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  • 1990-1994  (4,088)
  • 1985-1989  (3,460)
  • 1975-1979  (1,691)
  • Engineering General  (6,563)
  • pharmacokinetics  (1,358)
  • Ultrastructure
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  • 101
    Electronic Resource
    Electronic Resource
    Structure of Golgi apparatus (1994)
    Springer
    Protoplasma 180 (1994), S. 14-28 
    Details
    ISSN: 1615-6102
    Keywords: Golgi apparatus ; Dictyosome ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Golgi apparatus (GA) of eukaryotic cells consist of one or more stacks of flattened saccules (cisternae) and an array of fenestrae and tubules continuous with the peripheral edges of the saccules. Golgi apparatus also are characterized by zones of exclusion that surround each stack and by an assortment of vesicles (or vesicle buds) associated with both the stacks and the peripheral tubules of the stack cisternae. Each stack (sometimes referred to as Golgi apparatus, Golgi complex, or dictyosome) is structurally and functionally polarized, reflecting its role as an intermediate between the endoplasmic reticulum, the cell surface, and the lysosomal system of the cell. There is probably only one GA per cell, and all stacks of the GA appear to function synchronously. All Golgi apparatus are involved in the generation and movement of product and membrane within the cell or to the cell exterior, and these functions are often reflected as structural changes across the stacks. For example, in plants, both product and membrane appear to maturate from the cis to the trans poles of the stacks in a sequential, or serial, manner. However, there is also strong ultrastructural evidence in plants for a parallel input to the stack saccules, probably through the peripheral tubules. The same modes of functioning probably also occur in animal GA; although here, the parallel mode of functioning almost surely predominates. In some cells at least, GA stacks give rise to tubular-vesicular structures that resemble the trans Golgi network. Rudimentary GA, consisting of tubular-vesicular networks, have been identified in fungi and may represent an early stage of GA evolution.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01379220
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  • 102
    Electronic Resource
    Electronic Resource
    Actin associated with plasmodesmata (1994)
    Springer
    Protoplasma 180 (1994), S. 169-184 
    Details
    ISSN: 1615-6102
    Keywords: Actin ; Cell-cell communication ; Plasmodesmata ; Regulation ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary We have used several methods to localise actin associated with plasmodesmata. In meristematic plant material fixed in 0.1% glutaraldehyde/1% paraformaldehyde and embedded in LR White resin, actin was localised (in TEM using 5 nm gold-labelled secondary antibody to C4 anti-actin primary antibody) in the neck region by the plasma membrane and endoplasmic reticulum, and also down the length of the plasmodesma, deep in the cell wall. When the chemical fixation was replaced by rapid freezing in liquid propane (without cryoprotectants) and substitution in acetone, the plasmodesmata were labelled in similar positions, but with less background label on sections. While only 8–20% of plasmodesmata were labelled, the label was 10 to 100 fold denser over plasmodesmata than over the surrounding wall indicating specific association with plasmodesmata. We presume the apparent extracellular location of some label was due to the size of the antibodies between the site of attachment and the observed position of the gold particle. Gold label was found in similar locations in material fixed in 3% paraformaldehyde, infiltrated with sucrose, frozen, sectioned (10–12 μm thick), then labelled with antibodies before resin embedding. Furthermore, cell walls in epidermal peels stained with rhodamine-phalloidin showed localised patches of fluorescence, presumably at the site of plasmodesmata (or primary pit-fields), which were connected on either side to fluorescent strands of actin in the cytoplasm. Suspension cultured cells ofNicotiana plumbaginifolia similarly stained showed very faint, narrow fluorescent strands crossing the walls of sister cells, which may indicate actin associated with individual plasmodesmata, shown in TEM to be sparsely distributed in these walls. In addition, the neck regions of cytochalasin-treated plasmodesmata were greatly enlarged and lacked the normal extracellular ring of particles. We propose that actin associated with plasmodesmata stabilizes the neck region and possibly also the cytoplasmic sleeve, and may be actively involved in regulating cell-to-cell transport.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01507853
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  • 103
    Electronic Resource
    Electronic Resource
    Production and modifications of extracellular structures during development of chytridiomycetes (1994)
    Springer
    Protoplasma 181 (1994), S. 123-141 
    Details
    ISSN: 1615-6102
    Keywords: Carbohydrates ; Chytridiomycetes ; Extracellular material ; Membranes ; Ultrastructure ; Zoospores
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary In development of the primitive fungi, chytridiomycetes, unwalled zoospores bearing single, posterior flagella are transformed into walled, round-cells which elaborate the thallus. Production, structural modification, or release of extracellular material are involved with each transition of developmental stage. This article reviews the variety and developmental changes of extracellular materials found at the cell surface of chytridiomycetes. A cell coat, produced from Golgi-derived vesicles during zoosporogenesis, is visible around free swimming zoospores of some chytridiomycetes. How the zoospore surface receives and transduces signals is not widely explored, but it is known that fenestrated cisternae and simple cisternae, which are integrated into the microbody-lipid globule complex, are spatially and structurally associated with the plasma membrane and flagellar apparatus. This spatial association, as well as the cytochemical localization of calcium in fenestrated cisternae, suggest a mechanism for signal transduction and for regulation of zoospore motility. Zoospores become encased in a new layer of extracellular material as the zoospore encysts. Among some chytrids the source of this material is preexisting vesicles which fuse with the plasma membrane. Among other zoospores, a readily identifiable population of encystment vesicles is not apparent, demonstrating that there is no single pattern or mechanism for zoospore encystment in chytridiomycetes. Encysted zoospores developing into thalli, typically produce cell walls with a microfibrillar substructure. Ultrastructural analysis of walls reveals distinctive architecture and remarkable sculpturing which have been used in systematics of some members of chytridiomycetes. Nothing is known as to underlying controls of cytoskeletal elements and plasma membrane enzyme complexes in wall biogenesis. Many changes in cell surface structures accompany thallus maturation. Septa, many traversed with plasmodesmata, are produced in most chytrid thallus types. As sporangia and resting spores prepare for the production and release of zoospores, additional extracellular layers of material are frequently produced. Polarized deposits of extracellular material become discharge plugs, discharge vesicles, or endoopercula. Interstitial material is also released into cleavage furrows. Circumscissile or localized digestion of walls produce operculate or inoperculate exit ports for zoospore release. Cryofixation preserves more extensive extracellular material than does conventional chemical fixation, and broader application of cryofixation may radically alter our current view of cell surface structure. Thus chytridiomycetes exhibit a range in patterns for the occurrence and subsequent modifications of extracellular materials, even for members within the same order. The most universally recognized role for these extracellular materials is protection. Although there is a reasonable view of the types of extracellular material involved in chytridiomycete development, we have only limited understandings of their biogenesis or roles in regulation and communication, areas awaiting more investigations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01666392
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  • 104
    Electronic Resource
    Electronic Resource
    Characterization of zoospore and cyst surface structure in saprophytic and fish pathogenicSaprolegnia species (oomycete fungal protists) (1994)
    Springer
    Protoplasma 181 (1994), S. 142-163 
    Details
    ISSN: 1615-6102
    Keywords: Saprolegnia ; Lectins ; Concanavalin A ; Wheat germ agglutinin ; Monoclonal antibodies ; Ultrastructure ; Pathogenesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The importance of the surface structure and chemistry in zoospores and cysts of oomycetes is briefly reviewed and the organelle systems associated with encystment described. The surface structure and chemistry of primary and secondary zoospores and cysts ofSaprolegnia diclina (a representative saprophytic species) andS. parasitica (a representative salmonid fish pathogen) were explored using the lectins concanavilin A (Con A) and wheat germ agglutinin (WGA) and monoclonal antibodies (MAbs) raised against a mixed zoospore and cyst suspension ofS. parasitica. The binding of lectins and antibodies to spores was determined using immunofluorescence microscopy with fluorescein isothiocyanate-labelled probes and with electron microscopy with gold-conjugated probes applied to spore suspensions post-fixation. In both species Con A, which is specific for glucose and mannose sugars, bound to both the surface of primary and secondary zoospores (the surface glycocalyx) and their cyst coats and readily induced zoospore encystment. The binding to the cysts appeared to be mainly associated with the matrix material released from the primary and secondary encystment vesicles and which appeared to diminish with time. No binding to germ tube walls was observed with this lectin. The MAb labelling showed a generally similar binding pattern to the primary and secondary cysts to that observed with Con A, although the binding to zoospores was more variable. Primary zoospores bound the antibodies but secondary zoospores appeared less reactive. It is suggested that the MAbs share a common epitope with one or more of the Con A-binding components. In both species WGA, which is specific for amongst other things the sugar N-acetyl glucosamine, bound to localised apical patches on the primary zoospores. This lectin also binds to the ventral groove region of secondary zoospores ofS. diclina, which were induced to encyst by this lectin. In contrast secondary zoospores ofS. parasitica were not induced to encyst by the addition of WGA and showed a patchy dorsal binding with this lectin. WGA also binds to both the inner wall of discharged primary cysts and the young germ tube walls of both species. These observations are discussed both in relation to other oomycete spores and to their possible functional and ecological significance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01666393
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  • 105
    Electronic Resource
    Electronic Resource
    Phase I and pharmacologie study of liposomal daunorubicin (DaunoXome) (1994)
    Springer
    Investigational new drugs 12 (1994), S. 103-110 
    Details
    ISSN: 1573-0646
    Keywords: daunorubicin ; liposomes ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have completed a phase I and pharmacology study of liposomally-encapsulated daunorubicin (DaunoXome). Of 32 patients entered, 30 were evaluable. No toxicity was encountered at the initial doseescalation steps from 10 to 60 mg/m2. At 80 mg/m2, two patients manifested grade 2 neutropenia. At least grade 3 neutropenia occurred in all patients receiving 120 mg/m2. Alopecia and subjective intolerance were mild. Cardiotoxicity was not observed except for an episode of arrhythmia in a patient with lung cancer and prior radiation. Only one minor objective response was observed in this population of refractory solid tumors. Pharmacokinetics differed from those of the free drug with no detection of daunorubicinol. We recommend future phase II studies with a dose of 100 mg/m2 in previously treated and 120 mg/m2 of DaunoXome in previously untreated patients with solid tumors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00874439
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  • 106
    Electronic Resource
    Electronic Resource
    Pyrazine diazohydroxide (NSC-361456) (1994)
    Springer
    Investigational new drugs 12 (1994), S. 207-216 
    Details
    ISSN: 1573-0646
    Keywords: pyrazine diazohydroxide ; phase I trial ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pyrazine diazohydroxide (NSC-361456) was identified as an active congener of pyridine 2-diazohydroxide with enhanced stability under physiologic conditions. In this phase I study, 35 patients with advanced cancer received 62 courses of PZDH administered intravenously every 3 weeks at doses ranging from 15–608 mg/m2. The dose-limiting toxicity was myelosuppression and the maximal tolerated dose was 487 mg/m2. Hematologie toxicity was delayed and prolonged with median time to recovery about 5 weeks. Mild gastrointestinal toxicity in the form of nausea and vomiting was fairly common. Ondansetron was effective in reducing nausea and vomiting at higher dose levels. Other less common reactions included stomatitis, diarrhea, fatigue, alopecia, and mild abnormalities of renal function and hepatic enzymes. PZDH pharmacokinetics were characterized in 16 patients who received doses of 100–608 mg/m2. Plasma elimination was fit to one (12/16) or two (4/16) compartment model with a mean k10 half-life of 11.5 min. Clearance was dose dependent. Hematologic toxicity was related to PZDH dose, AUC and peak plasma concentration. The sigmoidal relationships between hematologic toxicity and AUC or peak plasma concentration were well described by the Hill equation. There were no objective responses observed in this study. Based on this study, the recommended dose for phase II evaluation of PZDH using this schedule is 390 mg/m2.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00873961
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  • 107
    Electronic Resource
    Electronic Resource
    Clinical pharmacokinetics of nitrates (1994)
    Springer
    Cardiovascular drugs and therapy 8 (1994), S. 693-699 
    Details
    ISSN: 1573-7241
    Keywords: nitrates ; glyceryl trinitrate ; glyceryl dinitrates and mononitrates ; isosorbide dinitrate ; isosorbide 5-mononitrate ; pharmacokinetics ; plasma concentrations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The pharmacokinetics of organic nitrates are discussed with emphasis on the possible clinical relevance. For glyceryl trinitrate, the measurement of plasma concentrations is very difficult. Its pharmacokinetics are unusual, with a very rapid disappearance from plasma, and large intraindividual and interindividual variations. After oral administration, there seems to be a very extensive first-pass hepatic extraction and the plasma concentrations are often below the detection limit; after sublingual administration, glyceryl trinitrate appears in plasma. With transdermal glyceryl trinitrate controlled-release systems, plasma concentrations of glyceryl trinitrate can be maintained over 24 hours, although with fluctuations and important intraindividual and interindividual variability. After administration of glyceryl trinitrate via different routes, glyceryl dinitrates and mononitrates are present in plasma. The pharmacokinetics of isosorbide dinitrate are somewhat easier to understand. The substance disappears less rapidly from the plasma than does glyceryl trinitrate. After oral administration, there is also a hepatic first-pass extraction; the plasma concentrations can be prolonged by administering slow-release products. Sublingual administration leads to higher plasma concentrations than oral administration. Isosorbide dinitrate is metabolized in the organism to isosorbide 5-mononitrate and isosorbide 2-mononitrate, which both have vasodilator activity: after administration of isosorbide dinitrate, the mononitrates, and mainly the 5-mononitrate, reach very high concentrations in plasma. Isosorbide 5-mononitrate has been studied in its own right as an antianginal agent: it is completely absorbed after oral administration; it has a half-life of around 4 hours, and oral standard and controlled-release formulations have been extensively studied. For several reasons, including attenuation of the effects with time and the appearance of active metabolites, the relationship between the plasma concentrations of nitrates and their therapeutic effects is very complex. Knowledge of the pharmacokinetics of these substances is only of limited interest.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00877116
