bluuebunny/crossref_metadata_2025_split huggingface dataset:
Renal Handling of Iodobenzoates in Rats
Authors: Laznicek Milan , Laznickova Alice 
Published: October 2002

Abstract
Renal elimination pathways of three positional isomers of iodobenzoic acid (2-iodobenzo-ate, 3-iodobenzoate and 4-iodobenzoate radiolabelled with 125I) were compared using the perfused rat kidney in-situ.
All agents were eliminated both in a parent form (involving all renal elimination mechanisms i.e. glomerular filtration, tubular secretion, and tubular reabsorption) and also metabolized to a large extent in the kidney. After 3-iodobenzoate and 4-iodobenzoate administration, the major fractions of radioactivity found in urine were in the form of their metabolites, whereas 2-iodobenzoate was eliminated into urine mostly as the parent compound. Proportions of the individual metabolites in the urine of the perfused rat kidney were similar to those in intact rats for all agents.
The results suggest that the kidney is the major organ for both the excretion and metabolism of iodobenzoates in rats. The principal renal metabolic reaction for all compounds under study was conjugation with glycine to produce the corresponding hippuric acid derivatives.
Gastrointestinal First-pass Effect of YJA-20379-8, a New Reversible Proton Pump Inhibitor, in Rats
Authors: Kim Jonghan , Kim Eun J , Han Kye S , Chang Man S , Lee Myung G 
Published: October 2002

Abstract
Since low bioavailability of YJA-20379-8 (3-butyryl-4-[5-R-(+)-methylbenzylamino]-8-ethoxy-1, 7-naphthyridine), a new reversible proton pump inhibitor, has been reported after oral administration of the drug to rats, the first-pass organ of the drug was investigated in rats. YJA-20379-8, 50 mg kg−1, was infused over 1 min via the jugular vein (n = 5) or the portal vein (n = 5), or was instilled directly into the stomach (n = 5) or the duodenum (n = 5).
After intravenous or intraportal infusion of the drug, the total body clearance of YJA-20379-8 (18.1 and 19.7 mL min−1 kg−1 based on plasma data) was considerably lower than the reported cardiac output (296 mL min−1 kg−1 based on blood data) in rats. This data indicated that the first-pass effect of YJA-20379-8 by the lung and heart was negligible. The areas under the plasma concentration-time curve from time zero to time infinity (AUC) after intravenous or intraportal administration of YJA-20379-8 (2760 and 2540 μg min mL−1) were not significantly different, indicating that the hepatic first-pass effect of the drug was also negligible in rats.
After intragastric or intraduodenal instillation of YJA-20379-8, the extent of absolute oral bioavailability was 18.2 and 33.8%, respectively. Based on gastrointestinal recovery studies, approximately 86.5 and 91.2% of YJA-20379-8 was absorbed from rat gastrointestinal tract after intragastric or intraduodenal instillation, respectively. The data indicated that gastrointestinal and intestinal first-pass effects of YJA-20379-8 were approximately 68% (86.5–18.2) and 57% (91.2–33.8), respectively. The AUC0-24h values of YJA-20379-8 were significantly different between intragastric and intraduodenal instillation, indicating that the gastric first-pass effect of the drug was approximately 10% in rats. Therefore, it could be concluded that the low F value of YJA-20379-8 after oral administration of the drug could be due to a considerable (approx. 60%) intestinal first-pass effect in rats.
Insulin Delivery Governed by Covalently Modified Lectin-Glycogen Gels Sensitive to Glucose
Authors: Tanna S , Taylor M J , Adams G 
Published: October 2002

