592
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Growth of a hybridoma culture, along with production of monoclonal antibody, was demonstrated over extended periods in polysulfone hollow fiber membrane modules. The molecular weight cutoffs of the membranes were 70,000, 50,000, and 100,000 daltons. The hybridoma cell line, designated 65/26, produced IgG (2b/κ) directed at mouse thymus cell surface antigen, TL.1. Cell growth occurred in the shell space of the reactor, using supplemented RPMI 1640 (20% fetal bovine serum) supplied from a separate reservoir vessel through the hollow fiber lumen. The reservoir contained 125 mL media, which was changed every 4 days. Concentrations of immunoglobulin were determined by an enzyme immunoassay (using protein A and alkaline phosphatase-labeled antibody conjugate). For the 10K, 50K, and 100K hollow fiber membrane modules, the maximum IgG concentrations detected in the 2.5-mL shell space were 47.5-80, 510, and 740 μg/mL, respectively. In the 125-mL reservoir for the 100K hollow fiber membrane module, the IgG concentration was measured at 260 μg/mL These values compare with an IgG concentration of 1 μg/mL when grown in a standard tissue culture flask and 3.2-7.6 μg/mL when grown in 100 ml media in a spinner flask. In addition, 10K and 50K hollow fiber membrane modules were run in a mode that decreased the fetal bovine serum supplement with time. Differences between these systems suggest that it is possible to obtain high IgG accumulation rates, both during and after the exponential growth phase of the hybridoma population.
    Additional Material: 8 Ill.
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  • 9
    Electronic Resource
    Electronic Resource
    Hoboken, NJ : Wiley-Blackwell
    Journal of Biomedical Materials Research 32 (1996), S. 111-118 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: Calcium phosphate coatings were nucleated and grown from aqueous solution onto titanium metal substrates via surface-induced mineralization (SIM) processing techniques. This process is based on the observation that in nature organisms use biopolymers to produce ceramic composites, such as teeth, bones, and shells. The SIM process involves modification of a surface to introduce surface functionalization followed by immersion in aqueous supersaturated calcium phosphate solutions. This low-temperature process (〈100°C) has advantages over conventional methods of calcium phosphate deposition in that uniform coatings are produced onto complex-shaped and/or microporous samples. Additionally, because it is a low-temperature process, control of the phase and crystallinity of the deposited material can be maintained. © 1996 John Wiley & Sons, Inc.
    Additional Material: 8 Ill.
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  • 10
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Fire and Materials 18 (1994), S. 121-130 
    ISSN: 0308-0501
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Architecture, Civil Engineering, Surveying , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Experiments were conducted on 34 plastic materials having a variety of metallic coatings to determine the toxicity of their thermal decomposition products. Mice were exposed for 30 min in a dome exposure chamber to the products obtained by ramp-heating the samples from 200°C to 800°C. An LC50 value was obtained for each material. Postmortem examinations were conducted on all dead mice, and on survivors after 14 days, to determine the gross pathological effects of exposure; particular attention was devoted to pulmonary pathology. The exposure protocol chosen has been extensively criticized, but it is very useful to study the effects of stress on mice, which was the most important part of this work. Experiments were made involving unrestrained mice in groups of four, restrained mice in groups of four and unrestrained single mice. The LC50 values for single unrestrained mice were greater, by factors of 2-3, than those for four restrained mice, with the differences being shown to be statistically significant. This suggests that stress on the test animals will tend to reduce the LC50 values in bench-scale smoke toxicity tests. The LC50 values for all of the materials tested were equal to or higher than the value of 8 mg1-1 representative of the contribution of carbon monoxide to post-flashover fires. Moreover, no ‘supertoxicants’ were found in the smoke of any of the materials tested. Finally, the coatings did not adversely affect the smoke toxicity of the substrate materials by a factor higher than 2-3 in any of the cases investigated. Uncoated polyethylene was the most toxic substrate material tested (LC50 = 16 mgl-1) and uncoated NORYL® resin was the least toxic (LC50 = 91mgl-1). Metallic coatings involving Cu, Ni, graphite, and Zn typically had no statistically significant effect on the smoke toxicity of the substrate materials, although Ni coatings increased the smoke toxicity of ABS I and of white polycarbonate structural foam, by factors of 2-3. Overall smoke toxicities were well correlated with production of carbon monoxide (r=0.84) and carbon dioxide (r=0.82); oxygen levels and chamber temperature did not vary beyond acceptable limits. The materials tested generating the more toxic smokes (including polyethlene, polystyrene, and several polycarbonates) produced severe lung damage at low concentrations. The LC50 of these materials was also typically greater than predicted on the basis of CO production. Other materials (including several coating on NORYL® resin and Lexan® polycarbonate) produced pulmonary damage at higher concentrations amd had LC50 values more closely correlated with CO production. None of the polyurethane materials tested produced severe lung damage at the concentrations employed.
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