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  • 108
    Electronic Resource
    Electronic Resource
    Clinical experience with moxonidine (1994)
    Springer
    Cardiovascular drugs and therapy 8 (1994), S. 49-58 
    Details
    ISSN: 1573-7241
    Keywords: moxonidine ; hemodynamics ; pharmacokinetics ; comparative antihypertensive studies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Moxonidine is an imidazoline receptor modulator, specific for the I1-imidazoline receptor. The stimulation of imidazoline receptors represents a new mode of antihypertensive action to inhibit peripheral alpha-adrenergic tone by a central mechanism. Acute hemodynamic studies reveal moxonidine produces an acute fall of blood pressure and systemic vascular resistance. Heart rate, cardiac output, stroke volume, and pulmonary artery pressures are not affected. Left ventricular end-systolic and diastolic volumes are reduced. Ejection fraction is not significantly affected but 6-month studies showed a regression of left ventricular hypertrophy. After oral administration the maximum concentration of moxonidine is reached in about 1 hour, and elimination half-life is 2.5 hours, prolonged by renal insufficiency. The antihypertensive effect lasts longer than would be expected from the half-life. Open studies with moxonidine have revealed falls between 20 and 29 mmHg systolic, and between 10 and 19 mmHg diastolic blood pressure. In the largest study, over 12 months in 141 patients, most patients were controlled by 0.2mg daily (58%) or 0.2 mg b.i.d. (38%). Moxonidine has been compared with representatives from each important class of antihypertensive drugs. In a crossover trial of clonidine in 20 patients, blood pressure control was similar, but the incidence of tiredness and dry mouth was less on moxonidine, as was the total number of patients experiencing side effects, 85% versus 30% (p〈0.01). In a larger parallel group study of moxonidine (n=122) and clonidine (n=30), blood pressure control was similar, but the overall incidence of side effects was less on moxonidine. In comparative studies of moxonidine with atenolol, ACE inhibitors, dihydropyridine calcium antagonists, hydrochlorothiazide, and α1 blockade, the blood pressure control with representatives of these various classes of drugs was similar to moxonidine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00877084
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  • 109
    Electronic Resource
    Electronic Resource
    Neurotoxicity and pharmacokinetics of ventriculolumbar perfusion of methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-gluco-pyranoside (MCNU) in dogs (1994)
    Springer
    Journal of neuro-oncology 19 (1994), S. 239-244 
    Details
    ISSN: 1573-7373
    Keywords: meningeal gliomatosis ; methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-gluco-pyranoside ; ventriculolumbar perfusion ; toxicity ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Ventriculolumbar perfusion of methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside (MCNU), a water soluble nitrosourea with log P-0.71, may be efficacious in the treatment of subarachnoid dissemination of malignant glioma. We used 2 dogs to study the neurotoxicity and pharmacokinetics of MCNU. MCNU (1 mg), dissolved in 10 ml of artificial CSF, was administered via the right lateral ventricle during a period of 18 to 42 min and the CSF was drained by lumbar puncture. The perfusion was repeated once a week for 10 consecutive weeks. No neurological and systemic symptoms were noted after perfusion. Histological examination of the brain and spinal cord showed local denudation of the ependyma and local subependymal spongy degeneration and gliosis in the lateral ventricle into which MCNU was administered in one dog and local denudation of the ependyma in the other. When administration was over a period of 21 to 38 min, the MCNU concentration in the lumbar CSF peaked at 11.11 to 50.67 Μg/ml, in 28 to 78 min. The area under the drug concentration-time curve (AUC) was 1152 Μg×min/ml on average, significantly larger than that of ACNU. The elimination phase followed linear kinetics and the half-time was 41.1 min on average, significantly longer than that of ACNU. These findings suggest that ventriculolumbar perfusion of MCNU may be effective in the treatment of subarachnoid dissemination of malignant glioma notwithstanding some local histological changes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01053277
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  • 110
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of intrathecal 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride in rats (1994)
    Springer
    Journal of neuro-oncology 19 (1994), S. 245-250 
    Details
    ISSN: 1573-7373
    Keywords: intrathecal chemotherapy ; ACNU ; pharmacokinetics ; leptomeningeal tumor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The pharmacokinetics of intrathecal 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) were studied in female Wistar rats by macroscopical autoradiography using14C labeled ACNU. In normal rats, ACNU rapidly distributed in the subarachnoid space and ventricles after intracisternal administration. Diffusional transport into the brain tissue was limited to a depth of 1 or 2 mm from the cerebrospinal fluid (CSF) surface of the brain. Clearance of ACNU from the CSF space and brain was relatively fast and the half time of ACNU concentration at the cortical or ventricular surface was 10 min. In rats with leptomeningeal tumor induced by intracisternal inoculation of Walker 256 carcinosarcoma cells, the distribution pattern of ACNU after intracisternal administration was essentially the same as in normal rats until the tumor had grown in the subarachnoid space to form more than 10 or 20 layers of tumor cells. ACNU was distributed in the tumor as well. When the tumor had grown to form masses in the subarach-noid space, ACNU failed to penetrate to more than a depth of 1 or 2 mm from the tumor surface. Our results suggest that intrathecal ACNU administration may have no, or minor side effects on the brain and that it can eliminate floating or thin layered tumor cells in the subarachnoid space but not bulky tumors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01053278
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  • 111
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of bumetanide after intravenous and oral administration to rats: Absorption from various GI segments (1994)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 22 (1994), S. 1-17 
    Details
    ISSN: 1573-8744
    Keywords: bumetanide ; pharmacokinetics ; pharmacodynamics ; multiple peaks ; absorption from various GI segments
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Bumetanide, 2, 8, and 20 mg/kg, was administered both intravenously and orally to determine the pharmacokinetics and pharmacodynamics of bumetanide in rats (n=10–12). The absorption of bumetanide from various segments of GI tract and the reasons for the appearance of multiple peaks in plasma concentrations of bumetanide after oral administration were also investigated. After iv dose, the pharmacokinetic parameters of bumetanide, such ast 1/2 (21.4, 53.8 vs. 127 min),CL (35.8, 19.1 vs. 13.4 ml/min per kg),CL NR (35.2, 17.8 vs. 12.6 ml/min per kg) andV SS (392, 250 vs. 274 ml/kg) were dose-dependent at the dose range studied. It may be due to the saturable metabolism of bumetanide in rats. After iv dose, 8-hr urine output per 100g body weight increased significantly with increasing doses and it could be due to significantly increased amounts of bumetanide exreted in 8-hr urine with increasing doses. The total amount of sodium and chloride exreted in 8-hr urine per 100g body weight also increased significantly after iv dose of 8 mg/kg, however, the corresponding values for potassium were dose-independent. After oral administration, the percentages of the dose excreted in 24-hr urine as unchanged bumetanide were dose-independent. Bumetanide was absorbed from all regions of GI tract studied and approximately 43.7, 50.0, and 38.4% of the orally administered dose were absorbed between 1 and 24 hr after oral doses of 2, 8, and 20 mg/kg, respectively. Therefore, the appearance of multiple peaks after oral administration could be mainly due to the gastric emptying patterns. The percentages of bumetanide absorbed from GI tract as unchanged bumetanide for up to 24 hr after oral doses of 2, 8, and 20 mg/kg (96.2, 95.4 vs. 98.2%) were not significantly different, suggesting that the problem of precipitation of bumetanide in acidic gastric juices or dissolution may not contribute significantly to the absorption of bumetanide after oral administration. Urine output per 100g body wt increased at oral doses of 8 and 20 mg/kg.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02353407
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  • 112
    Electronic Resource
    Electronic Resource
    Identifiability and indistinguishability of nonlinear pharmacokinetic models (1994)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 22 (1994), S. 229-251 
    Details
    ISSN: 1573-8744
    Keywords: compartmental models ; identification ; indistinguishability ; Michaelis-Menten kinetics ; model discrimination ; nonlinear systems ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Three nonlinear model structures of interest in pharmacokinetics are analyzed to determine whether the unknown, independent, model parameters can be deduced if perfect input-output data were available. This is the problem of identifiability. The method used is based on the local state isomorphism theorem. In certain circumstances, the modeler may be undecided between several model structures and it is then of interest to determine whether different model structures can be distinguished from perfect input-output data. This is the problem of model indistinguishability. The technique used, again based on the local state isomorphism theorem, parallels the similarity transformation approach for linear systems described previously in this journal. The analysis is performed on three two-compartment examples having one linear and one nonlinear (Michaelis-Menten) elimination pathway. In each model there is, on physiological and other grounds, some uncertainty over the precise location (central compartment or peripheral compartment) of one of the elimination pathways.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02353330
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  • 113
    Electronic Resource
    Electronic Resource
    Comparative pharmacokinetics of fenbendazole in buffalo and cattle (1994)
    Springer
    Veterinary research communications 18 (1994), S. 209-216 
    Details
    ISSN: 1573-7446
    Keywords: absorption ; availability ; benzimidazole ; buffalo ; cattle ; fenbendazole ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Swamp buffalo (Bubalus bubalis) and Droughtmaster cattle (Bos indicus × B. taurus), fitted with gastrointestinal cannulae, were dosed intraruminally with fenbendazole at 7.5 mg/kg liveweight, together with a chromium oxide capsule and a pulse dose of NaCoEDTA, to estimate the flow dynamics of the digesta in the rumen and duodenum. The concentrations of fenbendazole (FBZ) metabolites were measured in plasma and duodenal fluid collected over 120 h. In plasma, significantly lower peak concentrations and earlier disappearance of FBZ and its sulphoxide (OFZ) metabolite were observed in buffalo, which considerably reduced systemic availability in comparison with cattle. The availability of OFZ in the duodenal fluid of buffalo was significantly lower, whereas FBZ disposition was similar to that in cattle. The turnover rate of fluid in the rumen was higher in buffalo than in cattle, while the flow parameters for other digesta were similar in the two species. It is concluded that the decreased absorption of drug in buffalo was attributable to the shorter residence time of the dose in the rumen, and probably in the entire gastrointestinal tract. This may reduce the efficacy of treatment and indicate the need for higher dose rates for benzimidazole anthelmintics in buffalo than in cattle.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01839270
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  • 114
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and dosage regimen of cefotaxime in cross-bred calves following single intramuscular administration (1994)
    Springer
    Veterinary research communications 18 (1994), S. 313-318 
    Details
    ISSN: 1573-7446
    Keywords: calves ; cefotaxime ; cephalosporin ; dose ; intramuscular ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The pharmacokinetics, penetration into erythrocytes and plasma protein binding of cefotaxime were investigated in cross-bred calves. Following a single intramuscular dose of cefotaxime (10 mg/kg), the absorption half-life and elimination half-life were 0.13±0.03 h and 2.97±0.72 h, respectively. The apparent volume of distribution and total body clearance were 3.28±0.72 L/kg and 0.78±0.08 L/kg per h, respectively. The extent of penetration into erythrocytes was 24–40% of the total blood concentration. Cefotaxime was bound to plasma proteins of calves to the extent of 25.5–33.6%. A satisfactory intramuscular dosage regimen for cefotaxime in calves would be 11 mg/kg followed by 10 mg/kg at 7 h intervals.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01839199
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  • 115
    Electronic Resource
    Electronic Resource
    Caffeine clearance in the horse (1994)
    Springer
    Veterinary research communications 18 (1994), S. 367-372 
    Details
    ISSN: 1573-7446
    Keywords: caffeine ; horse ; liver function ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The pharmacokinetic properties of intravenously administered caffeine were studied in 10 horses using a commercially available automated enzyme immunoassay. The harmonic mean for the distribution half-life was 5.2 min (range 1.4–18.7). The harmonic mean for the elimination half-life was 10.18 h (range 6.82–20.92). The harmonic mean of the volume of distribution was 0.32 L/kg (range 0.22–0.53). There was no correlation between the dose of caffeine/kg body weight and the elimination half-life (Spearman's coefficient of rank correlation =0.19).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01839287
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    Interaction of Zidovudine (Azidothymidine) with Isoprinosine and Probenecid in Macaca fascicularis (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 181-183 
    Details
    ISSN: 1573-904X
    Keywords: zidovudine ; azidothymidine ; isoprinosine ; inosine pranobex ; probenecid ; pharmacokinetics ; drug interactions ; macaque
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018982703049
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  • 117
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    Relationship Between Enoxacin and Ciprofloxacin Plasma Concentrations and Theophylline Disposition (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 1424-1428 
    Details
    ISSN: 1573-904X
    Keywords: enoxacin ; ciprofloxacin ; theophylline ; pharmacokinetics ; drug-drug interactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Certain fluoroquinolone antibiotics affect theophylline (THEO) disposition by inhibition of its metabolism, yet no studies to date have investigated the relationship between fluoroquinolone plasma concentration and THEO pharmacokinetics. The effects of two fluoroquinolones, enoxacin (ENOX) and ciprofloxacin (CIPRO), have been studied in male Sprague-Dawley rats (n = 33–46) at steady state plasma concentrations of 0–33 mg · 1−1, achieved by supplementing an intravenous bolus dose with a constant rate infusion. The effects of steady state ENOX and CIPRO plasma concentrations on the clearance of THEO determined after an intravenous bolus dose of 6 mg · kg−1 were described using a competitive inhibition model. The model consisted of two components, one describing a residual component of THEO clearance, which was unaffected by fluoroquinolone, the other describing the non-linear reduction of THEO clearance by fluoroquinolone. The residual clearance estimated from the model was comparable to renal clearance for THEO in the rat. The potency of each fluoroquinolone was characterised by a Ki value, the concentration reducing THEO clearance by 50% of the maximum change. These values were 4.7 µM and 16.3 µM for ENOX and CIPRO, respectively. Thus, in this study, ENOX was found to be a more potent inhibitor of THEO clearance than CIPRO. The method allowed direct in vivo comparison of potency between different fluoroquinolones, as pharmacokinetic differences, such as clearance, volume of distribution and bioavailability, were ‘designed out.’