Abstract
A glucose-sensitive gel formulation containing concanavalin A and glycogen has been reported previously. Precipitation resulting from the addition of concanavalin A to glycogen has been documented, but the formation of glucose-sensitive gels based on lectin-glycogen interactions is novel and used here in our studies. An improved in-vitro self-regulating drug-delivery system, using covalently modified glucose-sensitive gels based on concanavalin A and a polysaccharide displacement mechanism, is described. The successful use of the covalently modified gels addresses a problem identified previously where significant leaching of the mitogenic lectin from the gel membranes of non-coupled gels was encountered.
Concanavalin A was covalently coupled to glycogen by use of derivatives of Schiff's bases. The resulting gels, like the non-coupled gels, were shown to undergo a gel-sol transformation in response to glucose. Insulin delivery was demonstrated using this covalently modified system in conditions of repeated glucose triggering at 20°C and 37°C. The magnitude of the response was less variable than for the dextran-based gels studied previously.
The performance of this system has been improved in terms of concanavalin A leaching. This could, therefore, be used as the basis of the design of a self-regulating drug-delivery device for therapeutic agents used to treat diabetes mellitus.
Conjugation of an Anti-B-cell Lymphoma Monoclonal Antibody, LL2, to Long-circulating Drug-carrier Lipid Emulsions
Authors: Lundberg Bo B , Griffiths Gary , Hansen Hans J 
Published: October 2002

Abstract
Long-circulating submicron lipid emulsions, stabilized with poly(ethylene glycol)-modified phosphatidylethanolamine (PEG-PE), are promising drug carriers with substantial capacity for solubilization of lipophilic anticancer agents. This study describes the conjugation of the anti-B-cell lymphoma monoclonal antibody LL2 to the surface of lipid-emulsion globules by use of a novel poly(ethylene glycol)-based heterobifunctional coupling agent.
The efficiency of coupling of LL2 to the lipid emulsion was 85% (approx.) and essentially independent of the LL2/emulsion particle ratio and amount of surface-bound PEG-PE. Results from sucrose-gradient centrifugation and Sepharose CL-4B gel filtration indicated stable binding of the antibody to the emulsion. The immunoreactivity of the emulsion-LL2 conjugates was tested with alkaline phosphatase-conjugated LL2 against a monoclonal anti-idiotype antibody, WN. The binding of the conjugates to WN increased with increasing surface density of LL2 up to 40 monoclonal antibodies/emulsion particle, and exceeded that for the free monoclonal antibody (approx. 20 molecules/particle). Results from competitive-binding ELISA were indicative of similar displacement curves for free LL2 and emulsion-LL2 conjugates. Direct cellular ELISA revealed similar binding of emulsion-LL2 complexes to three types of Burkitt's lymphoma cell lines, Raji, Ramos and Daudi.
The results from this study indicate that emulsion-LL2 complexes might be a useful drug-carrier system for more specific delivery of anticancer drugs to B-cell malignancy.
Delivery of Erythromycin to Subcutaneous Tissues in Rats by Means of a Trans-phase Delivery System
Authors: Peng Lynnus , Nimni Marcel E 
Published: October 2002

Abstract
Topical administration of antibiotics is associated with reduced risk of systemic side-effects and alteration of gut microflora, and results in higher concentrations of antibiotics at the site of application (and so a lower dose of the drug is required). In conditions such as acne vulgaris, infiltration of the antibiotics into the infected subcutaneous layers is highly desirable. A trans-phase delivery system (TPDS), a mixture of benzyl alcohol, acetone and isopropanol, has been shown to enhance the effective transport of the antibiotic erythromycin across the epidermal barrier and enhance accumulation in the dermis.
Two formulations containing N-methyl[14C]erythromycin were compared, a TPDS solution and a propylene glycol solution. They were applied to the dorsal areas of 4–6 week old Fischer rats and tissues were removed for analysis of radioactivity after 2, 4, 8, 12 or 24 h and skin was biopsied and sectioned for autoradiography. The erythromycin dissolved in the TPDS solvent mixture penetrated the stratum corneum and a relatively high concentration was maintained in adjacent tissues for up to 24 h. Penetration was very effective and the erythromycin was detected in significant amounts in the underlying muscle, various organs and later in the urine. In contrast the propylene glycol carrier, probably because of its primarily hydrophilic character, caused the erythromycin to traverse tissue barriers rapidly and appear in the urine. Microautoradiographs qualitatively revealed progressive disappearance of radioactivity from the surface; this correlated with results obtained by direct isotope counting. The route of penetration, in addition to following the interkeratinocyte spaces, seemed to include the perimeter of the pilosebaceous glands and their appendages before diffusion into the capillaries. The propylene glycol solution seemed to traverse the epidermis and the papillary and reticular dermis more rapidly, which might explain its rapid appearance in the urine. These data suggest that the different solutions penetrate the skin by different mechanisms.
Disposition of Morphine in Tissues of the Pregnant Rat and Foetus Following Single and Continuous Intraperitoneal Administration to the Mother
Authors: Devane C L , Simpkins J W , Boulton D W , Laizure S C , Miller R L 
Published: October 2002