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018991822440
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  • 118
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    Pharmacokinetics and Tissue Distribution of Recombinant Human Transforming Growth Factor Beta1 After Topical and Intravenous Administration in Male Rats (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 213-220 
    Details
    ISSN: 1573-904X
    Keywords: recombinant human transforming growth factor beta1 ; wound-healing ; pharmacokinetics ; plasma-based enzyme-linked immunosorbent assay (ELISA) ; tissue distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Recombinant human transforming growth factor beta (rhTGF-β1) enhances the healing process after topical application to various animal wound models. A detailed pharmacokinetic and tissue distribution study was performed to support the clinical development of rhTGF-β1 for wound healing indications. Rats received radioiodinated or unlabeled rhTGF-β1 as an intravenous (iv) bolus or as a topical formulation applied to a full thickness wound. Plasma concentrations of TGF-β1 were estimated from TCA-precipitable radioactivity or were measured by ELISA. Following iv administration, the initial half-life was rapid (〈11 min), regardless of whether radi-olabeled or unlabeled rhTGF-β1 was used. The terminal half-life was long (163 min) when the test material was radioiodinated and administered as a trace dose and relatively short (≤61 min) when given at high doses and assayed by ELISA. Analysis of plasma radioactivity by SDS-PAGE revealed a time-dependent clearance of the 25-kDa parent molecule without a significant appearance of lower molecular weight radiolabeled metabolites. The majority of the radioactivity was associated with highly perfused organs, known iodide elimination pathways, and the thyroid at 1 and 8 hr after iv injection. After topical administration of a high dose (0.8 mg/kg), no immunoreactive TGF-β1 was detectable in plasma samples taken over a 48-hr period. However, trace amounts (≤0.05 ng/mL) of acid-precipitable radioactivity were detected in plasma after topical application of [125I]rhTGF-β1 (1 µg/kg, 126 µCi/kg). A significant portion (35%) of the [125I]rhTGF-β1 persisted intact (25 kDa) at the wound site 24 hr after application. In conclusion, rhTGF-β1 was rapidly cleared after iv bolus administration and distributed primarily to the liver, lungs, kidney, and spleen. Little systemic exposure was observed after applying a single topical dose of rhTGF-β1 to a wound, and the intact molecule persisted at the wound site.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018995005775
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  • 119
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    Improved Dose Linearity of Cyclosporine Pharmacokinetics from a Microemulsion Formulation (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 301-304 
    Details
    ISSN: 1573-904X
    Keywords: cyclosporine ; dose proportionality ; pharmacokinetics ; formulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetic dose proportionality and relative bioavailability of cyclosporine from a microemulsion formulation (Sandimmune Neoral) were compared to those of the commercial formulation (Sandimmune) over the dosage range 200 to 800 mg. Single oral administrations were given as soft gelatin capsules in an open randomized study with 48 healthy volunteers. Whole-blood cyclosporine concentrations were determined by a specific monoclonal radio-immunoassay. In comparison to Sandimmune, the absorption rate (maximum concentration) and systemic availability (area under the curve) of cyclosporine were greater for Sandimmune Neoral at all dose levels investigated. The area under the curve for Sandimmune increased in a less than proportional manner with respect to dose, whereas that for Sandimmune Neoral was consistent with linear pharmacokinetics. Because of this difference, no global assessment of relative bioavailability could be performed. The relative bioavailability of cyclosporine from Sandimmune Neoral ranged from 174 to 239% compared to Sandimmune, depending on the dose level. The improvements in oral bioavailability and dose linearity of cyclosporine exposure after administration as Sandimmune Neoral should facilitate more accurate dosage titration in the clinical setting.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018923912135
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  • 120
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    Pharmacokinetics of Levodopa and Carbidopa in Rats Following Different Routes of Administration (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 549-555 
    Details
    ISSN: 1573-904X
    Keywords: levodopa ; carbidopa ; rat ; pharmacokinetics ; absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract This study examined the pharmacokinetics of levodopa and carbidopa in the rat after different modes of administration. The drugs were given simultaneously by the intravenous, intraarterial, oral, duodenal, and intraperitoneal routes, as single doses. The ratio of levodopa to carbidopa given was always 4:1. Two iv doses (5 and 15 mg/kg of levodopa) were given to test for nonlinearity. Three ip doses of levodopa were given (5, 7.5, and 15 mg/kg), and the 15 mg/kg dose was given in three volumes (2, 4, and 20 mL/kg). One oral dose and two intraduodenal doses of 15 mg/kg were given. The drugs were dissolved in saline in one of the intraduodenal doses and suspended in 1.8% methylcellulose in the other. The elimination of levodopa was nonlinear. There was a comparatively high degree of interindividual variability in absorption with the oral route, but this was substantially reduced when levodopa was given intraduodenally. There was also much less variability with the intraperitoneal route compared to the oral, and the degree of absorption was generally high. There was a significantly higher extent and slower rate of absorption when levodopa was administered ip in a large volume of vehicle. These results suggest that the oral route may not be the optimal method of delivering levodopa to patients who have a fluctuating response and that a continuous delivery system via the intraperitoneal or intraduodenal routes might be a better alternative.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018970617104
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  • 121
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    Brain Delivery of Biotin Bound to a Conjugate of Neutral Avidin and Cationized Human Albumin (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 1257-1264 
    Details
    ISSN: 1573-904X
    Keywords: blood-brain barrier ; pharmacokinetics ; drug delivery ; avidin ; biotin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The delivery of pharmaceuticals through the brain capillary endothelial wall, which makes up the blood-brain barrier (BBB) in vivo, may be facilitated by conjugation of therapeutics to brain drug delivery vectors. Since cationized albumin has been shown to undergo absorptive-mediated transcytosis through the BBB in vivo, cationized human serum albumin (cHSA) is a potential brain drug delivery vector in humans. Conjugation of biotinylated therapeutics to brain drug delivery vectors is facilitated by the preparation of vector/ avidin conjugates. Therefore, the present studies describe the preparation of a cHSA-avidin conjugate and the delivery of 3H-biotin bound to this conjugate through the BBB in vivo in anesthetized rats. Since the cationic nature of avidin (AV) accelerates the removal of avidin-based conjugates from blood in vivo, the present studies also describe the preparation and the pharmacokinetics of 3H-biotin bound to a conjugate of cHSA and neutral avidin (NLA). The bifunctional nature of the conjugate was retained: the cHSA/ NLA conjugate contained 2.8 to 6.8 biotin binding sites per conjugate, and the BBB permeability-surface area (PS) product for 3H-biotin bound to cHSA/NLA was at least 7-fold greater than the BBB PS product for 3H-biotin bound to a conjugate of NLA and native HSA (nHSA). The systemic clearance of the cHSA conjugate was reduced 10-fold by the use of NLA as opposed to AV. The increased area under the plasma concentration curve (AUC) of the cHSA-NLA conjugate correlated with an increase in brain delivery of 3H-biotin as compared to the brain delivery achieved with the cHSA/AV conjugate. In conclusion, these studies demonstrate that cHSA serves as a brain drug delivery vector and that the use of neutral forms of avidin increases the plasma AUC of the conjugate and enhances the brain delivery of biotin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018982125649
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  • 122
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    Influence of a Fat-Rich Meal on the Pharmacokinetics of a New Oral Formulation of Cyclosporine in a Crossover Comparison with the Market Formulation (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 151-155 
    Details
    ISSN: 1573-904X
    Keywords: cyclosporine ; food effect ; pharmacokinetics ; formulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The influence of a fat-rich meal on the pharmacokinetics of cyclosporine from a new oral formulation (Sandimmune Neoral) was compared in a randomized, four-way crossover study to the currently marketed formulation (Sandimmune) in 24 healthy male volunteers. Single oral doses of 300 mg Sandimmune and 180 mg Sandimmune Neoral were each administered once under fasting conditions and once 30 min after starting a high-fat meal. Serial blood samples were obtained over a 48-hr period after each administration, and whole-blood cyclosporine concentrations were determined by a specific monoclonal radioimmunoassay method. Food had a marked effect on cyclosporine absorption from Sandimmune manifested by a nearly doubled time to reach the peak concentration and a 37% increase in the area under the curve. This was associated with significant elevations in subsequent whole-blood cyclosporine concentrations compared to the fasting administration. For Sandimmune Neoral the influence was less pronounced. The maximum concentration was decreased by 26%, without a relevant change in the time to reach the peak; the area under the curve showed a slight reduction of 15%. The relatively minor influence of a fat-rich meal on the absorption of cyclosporine from Sandimmune Neoral is advantageous when individualizing a dosage regimen under clinical and out-patient administration conditions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018922517162
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  • 123
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    Pharmacokinetics of Intranasally-Administered Dihydroergotamine in the Rat (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 1530-1534 
    Details
    ISSN: 1573-904X
    Keywords: dihydroergotamine ; ergot alkaloids ; intranasal delivery ; pharmacokinetics ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Intranasal dosing of dihydroergotamine (DHE) allows convenient self-administration and provides an alternate route of administration for the treatment of migraine in addition to the existing parenteral dosage forms. In this study, the pharmacokinetics of 3H-DHE were investigated following intravenous and intranasal dosing (0.343 mg DHE/animal) in the rat. Intranasal administration of DHE resulted in rapid absorption. The extent of absorption of the radiolabeled dose was approximately 45%–60%. Absolute bioavailability of the parent drug was 35%–40%, as determined by deconvolution and by the ratios of AUC0−∞ following intranasal and intravenous dosing. Due to the limited capacity of the nostrils, approximately half of the intranasal dose was swallowed into the gastrointestinal tract. Biliary excretion was found to be the predominant pathway of radioactivity excretion following both routes of administration. The results from this study suggest that intranasal administration provides a viable means of delivering DHE into the systemic circulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018937132434
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  • 124
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    Effects of Acute and Chronic Inflammation on the Pharmacokinetics of Prednisolone in Rats (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 541-544 
    Details
    ISSN: 1573-904X
    Keywords: prednisolone ; pharmacokinetics ; inflammation ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The effects of acute and chronic stages of carrageenan-induced air-pouch inflammation on the pharmacokinetics of prednisolone were studied in male Wistar rats. Chronic inflammation produced a significant increase in the area under the curve (AUC) of prednisolone compared to control animals (6594 ± 2144 vs 3530 ± 2164 µg · hr/ L). The effect of acute inflammation was not significant (AUC = 4996 ± 3813). Both acute and chronic inflammation also reduced the⋅in vitro plasma protein binding of prednisolone, the reduction being much greater after chronic inflammation. The AUC of free prednisolone after chronic inflammation was 3141 µg · hr/L, compared to 1121 µg · hr/L in the control group and 1823 µg · hr/L after acute inflammation. The mean values of half-life and apparent volume of distribution at steady-state in each group were similar. These results indicate that prednisolone must be used with caution in the treatment of inflammatory diseases because of higher free concentrations of the steroid.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018966516195
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  • 125
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    Pharmacokinetics and Metabolism of Diclofenac Sodium in Yucatan Miniature Pigs (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 698-703 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; metabolism ; diclofenac ; minipigs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pig has been suggested as an animal model in biomedical research because of its physiological similarity to man. Therefore, the pharmacokinetics and metabolism of diclofenac sodium (Voltaren) were studied in four Yucatan minipigs after intravenous administration of 25 and 50 mg and oral administration of 50 mg in a solution of 50 mL buffer, 50 mL water, and 200 mL water, and the results compared to historical data in man. The absolute bioavailability after oral administration of 50 mL buffer, 50 mL water, and 200 mL water solutions were 107, 97, and 109%, respectively, compared to approximately 50% in man. The total plasma clearance in minipigs was fivefold slower than in humans (57 ± 17 vs 252 ± 54 mL/hr/kg). The plasma levels of the metabolites 4′-hydroxy, 5-hydroxy, 3′-hydroxy, 4′,5-dihydroxy, and 3′-hydroxy-4′-methoxy diclofenac were considerably lower in minipigs than in man after both iv and oral administration. These results suggest slower metabolism and/or enterohepatic recirculation of the parent drug in minipigs. The volume of distribution of the central compartment was 40% less in humans than in pigs (39 vs 67 mL/kg). The terminal half-lives of the parent drug were similar in pigs (2.4 hr) and humans (1.8 hr). The rate of oral drug absorption increased in the order of 50 mL aqueous, 200 mL aqueous, and 50 mL buffered solutions (K a = 0.52±0.11, 0.59±0.13, and 1.2±0.7 hr−1, respectively). These trends are similar in man and suggest that both buffering and intake volume can affect diclofenac absorption. Possible reasons for these results include the pH-dependent solubility of this drug and the effect of volume on gastric emptying.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018976212986
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  • 126
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    Phenobarbital Disposition in Adult and Neonatal Rabbits (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 1204-1206 
    Details
    ISSN: 1573-904X
    Keywords: phenobarbital ; pharmacokinetics ; milk ; rabbit ; neonate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018957420197
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  • 127
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    Pharmacokinetics of Two Enteric-Coated Ketoprofen Products in Humans with or Without Coadministration of Omeprazole and Comparison with Dissolution Findings (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 1669-1672 
    Details
    ISSN: 1573-904X
    Keywords: ketoprofen ; pharmacokinetics ; interaction ; ketoprofen-omeprazole ; dissolution ; humans
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018934526499
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  • 128
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    Pharmacokinetics of bupivacaine enantiomers in sheep: Influence of dosage regimen and study design (1994)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 22 (1994), S. 481-498 
    Details
    ISSN: 1573-8744
    Keywords: anesthetics local ; bupivacaine ; pharmacokinetics ; enantiomers ; administration rate ; dosage regimen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Bupivacaine is used as a racemate. In previous studies the mean total body clearance ofR(+)-bupivacaine was found to be greater thanS(−)-bupivacaine by 65% after iv bolus dose of separate enantiomers and by 20% after iv infusion to steady state of racemate. The present studies were performed to determine whether different study designs using different iv dosage regimens could influence the pharmacokinetic parameters determined for either bupivacaine enantiomer. rac-Bupivacaine·HCl was administered iv to 6 adult Merino ewes by bolus, brief infusion, and prolonged infusion. Arterial blood concentrations ofR(+)- andS(−)-bupivacaine were measured by enantioselective HPLC. These regimens consistently produced lower arterial blood concentrations ofR(+)-bupivacaine thanS(−)-bupivacaine due toR(+)-bupivacaine having a greater initial dilution volume by 16 (95%CI=3–29)%, volume of distribution at steady state equilibrium by 32 (95%CI=17–32)% and mean total body clearance by 28 (95%CI=21–35)%. The slow half-life ofR(+)-bupivacaine, however, was found to be 15 (95%CI=0–31)% longer than that ofS(−)-bupivacaine. The difference between enantiomers in mean total body clearance thus was similar to the previous study based upon infusion to steady state of rac-bupivacaine. Differences in pharmacokinetics attributable to the dosage regimen consisted of a greater mean total body clearance forR(+)-bupivacaine along with a smaller terminal half life with the bolus regimen and a longer half-life ofS(−)-bupivacaine after prolonged infusion. Differences in pharmacokinetics between the bupivacaine enantiomers occurred consistently in both distribution and clearance but the magnitude of the effect was less than 50% in each case. Systematic differences in pharmacokinetics associated with the dosage regimen were found mainly in terminal half-life. Dosage regimen, thus, was found to influence the pharmacokinetic results found experimentally and is therefore a significant variable in its own right.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02353791
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    Comparison of some control strategies for three-compartment PK/PD models (1994)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 22 (1994), S. 525-550 
    Details
    ISSN: 1573-8744
    Keywords: Bayesian ; compartment model ; dose regimen design ; pharmacokinetics ; pharmacodynamics ; stochastic control ; effect site
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In drug therapy, effective dosage strategies are needed to maintain target drug effects. The relationship between drug dose and drug effect is often described by pharmacokinetic/pharmacodynamic (PK/PD) models where typically the PK model has a multicompartment form and the PD model is the sigmoidal Emax model. The parameters in the PK/PD model are generally unknown in the individual patient, although prior knowledge may be available and can be updated after measurements of drug effect are taken during the therapy. This fact, together with the complexity of the PK/PD model, makes the control problem complex. This paper investigates several control strategies in the framework of a three-compartment PK model plus an effect site with a PD model. Using computer simulations under different assumptions, we show that a MAP (maximum a posteriori) Bayesian type of strategy is effective, nevertheless in high-risk situations a stochastic control strategy hedging against estimation errors provides better performance at computational cost.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02353793
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  • 130
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    An analysis of errors arising from the direct use of mass balance principles to describe regional drug uptake and elution (1994)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 22 (1994), S. 309-321 
    Details
    ISSN: 1573-8744
    Keywords: mass balance principles ; error ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Errors occurring during the direct application of mass balance principles to describe the uptake and elution of a drug in an organ during and after a constant rate infusion were analyzed. The uptake of lignocaine in the hindquarters of sheep was used as an example—the net mass of lignocaine was calculated from the arterial and inferior vena cava blood lignocaine concentrations and hindquarter blood flow using an integrated form of the Fick equation. The general strategy was to generate a continuous time course of arterial and inferior vena cava drug concentrations that closely resembled the data obtained fromin vivo experiments (the “true” blood concentrations). These were used to calculate the time course of the “true” net mass of lignocaine in the hindquarters by numerical integration with a small step size. The true blood concentrations were then used to generate data sets that simulated different blood sample intervals and random, normally distributed errors added to the blood concentration and blood flow measurements. Simulated data sets were also used to compare different numerical integration methods. There were significant absolute errors in the calculated net mass in the period after the start and end of the constant rate infusion due to numerical integration, but the error resulting from the latter to some extent canceled the error from the former. These errors did not greatly change the time course of the calculated net mass. Decreasing the interval between regular blood samples from 30 to 10 min reduced this absolute error, but greater reductions in error were achieved by optimizing the time interval between blood samples to give an approximate constant error due to numerical integration. There was no advantage in using numerical integration methods other than the linear trapezoidal method. Random noise added to the blood concentration and blood flow terms of the net mass equation added a small bias to the mean value of the calculated net mass. More important, such noise rapidly increased the number of studies required to characterize the calculated mean net mass to a given level of accuracy. It is concluded best results are obtained by minimizing the variability of blood concentration and blood flow measurements, and by using an optimized blood sampling regimen. The direct mass balance calculations and an analysis of their errors are simple enough to be performed using a spreadsheet program on a personal computer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02353624
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    An efficient control strategy for dosage regimens (1994)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 22 (1994), S. 73-94 
    Details
    ISSN: 1573-8744
    Keywords: Bayesian ; compartment model ; discrete prior ; dose regimen design ; pharmacokinetics ; stochastic control
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In medical drug therapy, efficient dosage strategies are needed to maintain target drug concentrations. The relationship between the concentration of a drug and the dosages is often described by compartment models in which the parameters are unknown, although prior knowledge may be available and can be updated after blood samples are taken during the therapy. Currently MAP (maximum a posteriori) Bayesian is the most often used control strategy in this setting. We show by simulation in a one-compartment context that the performance of the MAP Bayesian strategy depends on the assumptions in prior distribution of the parameters as well as the cost function. We propose an alternative control strategy, VU, that outperforms and is more robust than the MAP Bayesian strategy in a variety of problem settings.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02353411
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  • 132
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    Pharmacokinetics of rec-hirudin in healthy volunteers after intravenous administration (1994)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 22 (1994), S. 147-156 
    Details
    ISSN: 1573-8744
    Keywords: rec-hirudin ; pharmacokinetics ; ELISA ; intravenous administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of recombinant hirudin (rec-hirudin, Ciba-Geigy, CGP 39 393) in healthy volunteers after iv administration was investigated on the basis of the data from five different studies. A total of 77 plasma profiles following a single iv bolus dose of either 0.1, 0.3, 0.5, or 1 mg/kg of rec-hirudin was used for the evaulation. Plasma concentrations and especially AUC were proportional to the dose. Kinetics of rec-hirudin after a bolus iv injection were best described by a three-compartment open model. Mean apparent terminal half-life was 2.8 hr and the total clearance 0.138 L/hr per kg.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02353540
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    Pulmonary Delivery of Detirelix by Intratracheal Instillation and Aerosol Inhalation in the Briefly Anesthetized Dog (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 1048-1055 
    Details
    ISSN: 1573-904X
    Keywords: pharmaceutical aerosols ; detirelix ; LHRH antagonist ; peptide delivery ; pulmonary administration ; pharmacokinetics ; jet nebulizer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Pulmonary delivery of the decapeptide detirelix was studied in briefly anesthetized dogs and the pharmacokinetics were examined following intravenous administration, intratracheal instillation, and aerosol inhalation. Detirelix administrations to the lung gave plasma profiles that were extended over two days, and that differed markedly from those of similarly sized peptides. Absorption from the lung after instillation was slow (Tmax= 6.5 ± 3.6 h) with a relative bioavailability of 29 ± 10%. Administration of detirelix-containing aerosols resulted in similar plasma profiles as for administration by instillation. Compartmental and non-compartmental methods of pharmacokinetic analysis indicated no faster absorption from aerosols than from instilled solutions; an absorption rate limiting process may be an explanation. Plasma profiles were not affected by the use of detirelix liquid crystal favoring formulations or destabilizing formulations, and suggested that in situ liquid crystal formation was not an explanation for the slow absorption. No significant changes in pharmacokinetics or systemic uptake were observed during the five-month period of repeated pulmonary administrations. Histopathologic examination revealed the lungs to be essentially normal.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018999707476
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    Estimation of Skin Target Site Acyclovir Concentrations Following Controlled (Trans)dermal Drug Delivery in Topical and Systemic Treatment of Cutaneous HSV-1 Infections in Hairless Mice (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 1035-1041 
    Details
    ISSN: 1573-904X
    Keywords: transdermal delivery ; pharmacokinetics ; skin target site ; Herpes Simplex Virus-1 ; antiviral efficacy ; animal model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The use of controlled transdermal delivery of acyclovir (AC V) in the treatment of cutaneous herpes simplex virus type 1 infections in hairless mice was investigated. Using an in vivoanimal model (A. Gonsho, et al. Int. J. Pharm. 65:183–194 (1990)) made it possible to quantify both, the topical and the systemic antiviral efficacy of ACV transdermal patches as a function of the drug delivery rate of the patches. Drug delivery rates required to attain systemic efficacy were found to be higher than the rates required to attain the same magnitude of topical efficacy. The ACV concentrations in the basal cell layer of the epidermis for 50% topical efficacy and 50% systemic efficacy were estimated. The basal epidermis layer was considered to be the site of antiviral drug activity (skin target site). Systemic plasma levels were obtained from pharmacokinetic studies and were used to estimate the ACV concentration achieved systemically in the basal epidermis layer. A computational model for drug permeation across skin was employed to estimate the ACV concentration achieved topically in the basal epidermis layer. Equal topical and systemic efficacies were found to correspond to equal drug concentrations at the site of antiviral activity. The length of the effective diffusion pathway of drug molecules in the dermis prior to entering the blood circulation was assumed to be approximately equal to 1/20 of the anatomical dermis thickness because of dermis vascularization.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018995606568
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  • 135
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    Pulmonary Delivery of Powders and Solutions Containing Recombinant Human Granulocyte Colony-Stimulating Factor (rhG-CSF) to the Rabbit (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 1101-1109 
    Details
    ISSN: 1573-904X
    Keywords: rhG-CSF ; intratracheal instillation ; lung ; pharmacokinetics ; pharmacodynamics ; pulmonary absorption ; Tc-99m
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Two powder formulations (MMAD 〈4 µm) containing rhG-CSF were insufflated (IF) via an endotracheal tube at doses of 5, 75 or 500 µg/kg to New Zealand white rabbits. Doses of 5 and 500 µg/kg of solutions were administered by intratracheal instillation (IT), subcutaneous (SC) injection in the thigh and intravenous injection (IV) via the marginal ear vein. Blood samples were removed at regular intervals from an indwelling jugular catheter. Blood was analyzed directly for total white blood cell counts (WBC). Plasma was assayed for rhG-CSF by a specific ELISA. The distribution of radioactive dose in lung tissue was found after administering Tc99m HSA in solution or when incorporated into powders. The pharmacokinetics and pharmacodynamics were determined for all routes of administration. High dose IV concentration vs. time profiles declined biexponentially (t1/2 α = 0.6 ± 0.2 hrs, t1/2 β = 4.6 ± 0.2 hrs, n = 8). Clearance was dose dependent (11.6 ± 2.6 [500 µg/kg, n = 8] vs. 21.8 ± 3.3 ml/hr/kg [5 µg/kg, n = 5]). A normal systemic response was obtained after IF, indicating that rhG-CSF retains activity in the solid state. Dissolution and absorption of rhG-CSF from the powders were not rate limiting. The plasma concentration vs. time profiles peaked at similar times to those after IT (Tmax 1 -2 hrs) but were earlier than obtained after SC (Tmax 6-10 hrs). Powders were less efficiently dosed to the lung lobes after insufflation compared with instillates (14.7 ± 10.5 vs. 60.1 ± 10.6%), resulting in bioavailabilities ranging from 5 to 33%. Bioavailability after SC was 11.0 ± 7.0% and 95.3 ± 7.9% (n = 6) for the low and high doses, respectively.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018924512928
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  • 136
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    Observations on the flagellar apparatus of a coccolithophorid,Cruciplacolithus neohelis (Prymnesiophyceae) (1994)
    Springer
    Journal of plant research 107 (1994), S. 53-62 
    Details
    ISSN: 1618-0860
    Keywords: Coccolithophorid ; Cruciplacolithus neohelis ; Flagellar apparatus ; Haptophyceae ; Prymnesiophyceae ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The flagellar apparatus ofCruciplacolithus neohelis (McIntyre and Bé) Reinhardt including its transition region is described. The transition region contains a hat-shaped structure, which is suggested to be one of the common features of the Prymnesiophyceae. Its flagellar root system resembles that of most coccolithophorids examined so far, except that only one vestigial crystalline root is present associated with root 1. Two well-developed crystalline roots associated with roots 1 and 2, respectively, appear in the preprophase of nuclear division, suggesting conversion to a mitotic spindle. The taxonomic and evolutionary significance of the flagellar apparatus is discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02344530
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  • 137
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    Electronic Resource
    Vorozole, a specific non-steroidal aromatase inhibitor (1994)
    Springer
    Breast cancer research and treatment 30 (1994), S. 89-94 
    Details
    ISSN: 1573-7217
    Keywords: aromatase inhibitor ; pharmacology ; pharmacokinetics ; vorozole
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Vorozole, the (+)-(S)-isomer of a new triazole compound, is a potent and selective aromatase inhibitor.In vitro, the compound is over a thousandfold more active than aminoglutethimide.In vivo, the compound very potently inhibits ovarian, peripheral, and tumoral aromatase. Vorozole shows anin vitro selectivity margin of 10,000-fold for aromatase inhibition as compared to inhibition of other P450- and non-P450-dependent reactions. This selectivity was confirmed in the ratin vivo. Vorozole, like ovariectomy, almost completely reduces tumor growth in the DMBA-induced mammary carcinoma model in the rat. In postmenopausal women, vorozole very potently inhibits peripheral conversion of androstenedione to estrone. After chronic administration, plasma estradiol levels are reduced while the levels of adrenal gluco- and mineralo-corticoids remain unchanged. Vorozole has excellent oral bioavailability and exerts linear, dose-proportional pharmacokinetics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00682743
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  • 138
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    Arimidex®: A potent and selective fourth-generation aromatase inhibitor (1994)
    Springer
    Breast cancer research and treatment 30 (1994), S. 103-111 
    Details
    ISSN: 1573-7217
    Keywords: Arimidex ; ICI D1033 ; ZD1033 ; aromatase inhibitor ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Arimidex® is a potent and selective aromatase inhibitor undergoing evaluation as a treatment for postmenopausal women with advanced breast cancer. Studies to determine the pharmacology of Arimidex were conducted in both animals and humans. In animals, Arimidex was selective for the aromatase enzyme, elicited maximal activity at about 0.1 mg/kg, did not interfere with steroid hormones produced by the adrenal glands, and, at a dose of 1 mg/kg, had no detectable pharmacologic activity other than aromatase inhibition. Absorption of ZD1033, the active component of Arimidex, was rapid and virtually complete after oral administration to animals. ZD1033 was extensively metabolized in animals after oral administration; the metabolites were excreted predominantly in urine. The pharmacodynamic, pharmacokinetic, and safety profiles of single and multiple daily doses of Arimidex were determined in humans. Doses of 1 to 10 mg of Arimidex suppressed estradiol to the maximum degree measurable. Arimidex had no clinically significant effects on key enzymes that regulate cortisol and aldosterone biosynthesis. Absorption of ZD1033 was rapid, with maximum plasma concentrations occurring within 2 hours after oral administration. Plasma concentrations of ZD1033 rose with increasing doses of Arimidex. The elimination half-life of ZD1033 in humans ranged from 30 to 60 hours. Urinary excretion accounted for a small percentage of each dose. A 3- to 4-fold accumulation of ZD1033 in plasma occurred after daily administration of 3-, 5-, or 10-mg doses. Arimidex was well tolerated. Phase III studies are under way to determine the efficacy and safety of Arimidex in postmenopausal women with advanced breast cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00682745
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  • 139
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    Ultrastructural changes in murine lymphocytes induced by aflatoxin B1 (1994)
    Springer
    Mycopathologia 125 (1994), S. 33-39 
    Details
    ISSN: 1573-0832
    Keywords: Aflatoxin ; Lymphocytes ; Mice ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract This investigation sought to determine whether splenic lymphocytes obtained from Balb/C mice exposed to aflatoxin B1 (AFB1) showed any ultrastructural changes which could account for the immunodysfunction attributable to aflatoxins. Lymphocytes obtained from Balb/C mice administered aflatoxin B1 in olive oil daily for three weeks were studied using both transmission and scanning electron microscopy. The lymphocytes demonstrated ultrastructural changes primarily in the mitochondria where marked internal dissociation of the cristae was revealed by transmission electron microscopy. All other cellular organelles were unaffected. No significant alterations in external structure were observed under scanning electron microscopy. The findings of this study indicate that AFB1 administration does not affect the surface topography of lymphocytes, but AFB1, by causing extensive mitochondrial damage, may affect the way in which these cells function. This could be a possible explanation for the immunodysfunction associated with AFB1.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01103973
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  • 140
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    Electronic Resource
    Normal and neoplastic Schwann cells in fish (1994)
    Springer
    Methods in cell science 16 (1994), S. 109-115 
    Details
    ISSN: 1573-0603
    Keywords: Animal model ; Neurofibroma ; Schwann cell ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Peripheral nerve sheath (PNS) neoplasms, primarily neurofibromas, schwannomas and maliganant schwannomas, are among the most common tumors in fishes. Model systems involving PNS tumors in fishes are also valuable because mammalian models of PNS tumors are rare. Schwann cells, the primary cell type suspected of neoplastic transformation in these tumors, have been difficult to culture. We describe techniques for culturing normal and neoplastic Schwann cells from fish. We also present methods for preparing cells on culture dishes for electron microscopy which are especially useful when specific cells in a culture must be located for ultrastructural examination.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01404819
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  • 141
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    Kinocilia in the developing stria vascularis of the rat pup (1994)
    Springer
    European archives of oto-rhino-laryngology and head & neck 251 (1994), S. 267-270 
    Details
    ISSN: 1434-4726
    Keywords: Cochlea ; Ultrastructure ; Stria vascularis ; Development
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The mammalian stria vascularis undergoes certain developmental changes in the postnatal rat. The present study was designed to examine the ultrastructure of the stria vascularis in rat pups from immediately after birth to 20 days postpartum. The cochlea were removed with the animals under xylazine (Rompun) anesthesia and were prepared for transmission electron microscopy. Each of the three cell types in the stria were found to contain kinocilia up until 12–17 days of age. The presence of kinocilia in the intermediate and basal cells has not been previously described. Findings suggest that these organelles may serve a motile and/or sensory function to assist in the maturation of cell functions, particularly ion transport, during early stages of development.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00181882
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  • 142
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    The integumental ultrastructure of Parathalestris harpactoides (Claus, 1863) (copepoda, harpacticoida) (1994)
    Springer
    Hydrobiologia 292-293 (1994), S. 137-142 
    Details
    ISSN: 1573-5117
    Keywords: Ultrastructure ; morphology ; integument ; copepoda ; crustacea
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The integument of Parathalestris harpactoides (Claus, 1863) is studied by scanning and transmission electron microscopy. The general structure of the integument conforms to the common pattern known from Copepoda. Emphasis is given to the structural variation of the cuticle in different regions of the body. The cuticle measures about 6 µm in most parts of the body, and shows a laminate appearance. The epicuticle is about 60 nm thick. Numerous pore canals containing muscular tonofilaments penetrate the procuticular layer of the integument. A peculiar feature is the presence of a ‘honeycombed’ layer in the outermost zone of the cuticle of some parts of the body. The epidermal layer, muscle insertions and integumental pores are of common type. The cuticle of some specimens, both males and females, is covered with microorganisms.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00229933
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  • 143
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    Differentiation potential in medulloblastomas and primitive gliomas (1994)
    Springer
    Medical molecular morphology 27 (1994), S. 1-7 
    Details
    ISSN: 1860-1499
    Keywords: Medulloblastoma ; Primitive glioma ; Differentiation ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract To increase our understanding of the differentiation potential and cytogenesis of embryonal tumors in the brain, 12 medulloblastomas and 10 primitive gliomas were studied by electron microscopy. Of the medulloblastomas, 6 cases were undifferentiated tumors that demonstrated fine processes similar to microspikes. The remaining 6 cases were poorly-differentiated tumors. Axon-like processes were seen in 4 of these cases, including one with dense core vesicles. Astroglial processes were seen in 4 cases. Of the primitive gliomas, there were 2 undifferentiated tumors and 8 poorly-differentiated tumors. Some of the undifferentiated tumor cells had broad cytoplasmic processes. Of the 8 poorly-differentiated gliomas, there were groupings of junctional complexes in 7, microvilli in 4 and bundles of intermediate filaments in 5. It is concluded that medulloblastomas have both neuronal and glial differentiation potentials and that primitive gliomas have only glial differentiation potential. The origin of medulloblastomas may be from the remnants of cell nests with a multipotential differentiation capacity, and the origin for primitive gliomas may be from remnants of glial precursor cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02348220
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  • 144
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    Electron microscopic and immunohistochemical studies of oral malignant melanoma (1994)
    Springer
    Medical molecular morphology 27 (1994), S. 41-44 
    Details
    ISSN: 1860-1499
    Keywords: Ultrastructure ; Transferrin receptor ; Oral malignant melanoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A rare variety of malignant melanoma in the maxilla was studied by electron microscopic observation and an immunohistochemical investigation of the transferrin receptor (TfR). A number of low-stage melanosomes were seen, and the TfR was found in both the cell membrane and the cytoplasm.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02348226
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  • 145
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    Alterations in the distributory pattern of vasoactive intestinal polypeptide immunoreactivity in the ischemic intestines of dogs (1994)
    Springer
    Medical molecular morphology 27 (1994), S. 87-94 
    Details
    ISSN: 1860-1499
    Keywords: Vasoactive intestinal polypeptide (VIP) ; Intestinal ischemia ; Immunohistochemistry ; Ganglionic cells ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Alterations in the distribution of vasoactive intestinal polypeptide (VIP) in normal and ischemic small intestines of dogs were studied by using conventional transmission electron microscope, and immunohistochemistry for light and electron microscopy. At the light microscopic level, immunoreactivity was evident in the intestinal ganglionic cells of control segments. At the electron microscopic level using a pre-embedding method, the entire cytoplasm of the ganglionic cells in the control segments was filled with VIP immunoreactive products, while the post-embedding experiment showed positive reactions only within the VIP granules and Golgi vesicles. After 30 min of ischemia, immunoreactivity was greatly decreased in the ganglionic cells and a large amount of VIP immunoreactive product appeared in the striated border of epithelial cells and in nerve fibers of the subepithelial layer. These results suggest that intestinal ischemia might lead to the release of VIP, which seems to bind to the microvillus membrane of epithelial cells. The relationship between the changes in VIP distribution and its protecting mechanisms of ischemic damage is discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02348173
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  • 146
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    Electron microscopic studies of primary apocrine carcinoma of the breast (1994)
    Springer
    Medical molecular morphology 27 (1994), S. 113-122 
    Details
    ISSN: 1860-1499
    Keywords: Breast cancer ; Apocrine carcinoma ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Three cases of apocrine carcinoma of the breast were investigated by light and electron microscopy. Histologically, the tumor cells were shown to have eosinophilic granular cytoplasm and occasional cytoplasmic snouts protruding into the lumen. Ultrastructurally, light and dark tumor cells were identified, and there were many lysosome-like dense bodies of various sizes and small dense granules grouped in the subapical region. Many mitochondria with incomplete cristae and numerous small vacuoles were distributed in the cytoplasm. Occasionally, intracytoplasmic lumen were visible in the tumor cells. These ultrastructural findings are quite similar to those found in normal apocrine sweat glands. However, the presence of an intraductal component of carcinoma suggests the origin to be mammary epithelial cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02348176
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  • 147
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    Immunohistochemical and ultrastructural studies of thyroid tissue from a patient with Basedow's disease and immunopositive for human T-lymphotropic virus type I (HTLV-I) (1994)
    Springer
    Medical molecular morphology 27 (1994), S. 136-144 
    Details
    ISSN: 1860-1499
    Keywords: Human T-lymphotropic virus type I (HTLV-I) ; Ultrastructure ; Basedow's disease ; Lymphocyte ; Thyroid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Thyroid tissue from a patient with Basedow's disease and immunopositive for HTLV-I was examined. Histopathological and immunohistochemical studies revealed that follicular-epithelial cells (FEC) had papillary projections reaching into the follicular lumina which were associated with diffuse T, but not B, lymphocyte infiltration and occasionally formed aggregations intermingled with T and B lymphocytes. Ultrastructurally, infiltrated lymphocytes possessing round or irregularly indented nuclei were detected in the capillary lumen, stroma and, also, FEC layers. The lymphocytes extended irregular processes, attached to long thin processes of FEC and infiltrated into FEC layers. Cocultivation of minced thyroid tissue with normal lymphocytes resulted in the establishment of a type-C virus-producing T-cell line.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02348178
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  • 148
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    Histogenesis and organogenesis of the gonads in human embryos (1994)
    Springer
    Medical molecular morphology 27 (1994), S. 254-256 
    Details
    ISSN: 1860-1499
    Keywords: Gonad ; Mesonephros ; Histogenesis ; Primordial sex cord ; Folliculogenous sex cord ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The histogenesis and organogenesis of the human gonad in twelve embryos and six fetuses of ovulational ages 5 to 18 weeks was investigated by histological and ultrastructural examination, including observation of almost complete serial Epon-embedded sections of the entire gonads of 10 embryos. This investigation revealed that the main constituent cells of the gonads are derived from the mesonephros, and that the coelomic epithelium is not involved in the formation of the main component at any stage.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02349668
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  • 149
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    Ultrastructural changes in follicular cells induced by granulosa and theca cell interactions (1994)
    Springer
    Medical molecular morphology 27 (1994), S. 260-263 
    Details
    ISSN: 1860-1499
    Keywords: Cellular interaction ; Follicular wall ; Granulosa cell ; Theca cell ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Bovine granulosa and theca cells were cultured on the opposite sides of a collagen membrane, and the morphological and structural effects of the interaction between theca and granulosa cells were studied. The apical surface of both granulosa and theca cells in the cocultured group appeared convex, while control cells were thin and flat. Numerous filopodia spread over the cellular surface connecting the cells. Constituents of rough endoplasmic reticulum in the cocultured cells were extended and swollen when compared with those observed in the cells cultured alone. Cocultured granulosa cells formed multilayered sheets, while granulosa cells cultured alone formed monolayered sheets. Theca cells in the cocultured group were more densely packed than cells cultured alone. These results indicate that the levels of cellular activity and intercellular communication among each type of cell are increased by the granulosa and theca cell interactions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02349670
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  • 150
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    A new technique to prevent rehydration of freeze-dried sections for X-ray microanalysis: Papillary muscles and myocyte specimens (1994)
    Springer
    Medical molecular morphology 27 (1994), S. 326-329 
    Details
    ISSN: 1860-1499
    Keywords: X-ray microanalysis ; Freeze-drying ; Calcium ; Ultrastructure ; Isehemia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract There is considerable interest of the changes in intracellular electrolytes in various pathophysiological states in cardiology. X-ray microanalysis is a useful method to measure the concentration of intracellular elements, and freeze-drying is a required technique for X-ray microanalysis to preserve elements. In this study, we utilized a new technique by which ultrathin sections were evaporated by carbon in an external freeze-dryer after freeze-drying and we were able to obtain clear electron micrographs of papillary muscles and myocytes. Calcium concentrations of mitochondria and cytosol were measured during 120 min ischemia. We showed that mitochondria played a role in intracellular calcium regulation during 30 min ischemia.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02349687
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  • 151
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    Preparation and Characterization of Novel Poly(methylidene Malonate 2.1.2.)-Made Nanoparticles (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 1270-1277 
    Details
    ISSN: 1573-904X
    Keywords: drug targeting ; polymeric drug carrier ; nanoparticle ; polymerization ; biodegradation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Poly(methylidene malonate 2.1.2.) (PMM 2.1.2.) nanoparticles were prepared in phosphate buffer through emulsion polymerization of monomeric units; the kinetics of the reaction was monitored by spectrophotometry at 400 nm. Average nanoparticle sizes, molecular weights, and biodegradability of this potential drug carrier were determined under various conditions. As previously demonstrated for other similar monomers, i.e. IHCA or IBCA, pH influenced the physico-chemical characteristics of the nanoparticles obtained. Ethanol release from the ester-bearing side chains indicated that the polymers were susceptible to hydrolysis when incubated in basic pH or in rat plasma. A secondary degradation pathway, yielding formaldehyde through a reverse Knoevenagel’s reaction, was minimal. Cytotoxicity studies of this new vector, in vitro, against L929 fibroblast cells demonstrated that PMM 2.1.2. nanoparticles were better tolerated than other poly(alkylcyanoacrylate) (PACA) carriers. Pharmacokinetic studies were also carried out to observe the fate of 14C-labelled PMM 2.1.2. nanoparticles after intravenous administration to rats. Forty eight hour post-injection, more than 80% of the radioactivity was recovered in urine and faeces. The body distribution of the polymer was estimated by measuring the radioactivity associated with liver, spleen, lung and kidneys. Five minutes after injection, a maximum of 24 ± 2% of the total radioactivity was detected in the liver and less than 0.4% in the spleen. The liver-associated radioactivity decreased according to a biphasic profile and less than 8% of the total radioactivity remained after 6 days.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018986226557
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  • 152
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    Hepatic Blood Flow Measurements and Indocyanine Green Kinetics in a Chronic Dog Model (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 1511-1515 
    Details
    ISSN: 1573-904X
    Keywords: indocyanine green ; hepatic blood flow ; transit-time ultrasonic flowmeter ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The objective of this study was to compare hepatic blood flow measurements using ultrasonic flow probes and ICG in a conscious dog model and to evaluate whether ICG can be used to estimate relative change in hepatic blood flow. Seven mongrel dogs (3 M, 4 F, BW = 21 ± 1.8 kg, Hct = 0.39 ± 0.05) were used in the study. Catheters were surgically inserted into carotid artery and portal, hepatic and jugular vein. Transit-time ultrasonic flow probes were implanted around the portal vein and hepatic artery. After two weeks of recovery, a single i.v. bolus dose of ICG (0.5 mg/kg) was administered to each dog. The disposition profiles for ICG in the four catheters were measured for 15 minutes and the hepatic blood flow reading from the probes recorded. Jugular vein ICG blood clearance (Cl = 5.9 ± 1.1 ml/min/kg) was low compared to the electronically measured hepatic blood flow rate (Q = 27.8 ± 9.1 ml/min/kg). Extraction ratios (E = 0.15 ± 0.05) estimated using data from the inlet and the outlet of the liver were consistent with the clearance values, suggesting that ICG is not highly extracted by dog livers. Three dogs were used in experiments where liver blood flow was increased by food intake. Consistent with characteristics of low extraction ratio drugs, ICG was insensitive to blood flow changes while there was an overall increase in electronically measured liver blood flow of 30%. Therefore, ICG is a poor indicator of hepatic blood flow and the present dog model permits continuous and reliable measurements of hepatic blood flow and can be a useful tool in studying the effects of hepatic hemodynamics on pharmacokinetics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018928930617
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  • 153
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    Pharmacokinetics and Pharmacodynamics of L-703,014, a Potent Fibrinogen Receptor Antagonist, After Intravenous and Oral Administration in the Dog (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 426-431 
    Details
    ISSN: 1573-904X
    Keywords: fibrinogen receptor antagonist ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics and pharmacodynamics of L-703,014, a fibrinogen receptor antagonist, have been examined in the dog. An analytical method which utilizes methanol precipitation of dog plasma proteins followed by HPLC with an automated column switching technique using the chemical analogue L-704,326 as internal standard was developed for the determination of L-703,014 in dog plasma. The compound was not metabolized in the dog and was eliminated in the kidneys and into bile. Of the administered dose, 68.9 ± 1.3% (i.v.) and 80.5 ± 11.9% (p.o.) were recovered in the feces; 20.3 ± 3% (i.v.) and 2.2 ± 0.2% (p.o.) were recovered in the urine by 72 hr. L-703,014 was 23 ± 3.4% bound in dog plasma protein and the mean ratio of plasma/whole blood was 1.22 ± 0.05. The mean terminal half-life was 118 ± 36 min, the mean steady-state volume of distribution was 0.61 ± 0.22 L/kg, and the mean plasma clearance was 8 ± 2 mL/min/kg. Ex vivo platelet aggregation measurements were made by inducing platelet aggregation with 10 µg/ mL collagen in the presence of 1 µM epinephrine as an agonist. The mean C 50 was 44.4 ± 6.0 ng/mL, and the mean Hill coefficient was 1.5 ± 0.3. The mean bioavailability was 4.9 ± 1.4% in dogs administered 2.0 mg/kg (p.o.).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018973323039
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  • 154
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    Differential Disposition of Soluble and Liposome-Formulated Human Recombinant Interleukin-7: Effects on Blood Lymphocyte Population in Guinea Pigs (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 633-641 
    Details
    ISSN: 1573-904X
    Keywords: cytokine ; interleukin-7 ; sustained release ; liposome ; lymphopoietic ; pharmacokinetics ; drug delivery
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The effects of liposome formulation on interleukin-7 (IL-T)-dependent lymphopoietic activity was investigated based on the pharmacokinetics and tissue distribution profile of soluble and liposome-formulated recombinant human IL-7. Using 125I-IL-7, we determined the role of liposome formulation on in vivoIL-7 disposition by analyzing injection site, blood, tissue, and urinary kinetics. Following a 30- to 40-µg subcutaneous dose of soluble IL-7, most of the IL-7 was eliminated through urinary excretion within 24 hr. An equivalent subcutaneous dose of liposome-encapsulated IL-7 resulted in a peak level less than one-tenth that seen with soluble drug but produced sustained blood and urinary levels for 5 days. The bioavailability of liposome-encapsulated IL-7 was comparable to that of soluble IL-7, as determined by both blood and urinary data. Kinetic analysis of IL-7 at the subcutaneous injection site indicated that liposome encapsulation significantly reduced the rate of disappearance at the injection site. Studies with a mixture of 40% liposome-encapsulated and 60% soluble IL-7 gave an intermediate response between that of soluble IL-7 and that of liposome-encapsulated IL-7. Characterization of blood cells from IL-7-treated animals indicated that treatment with two weekly doses of mixed IL-7 liposomes (40% liposome encapsulated IL-7) significantly increased the total numbers of lymphocytes by day 14. In contrast, animals treated with soluble IL-7 on an identical dose and schedule did not produce any effect on blood lymphocytes. Collectively, liposome formulation provided a lower, but significantly sustained blood IL-7 level that enhanced IL-7 effects on blood lymphocyte numbers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018955708443
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  • 155
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    Bioequivalence: Performance of Several Measures of Extent of Absorption (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 715-722 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; bioequivalence ; extent of absorption ; power analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The determination of the area under the concentration–time curve (AUC) is the method most commonly used by regulatory agencies to assess extent of drug absorption after single-dose administration of oral products. Using simulations, several approaches toward measuring the actual area, in whole or part, were tested. In addition, the performance of the peak concentration (C max), usually taken as a measure of the rate of absorption was assessed evaluating extent. Model scenarios for drugs with typical mean characteristics and statistical distributions were investigated. Using different kinetic models of disposition, the time course of the drug concentration in plasma was simulated. Intraindividual and interindividual variability and assay error were modeled using Monte Carlo techniques. The accuracy, precision, and ease of use of the various measures of extent were evaluated, and statistical power analyses were performed. Among the measures tested, the most reliable were the AUC computed up to the time of the last quantifiable concentration, without extrapolation, and C max. However, being also sensitive to rate, C max as a measure of extent is of limited potential.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018932430733
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  • 156
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    Pharmacokinetics and Bioinversion of Ibuprofen Enantiomers in Humans (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 824-830 
    Details
    ISSN: 1573-904X
    Keywords: ibuprofen enantiomers ; pharmacokinetics ; bioinversion ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract An open, randomized, six-way crossover study was conducted in 12 healthy males to assess pharmacokinetics and bioinversion of ibuprofen enantiomers. The mean plasma terminal half-life (t1/2) of R(–)ibuprofen was 1.74 hr when intravenously infused as a racemic mixture and was 1.84 hr when intravenously infused alone. The mean t1/2 of S( + )ibuprofen was 1.77 hr when dosed as S( + )ibuprofen. Examination of values of both the absorption and disposition parameters of R(–)ibuprofen revealed that the kinetics of R(–)ibuprofen were not altered by concurrent administration of S( + )ibuprofen. In this study, there was little or no presystemic inversion of R(–)ibuprofen to its S( + )isomer. Also, 69% of the intravenous dose of R(–)ibuprofen was systemically inverted and 57.6% of the oral dose of R(–)ibuprofen lysinate was bioavailable as S ( + )ibuprofen. These results indicate that the bioinversion of R(–)ibuprofen administered orally is mainly systemic. Because bioinversion of R(–)ibuprofen is not complete, S( + )ibuprofen produced higher bioavailability of S( + )ibuprofen (92.0%) than either racemic ibuprofen (70.7%) or R(–)ibuprofen (57.6%). However, bioavailability of R(–)ibuprofen (83.6%) when dosed alone was not significantly different from when dosed as racemic mixture (80.7%).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018969506143
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  • 157
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    Comparison of Two Otitis Media Models for the Study of Middle Ear Antimicrobial Pharmacokinetics (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 855-859 
    Details
    ISSN: 1573-904X
    Keywords: otitis media ; pharmacokinetics ; amoxicillin ; sulfamethoxazole ; trimethoprim
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We compared two models of acute otitis media that estimate middle ear antimicrobial pharmacokinetics. Using a crossover study design, we compared a systemic drug administration model with a diffusion model we devised that measures the disappearance of antimicrobials from the middle ear. We induced acute otitis media in 14 chinchillas by inoculating S. pneumoniae into the middle ear, then administered 3 antimicrobials: amoxicillin, trimethoprim, and sulfamethoxazole. Next we collected middle ear fluid samples to analyze drug concentrations and compare rate constants for the systemic and diffusion models by analysis of variance. We found that amoxicillin K values were not affected by model testing sequence (p = 0.827) or model type (systemic versus diffusion, p = 0.310), nor were sulfamethoxazole K values: model testing sequence (p = 0.917), model type (p = 0.963). Trimethoprim K values were also not affected by model testing sequence (p = 0/760), but were by model type (p = 0.0001). Trimethoprim elimination from the diffusion model was faster (K = 0.33 ± 0.17 versus 0.57 ± 0.09 hr−1) than from the systemic model, although it appears this was caused by sampling before drug distribution into the middle ear was complete. In conclusion, it appears K values derived from either systemic antimicrobial administration or direct middle ear instillation are similar for assessing middle ear anitmicrobial pharmacokinetics, and these models can be used interchangeably to study factors affecting otitis media treatment response.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018981808868
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  • 158
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    Effect of Streptococcus pneumoniae and Influenza A Virus on Middle Ear Antimicrobial Pharmacokinetics in Experimental Otitis Media (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 860-864 
    Details
    ISSN: 1573-904X
    Keywords: otitis media ; influenza A virus ; Streptococcus pneumoniae ; amoxicillin ; sulfamethoxazole ; trimethoprim ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Antimicrobial treatment failures in children with acute otitis media and concomitant viral respiratory tract infection prompted us to study the effects of influenza A virus infection on middle ear antimicrobial drug penetration. Using a chinchilla model of Streptococcus pneumoniae we compared middle ear elimination rates in 4 groups of chinchillas: (1) control, (2) influenza A virus inoculation alone intranasally, (3) both influenza A and S. pneumoniae inoculation directly into the middle ear, and (4) S. pneumoniae inoculation alone into the middle ear. After infection was established, a solution containing amoxicillin, sulfamethoxazole, and trimethoprim was instilled into the middle ear and removed 4 hours later. The rate constant of elimination and half-life were calculated from measured drug concentrations initially and at 4 hours. S. pneumoniae infection alone significantly shortened the middle ear elimination half-life compared with the control group: amoxicillin, 2.65 ± 0.73 vs. 6.63 ±  2.55 hr; sulfamethoxazole, 1.75 ± 0.28 vs. 2.74 ± 0.6 hr; and trimethoprim, 1.06 ±  0.14 vs. 1.56 ± 0.34 hr (n = 16 ears, p values all 〈0.01). The combined influenza virus and S. pneumoniae infection significantly lengthened the half-life compared with the S. pneumoniae infection alone: amoxicillin, 5.65 ± 6.44 vs. 2.65 ± 0.73 hr; sulfamethoxazole, 2.5 ± 0.85 vs. 1.75 ± 0.28 hr; and trimethoprim, 1.26 ± 0.42 vs. 1.06 ± 0.14 hr (n = 16 ears, p values all 〈0.01). Influenza virus produced the longest half-lives for all 3 antimicrobials: amoxicillin 25.52 ± 14.96 hr; sulfamethoxazole, 5.46 ± 0.87 hr; and trimethoprim, 2.57 ± 0.75 hr. These effects demonstrate that influenza and S. pneumoniae infections alone and together affect middle ear antimicrobial penetration. The decreased penetration of antimicrobials that occurred with the combined viral and bacterial infection vs. the bacteria alone supports the clinical observation that patients with infections caused by both organisms may have decreased middle ear antimicrobial concentrations, producing treatment failures.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018933925707
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    Masthead (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994) 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/cnm.1640100101
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  • 160
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    Iterative computation of second-order derivatives of eigenvalues and eigenvectors (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 1-9 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: An iterative method is introduced for computing second-order partial derivatives (sensitivities) of eigenvalues and eigenvectors of matrices which depend on a number of real design parameters. Numerical tests confirm the viability of the method and support our theoretical analysis. Alternative methods are reviewed briefly and compared with the one proposed here.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/cnm.1640100102
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  • 161
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    Semi-Loof element for plate instability (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 11-19 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: In the formulation of the semi-Loof element the rotation of the tangent plane is derived from the interpolation of the transverse displacement, while the rotation of the normal is interpolated separately by another set of shape functions. The geometric stiffness matrix can be formulated by use of either of the two rotation representations. It is demonstrated that the use of the tangent plane representation in the geometric stiffness matrix is far superior to the common form at present.
    Additional Material: 4 Ill.
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    URL: http://dx.doi.org/10.1002/cnm.1640100103
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  • 162
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    Least-squares T-elments: Equivalent FE and BE forms of a substructure-oriented boundary solution approach (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 21-32 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: An efficient solution to boundary-value problems may be based on the application of a suitably truncated T-complete set of Trefftz functions over individual subdomains and on linking the fields by a least-squares procedure. Although it yields a symmetric system of linear equations, this approach as originally presented by Zielinski and Zienkiewicz is not suited for implementation into FE codes. The present paper presents two equivalent formulations, which take respectively the form of the finite (FE) and non-conventional boundary-element (BE) approach. Both allow the resulting simultaneous equations to be assembled following the standard direct stiffness methods and can readily be implemented into existing FE codes.As in the conventional p-method, the accuracy may be controlled within large limits without increasing the number of elements. The present approach allows substantial saving in computer time in comparison with the so-called hybrid-Trefftz (HT) elements, though the assumed displacement fields are identical. The practical efficiency of the new T-element approach is assessed on the problem of stress concentration in a symmetrically compressed perforated panel.
    Additional Material: 6 Ill.
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    URL: http://dx.doi.org/10.1002/cnm.1640100104
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  • 163
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    High-order polynomial interpolation in boundary integral equation analysis (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 167-178 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: A sixth-order polynomial shape function is developed for BIE analysis. The function is applied over only three-noded elements, but with the support for the function extending over adjacent elements. This avoids the oscillations near the ends of the range which otherwise are characteristic of high-order polynomial interpolation. Various test problems are explored, and it is shown that results as accurate as those from conventional quadratic elements are obtained with larger nodal spacings, and thus giving the potential for significant reductions in matrix storage requirements and solution times.
    Additional Material: 9 Ill.
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    URL: http://dx.doi.org/10.1002/cnm.1640100208
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  • 164
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    Accurate finite element method for steady and quasisteady lifting aerofoil (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 155-166 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: A finite element formulation based on superposition is proposed for a lifting aerofoil in incompressible potential flow. An accuracy improvement technique for the singularity at the aerofoil trailing edge is discussed. It is shown that the quarter-node quadrilateral element can be readily employed to simulate this singularity. It is also demonstrated that the circulation in the flow field can be easily represented by a single constraint equation rather than introducing an artificial cut line in the mesh. The influence of finite-element mesh size on solution accuracy and the correct form of the boundary condition have been investigated as well. Numerical examples are given for both steady and quasisteady Joukowski aerofoils of various thicknesses and at a range of incidences. In all test cases, good agreement is observed between the analytical solution and the numerical result.
    Additional Material: 6 Ill.
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    URL: http://dx.doi.org/10.1002/cnm.1640100207
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    Masthead (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994) 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/cnm.1640100301
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  • 166
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    A 3D element for non-linear analysis of solids (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 183-194 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: An 8-node element (HMITC) for 3D non-linear analysis of solids is presented. The new element is based on an element developed by Wilson and Ibrahimbegovic, that incorporates incompatible modes, and on the method of mixed interpolation of tonsorial components. The HMITC element does not contain spurious zero energy modes and satisfies Irons' Patch Test. The numerical experimentation indicates that the HMITC has good performance even with distorted meshes.
    Additional Material: 6 Ill.
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    URL: http://dx.doi.org/10.1002/cnm.1640100302
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  • 167
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    Space-time oriented streamline diffusion methods for non-linear conservation laws in one dimension (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 203-215 
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    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: In this paper we consider an explicit finite-element method, with elements adaptively oriented in space-time, for the solution of one-dimensional conservation laws, extending previous work dealing with linear convection-diffusion and incompressible flow. In particular we consider Burgers' equation and the compressible Euler equations.
    Additional Material: 8 Ill.
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    URL: http://dx.doi.org/10.1002/cnm.1640100304
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  • 168
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    Neural-network-based approximations for solving partial differential equations (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 195-201 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: A numerical method, based on neural-network-based functions, for solving partial differential equations is reported in the paper. Using a ‘universal approximator’ based on a neural network and point collocation, the numerical problem of solving the partial differential equation is transformed to an unconstrained minimization problem. The method is extremely easy to implement and is suitable for obtaining an approximate solution in a short period of time. The technique is illustrated with the aid of two numerical examples.
    Additional Material: 4 Ill.
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    URL: http://dx.doi.org/10.1002/cnm.1640100303
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  • 169
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    Cyclic symmetry in boundary elements (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 217-225 
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    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: An efficient algorithm for consideration of axial and cyclic symmetry in the boundary-element method is presented. The appropriate transformation relationships was derived. The algorithm is then implemented in a boundary element program for the analysis of 2D elastostatic problems. Through analysis of typical problems the validity of the algorithm and its implementation is verified. A high level of accuracy and substantial reduction in computer time and storage was achieved.
    Additional Material: 5 Ill.
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    URL: http://dx.doi.org/10.1002/cnm.1640100305
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  • 170
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    Explicit variable time-step method for implicit moving boundary problems (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 227-235 
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    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: The diffusion of oxygen into an absorbing medium as an example of an implicit moving boundary problem has been dealt with by a number of authors using various numerical techniques, and, where appropriate, approximate analytical expressions. To evaluate the time for complete absorption, extrapolation is usually employed. An unconditionally stable explicit numerical scheme that avoids the limitations of such methods is presented and tested herein. Unlike existing schemes this method is fully numerical; it avoids the large array size, generally required for existing methods, by using a variable-length time step. The time for complete absorption emerges from the final step in the normal computing procedure with no recourse to extrapolation. Furthermore, owing to the implicit condition prevailing at the moving boundary, no iterations are needed to evaluate the time step required for the moving boundary to move a single space increment. The numerical results obtained compare very favourably with those due to earlier authors.
    Additional Material: 1 Ill.
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    URL: http://dx.doi.org/10.1002/cnm.1640100306
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  • 171
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    Boundary-element solution of some structural-acoustic coupling problems using the multiple reciprocity method (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 237-248 
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    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: In the paper we have developed a new formulation for solution of structural-acoustic coupling problems by boundary elements using the multiple reciprocity method. It is assumed that the structure is composed of plate components and is excited by the external or the internal noise source. The efficiency of the proposed formulation becomes especially remarkable if the boundary-value problem is to be solved repeatedly for different values of frequency. The accuracy of the numerical computations has been compared with the analytical solution in a test example.
    Additional Material: 2 Ill.
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    URL: http://dx.doi.org/10.1002/cnm.1640100307
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  • 172
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    Homogenization and effective elastoplasticity models for periodic composites (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 257-265 
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    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: Techniques for stress- and strain-controlled in situ homogenization of inelastic periodic composites are presented. The results of homogenization computations on a specific elastoplastic composite solid are then employed to validate the form of an orthotropic elastoplasticity model with a tensorial kinematic hardening law.
    Additional Material: 3 Ill.
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    URL: http://dx.doi.org/10.1002/cnm.1640100309
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  • 173
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    Lagrange multiplier approach for evaluation of friction in explicit finite-element analysis (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 249-255 
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    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: An algorithm for evaluation of friction in general contact-impact interfaces is described. The algorithm is based on an explicit finite-element method. Coulomb's friction law is assumed. The defence node algorithm is used such that the sticking condition can be imposed with the Lagrange multiplier method even in explicit dynamic analysis. The algorithm is supposed to be applicable in general situations, including large deformations of the contact-impact bodies and large relative sliding between the contact-impact boundaries. Numerical results are presented to demonstrate the performance of the algorithm.
    Additional Material: 5 Ill.
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    URL: http://dx.doi.org/10.1002/cnm.1640100308
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  • 174
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    Conference diary (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 275-277 
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    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/cnm.1640100311
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  • 175
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    Masthead (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994) 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/cnm.1640100401
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    General forming of transition elements (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 267-273 
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    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: A generalization of the r(1-m)/m strain singularity of higher-order isoparametric elements is presented. It is shown that, by variable placement of the side nodes between their original and singular positions, the point of singularity sensed by the element can be controlled. The transition elements have a strain singularity outside their domain. The singular and non-singular elements are elements are special cases of the general mapping. The transition elements, together with the singular isoparametric elements, can be used for solving crack problems.
    Additional Material: 4 Ill.
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    URL: http://dx.doi.org/10.1002/cnm.1640100310
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    Some geometric problems related to fracture-control in complex structures (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 279-290 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: In the design of members with flaws, it is necessary to keep the stress intensity factor K of any sharp crack below the fracture toughness Kcr of the materials. Stress-intensity factor equations for the more common basic specimen geometries and various loading conditions are available in the literature. The application of these equations to complex structures involves geometric problems such as the identification of the outline of each member and the sizing of the equivalent specimen for each flaw. The paper gives a response to such difficulties.
    Additional Material: 11 Ill.
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    URL: http://dx.doi.org/10.1002/cnm.1640100402
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  • 178
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    Modified simplex optimization program (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 303-312 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: A simple, yet storage-effective ‘linear’ programming code is given. The assumption of non-negative variables is bypassed without increasing the size of the problem. Furthermore, the objective is allowed to be summed over not just linear, but also concave, functions. A specific truss topology optimization example is shown.
    Additional Material: 1 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/cnm.1640100405
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  • 179
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    Fourth-order difference method for quasilinear Poisson equation in cylindrical symmetry (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 291-296 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: We propose in this paper a nine-point, fourth-order difference method for the numerical solution of the quasilinear Poisson equation \documentclass{article}\pagestyle{empty}\begin{document}$$ Au_{zz} + \frac{1}{r}u_r + Bu_{rr} = f\left({r,z,u,u_r,u_z} \right) $$\end{document} with appropriate boundary conditions. The method is based on five evaluations of f. The numerical results of four problems obtained using this method are listed. The results demonstrate the fourth-order accuracy of the method.
    Additional Material: 4 Tab.
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    URL: http://dx.doi.org/10.1002/cnm.1640100403
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  • 180
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    Use of central-difference operators for solution of singularly perturbed problems (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 297-302 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: Singularly perturbed second-order elliptic equations with boundary layers are considered. These may be considered as model problems for the advection of some quantity such as heat or a pollutant in a flow field or as linear approximations to the Navier-Stokes equations for fluid flow. Numerical methods composed of central-difference operators on special piece-wise-uniform meshes are constructed for the above problems. Numerical results are obtained which show that these methods give approximate solutions with error estimates that are independent of the singular perturbation parameter. An open theoretical problem is posed.
    Additional Material: 2 Ill.
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    URL: http://dx.doi.org/10.1002/cnm.1640100404
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  • 181
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    Superconvergent patch recovery of finite-element solution and a posteriori L2 norm error estimate (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 313-320 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: In the paper we present a superconvergent patch recovery technique for obtaining higher-order-accurate finite-element solutions and thus a postprocessed type of L2 norm error estimate. Two modifications make our procedure different from the one proposed by Zienkiewicz and Zhu (1992), in which higher-order-accurate derivatives of the finite-element solution at nodes are determined. Firstly, the recovery process is made for element, not for nodes. An ‘element patch’, which represents the union of an element under consideration and the surrounding elements, is introduced. Secondly, the local error estimate is calculated directly from the improved solution for this element. Numerical tests on both 1D and 2D model problems show that this method can provide an asymptotically exact a posteriori L2 norm error estimate if the used element possesses superconvergent points for the solutions.
    Additional Material: 7 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/cnm.1640100406
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  • 182
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    Universal matrices with new infinite elements for quasiharmonic equation (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 321-331 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: A new approach to developing serendipity quadrilateral infinite elements is presented. Using these elements universal matrices for quasiharmonic equation are developed. For a particular member of the family these matrices are independent of the size and shape of the element. Using these matrices the element stiffness matrix can be generated in a simpler manner by taking into account the size and shape of the element.
    Additional Material: 4 Ill.
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    URL: http://dx.doi.org/10.1002/cnm.1640100407
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  • 183
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    Accelerated modified Newton-Raphson iteration-based finite-element solution of structural problems involving non-linear deformation behaviour (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 333-338 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: A new global secant relaxation (GSR)-method-based improvement procedure is used to improve the overall convergency performance of the modified Newton-Raphson iteration in carrying out the solution of discrete systems resulting from the finite-element discretization of a certain class of structural problems involving non-linear deformation behaviour.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/cnm.1640100408
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  • 184
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    A simulation of free-surface electrohydrodynamic flow (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 339-353 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: Theoretical and experimental analysis of free-surface electrohydrodynamic flow is fragmented and incomplete. Simulation studies of this phenomenon are further limited by the inherent complexities in the modelling process. In this note a mathematical model is developed to analyse free-surface electrohydrodynamic flow in two dimensions, and preliminary results of the simulation are described. The configurations examined include electrified conducting surfaces, the dielectrophoretic forces, and a conducting jet. The simulation is compared with analytical results in the first two investigations and is shown to be quite accurate. In the last simulation it is demonstrated that in the initial formation of a conducting jet, a 10 per cent increase in applied voltage results in about a 10 per cent increase in fluid velocity.
    Additional Material: 7 Ill.
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    URL: http://dx.doi.org/10.1002/cnm.1640100409
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  • 185
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    Conference diary (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 355-357 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/cnm.1640100410
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  • 186
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    Announcements (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 359-360 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/cnm.1640100411
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  • 187
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    Masthead (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994) 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/cnm.1640100501
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  • 188
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    Improvement on dual reciprocity boundary element method for equations with convective terms (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 361-371 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: The dual reciprocity boundary element method, first proposed by Nardini and Brebbia (1982, 1985), is a powerful technique for solving elliptic partial differential equations. Adopting this approach, a singular volume integral, which needs to be evaluated with a traditional boundary element method, can be converted into a boundary integral. However, when the governing equation is of a certain type, this conversion fails due to the singularities being introduced inside the physical domain and on the boundary arising by differentiating distance functions. We avoid these artificially created singularities by constructing a transformation which leads to improved numerical results.
    Additional Material: 5 Ill.
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    URL: http://dx.doi.org/10.1002/cnm.1640100502
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  • 189
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    A direct solver for the least-squares problem arising from GMRES(k) (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 743-749 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: This is a study about one of the core questions in the GMRES(k) method regarding the obtaining of vector yk for the least-squares problem, argminy |Hky - β(n)e1|2 (see Saad and Schultz1). We propose a simple but efficient approach to the resolution of this problem and a low cost computation of the residual and the residual norm, including both in a complete and detailed FGMRES(k) algorithm. The whole algorithm of minimization only involves two backward substitutions with triangular matrices and a dot product. The residual and the residual norm are computed, making use of results in the least-squares problem.
    Additional Material: 1 Tab.
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    URL: http://dx.doi.org/10.1002/cnm.1640100909
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  • 190
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    Conference diary (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 759-760 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/cnm.1640100911
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  • 191
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    Announcements (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994), S. 761-762 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/cnm.1640100912
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  • 192
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    Masthead (1994)
    Chichester : Wiley-Blackwell
    Communications in Numerical Methods in Engineering 10 (1994) 
    Details
    ISSN: 1069-8299
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/cnm.1640101001
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  • 193
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    Effect of cytochrome P-450 1A induction on enantioselective metabolism and pharmacokinetics of an aryltrifluoromethyl sulfide in the rat (1994)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 6 (1994), S. 372-377 
    Details
    ISSN: 0899-0042
    Keywords: rat ; cytochrome P-450 ; toltrazuril ; sulfoxide ; sulfone ; pharmacokinetics ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The pharmacokinetics of the antiparasitic drug toltrazuril (1-methyl-3-[3-methyl-4-[4-[trifluoromethyl]thio]phenoxy]phenyl-1,3,5- triazine-2,4,6(1H,3H,5H)-trione) were studied in the rat following pretreatment with 3-methylcholanthrene, an inducer of rat liver cytochrome P-450 1A. The induction markedly modified the pharmacokinetics of the compound, leading to a decrease in the AUC value for toltrazuril sulfoxide. The results were explained on the basis of previous results from our laboratory relating to the product enantioselectivity of the formation of the sulfoxide and the substrate enantioselectivity of the subsequent formation of the sulfone. © 1994 Wiley-Liss, Inc.
    Additional Material: 6 Ill.
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    URL: http://dx.doi.org/10.1002/chir.530060503
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  • 194
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    Implications of chirality on pharmacodynamic modeling (1994)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 6 (1994), S. 467-471 
    Details
    ISSN: 0899-0042
    Keywords: enantiomers ; interaction ; pharmacokinetics ; pharmacodynamics ; pharmacology ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Although the implications of stereochemistry for pharmacokinetics are relatively well appreciated only recently has its influence on pharmacodynamics begun to be examined. The implications of different pharmacological interactions between enantiomers with similar and different kinetic properties are examined through the use of simulation of the pharmacological effect vs. time profile. The influences of assuming that the pharmacological effect is solely the result of the more active enantiomer are also discussed. The simulations demonstrate that the less pharmacologically active enantiomer may have a significant influence on the observed effect vs. time profile and that the assumption that all of the observed pharmacological activity arises from the more active enantiomer may lead to highly inaccurate prediction of the pharmacodynamic parameters. Finally, these observations suggest that the pharmacodynamic profiles of a drug administered as a racemate or as a “pure” formulation of the more active enantiomer may be significantly different. © 1994 Wiley-Liss, Inc.
    Additional Material: 1 Ill.
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    URL: http://dx.doi.org/10.1002/chir.530060604
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  • 195
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    A preliminary pharmacokinetic study of the enantiomers of the terfenadine acid metabolite in humans (1994)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 6 (1994), S. 479-483 
    Details
    ISSN: 0899-0042
    Keywords: terfenadine metabolite ; enantiomer separation ; HPLC ; pharmacokinetics ; humans ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: A stereoselective and sensitive achiral/chiral method for the determination of terfenadine acid metabolite in human plasma was developed. The metabolite was separated and quantitated using an achiral chromatographic procedure with a cyano column. The mobile phase was 1 mM sodium acetate buffer (pH 4.0) and acetonitrile (25:75% v/v) at a flow rate of 2 ml/min, at ambient temperature. The stereospecific resolution was accomplished using a chiral-AGP column and a mobile phase consisting of sodium acetate (0.01 M): methanol (98.7:1.3% v/v), and 20 mM di-n-butylamine at a flow rate of 1.2 ml/min. The column temperature was maintained at 32°C. The eluent was monitored at 230 nm (excitation) and 300 nm (emission) with a cut-off filter at 270 nm. This assay was used for a pharmacokinetic study in five subjects after administration of a single dose of 60 mg of terfenadine. The t½ values of the two enantiomers were similar, but the AUC values of the (+)-enantiomer were 2.05-2.35 times higher than those of (-)-enantiomer. © 1994 Wiley-Liss, Inc.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530060606
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  • 196
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    Stereoselective pharmacokinetics of methadone in beagle dogs (1994)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 6 (1994), S. 492-495 
    Details
    ISSN: 0899-0042
    Keywords: enantiomers ; methadone ; pharmacokinetics ; beagle dog ; iv administration ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The pharmacokinetics of methadone were studied in beagle dogs (n = 4) following intravenous administration of the racemate (0.5 mg/kg) and of the individual (R)-(0.25 mg/kg) and (S)-enantiomers (0.25 mg/kg) using a stereospecific HPLC assay. There was no significant difference between the pharmacokinetic parameters of (R)-methadone and (S)-methadone following administration of the individual enantiomers. Stereoselective differences were evident following administration of the racemate (P values for differences in AUC and CL were 0.001 and 0.046, respectively) and the clearance of the (S)-enantiomer was increased when administered as part of the racemate (316 ± 81 vs 487 ± 128 ml/min, P = 0.04). The data suggest that stereoselective disposition including potential enantiomer-enantiomer interactions should be considered in pharmacokinetic-pharmacodynamic studies of (R,S)-methadone. © 1994 Wiley-Liss, Inc.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530060608
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  • 197
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    Single dose pharmacokinetics of (S)-atenolol administered orally as a single enantiomer formulation and as a racemic mixture (tenormin™) (1994)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 6 (1994), S. 169-174 
    Details
    ISSN: 0899-0042
    Keywords: atenolol ; enantiomers ; pharmacokinetics ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The purpose of this study was to describe the pharmacokinetics of and heart rate and blood pressure responses to (S)-atenolol (SATN) and (R)-atenolol (RATN) after oral administration of (S)-atenolol and (R,S)-atenolol (Tenormin™) in man. Eight male subjects were given single oral doses of 50 mg of SATN as a single enantiomer formulation (SEF) and 100 mg of Tenormin™ (TMN) using a randomized, double-blind, 2-period, complete crossover study design. Subjects performed exercise tolerance tests (Bruce Protocol) before and 2, 4, 6, 8, 12, and 24 h after drug administration. Plasma samples were obtained 2 min before and 30 min, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, and 24 h after dosing. Urine was collected for the first 48 h after dosing. Plasma and urine samples were analyzed for SATN and RATN by an enantioselective HPLC method. SEF and Tenormin™ attenuated exercise-induced increases in heart rate and systolic blood pressure. Mean changes in exercise heart rates 4 h after dosing were -38 ± 3 bpm and -37 ± 3 bpm for SEF and TMN, respectively, P = 0.792. Mean changes in exercise systolic blood pressure were -42 ± 12 mm Hg and -55 ± 14 mm Hg for SEF and TMN, respectively, P = 0.484. Mean area under the plasma level time curve (AUC0-24) and mean Cmax for SATN for SEF were significantly lower than for SATN after TMN. Mean SATN AUCs0-24 were 1867 ± 261 and 2543 ± 223 ng · h/ml (P = 0.005) and mean Cmaxs were 225 ± 29 and 333 ± 30 ng/ml, for SEF and TMN, respectively (P = 0.011). Mean Tmax for SATN occurred significantly earlier after SEF than after TMN (2.9 ± 0.3 and 3.3 ± 0.3 h, P = 0.028). The amount of SATN excreted in urine was significantly lower after SEF than after TMN (18.7 ± 2.7 and 24.2 ± 2.0 mg, P = 0.017). AUC, Cmax, and amount excreted in urine (Au) were significantly higher for RATN than SATN after TMN. Mean AUCs, Cmaxs, and Aus for RATN compared to SATN were 2806 ± 239 vs 2543 ± 223 ng ± h/ml (P 〈 0.0001), 360 ± 31 vs 333 ± 30 ng/ml (P 〈 0.0001), and 25 ± 2.1 vs 24 ± 2 mg (P = 0.004), respectively. SEF and TMN are equieffective in attenuating exercise-induced increases in heart rate and systolic blood pressure. The SEF has lower bioavailability compared to TMN and RATN plasma levels are higher than SATN after TMN administration. © 1994 Wiley-Liss, Inc.
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    URL: http://dx.doi.org/10.1002/chir.530060303
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  • 198
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    Influence of endotoxin on the stereoselective pharmacokinetics of oxprenolol, propranolol, and verapamil in the rat (1994)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 6 (1994), S. 405-410 
    Details
    ISSN: 0899-0042
    Keywords: β-adrenergic blocking agent ; calcium antagonist ; enantiomers ; inflammation ; protein binding ; pharmacokinetics ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The influence of endotoxin-induced inflammation on the enantioselective pharmacokinetics of propranolol, oxprenolol, and verapamil, which bind to α1-acid glycoprotein, was studied in the rat. The racemic mixtures were given orally. In the control animals, for propranolol and oxprenolol, the plasma concentrations of the (R)-enantiomer were higher than those of the (S)-enantiomer, while for verapamil the reverse was true. Protein binding and intrinsic clearance are the main factors responsible for this enantioselectivity. After endotoxin treatment, for the three drugs tested the plasma concentrations and the plasma binding of both enantiomers were significantly increased. This effect was more pronounced for (R)-propranolol, (R)-oxprenolol, and (S)-verapamil than for their respective antipodes. The enantioselective effect of endotoxin on the plasma concentrations of the drugs studied seems mainly due to the enantioselective increase in binding to α1-acid glycoprotein. © 1994 Wiley-Liss, Inc.
    Additional Material: 1 Ill.
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    URL: http://dx.doi.org/10.1002/chir.530060508
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  • 199
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    Pharmacokinetics and pharmacodynamics of hydroxychloroquine enantiomers in patients with rheumatoid arthritis receiving multiple doses of racemate (1994)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 6 (1994), S. 355-359 
    Details
    ISSN: 0899-0042
    Keywords: pharmacokinetics ; antimalarials ; enantiomers ; pharmacodynamics ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Hydroxychloroquine, a slow acting antirheumatic drug, is administered as the racemic mixture. Blood concentrations of the two enantiomers of hydroxychloroquine were measured in two studies, one study of eight patients, in whom blood and urine concentrations were measured during the first 6 months of therapy with rac-hydroxychloroquine, and one of 43 patients who had received rac-hydroxychloroquine therapy for at least 6 months. In the latter study rheumatoid disease activity was also measured. The pharmacokinetics of hydroxychloroquine were found to be enantioselective. The concentrations of (-)-(R)-hydroxychloroquine were higher than those of the (+)-(S)-antipode in all patients at all time points, although the ratios of the two enantiomers did display a two to three fold variability between patients. Both total and renal clearance were greater for the (+)-(S)-enantiomer. From the observational, cross-sectional study design used, it was not possible to differentiate concentration-effect relationships of the two enantiomers. The 11-fold range of drug concentrations swamped any effect of variability between patients in enantiomer proportions. Blood concentrations of both enantiomers were significantly higher in groups of patients with less active disease. © 1994 Wiley-Liss, Inc.
    Additional Material: 7 Ill.
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    URL: http://dx.doi.org/10.1002/chir.530060420
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  • 200
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    Disposition and absorption of hydroxychloroquine enantiomers following a single dose of the racemate (1994)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 6 (1994), S. 360-364 
    Details
    ISSN: 0899-0042
    Keywords: hydroxychloroquine enantiomers ; absorption ; pharmacokinetics ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The disposition of hydroxychloroquine enantiomers has been investigated in nine patients with rheumatoid arthritis following administration of a single dose of the racemate. Blood concentrations of (-)-(R)-hydroxychloroquine exceed those of (+)-(S)-hydroxychloroquine following both an oral and intravenous dose of the racemate. Maximum blood concentrations of (-)-(R)-hydroxychloroquine were higher than (+)-(S) -hydroxychloroquine after oral dosing (121 ± 56 and 99 ± 42 ng/ml, respectively, P = 0.009). The time to maximum concentration and the absorption half-life, calculated using deconvolution techniques, were similar for both enantiomers. The fractions of the dose of each enantiomer absorbed were similar, 0.74 and 0.77 for (-)-(R)- and (+)-(S)-hydroxychloroquine, respectively (P = 0.77). The data suggest that absorption of hydroxychloroquine is not enantioselective. The stereoselective disposition of hydroxychloroquine appears to be due to enantioselective metabolism and renal clearance, rather than stereoselectivity in absorption and distribution. © 1994 Wiley-Liss, Inc.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530060421
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