Abstract
Foetal exposure to maternally administered opiates such as morphine represent a serious human health problem but disposition studies in man are difficult to perform. Morphine disposition was therefore investigated in pregnant rats and their foetuses near term as a model. Disposition was examined either following intraperitoneal dosing as a single dose or continuous infusion. A high-pressure liquid chromatography assay for morphine in plasma and tissue was developed and validated.
Following the single morphine dose, foetal distribution was rapid and concentrations in foetal and placental tissue were from 2.6 (whole foetus) to 27.6 (placenta) times higher compared with maternal plasma. The rank order of the area under the concentration vs time curve (AUC) of morphine in tissues was: placenta ≥ foetal liver &gt; foetal brain &gt; whole foetus &gt; maternal brain. The foetal brain to maternal brain AUC ratio for morphine was 9.5, suggesting large differences in their blood-brain barrier permeability. Following continuous administration of morphine there were significant linear relationships between maternal plasma and tissue concentrations with the same rank order as the single dose study. However, following continuous administration the relative amount of morphine in placenta and foetal liver was reduced by half and one-third, respectively, compared with the single dose study.
These results document why the rat foetus is particularly susceptible to the pharmaco-dynamic effects of morphine following maternal administration.
Effects of Some Malian Medicinal Plants on the Respiratory Tract of Guinea-pigs
Authors: Occhiuto F , Sanogo R , Germano M P , Keita A , D'Angelo V , De Pasquale R 
Published: October 2002

Abstract
Crossopteryx febrifuga, Pteleopsis suberosa and Entada africana are used in Mali traditional medicine for fever and various respiratory diseases. We have investigated the effects of these three drugs in the form of a decoction on the respiratory tract using different experimental models.
On citric acid-induced cough in guinea-pigs, the three drugs significantly decreased the number of coughs at the doses of 250 (P &lt; 0.01), 500 (P &lt; 0.05; P &lt; 0.01) and 1000 (P &lt; 0.01)mg kg−1. The percent inhibition was respectively 62.86, 69.03 and 77.44% for C. febrifuga, 57.80, 53.90 and 61.40% for E africana, and 37.13, 42.44 and 73.72% for P. suberosa. Codeine phosphate (10 mg kg−1) used as reference drug showed an inhibition of 76.32%.
E africana (1000 mg kg−1) reduced (65% inhibition) significantly (P &lt; 0.05) broncho-constriction induced by histamine (99.25% and 34.00% for control and extract, respectively). Furthermore, E africana (1000 mg kg−1) provoked a bronchodilatation response when administered under basal conditions.
On antigen-induced bronchospasm, C. febrifuga protected (54% inhibition) sensitized guinea-pigs with a pulmonary ventilation pressure (PVP) of 24.87% (control value &lt; 55.00%). P. suberosa was inactive in both experimental models. The reference drug, disodium cromoglycate (10 mg kg−1, i.v.) protected significantly (P &lt; 0.05) with a PVP of 12.00% (78% of inhibition).
This study confirmed the traditional use of these plants in the treatment of cough and other respiratory disorders.
The Evaluation of Long-term Effects of Cinnamon Bark and Olive Leaf on Toxicity Induced by Streptozotocin Administration to Rats
Authors: Onderoglu Selda , Sozer Sumru , Erbil K Mine , Ortac Ragip , Lermioglu FERZAN 
Published: October 2002

Abstract
The effects of cinnamon bark and olive leaf have been investigated on streptozotocin-induced tissue injury, and some biochemical and haematological changes in rats. The effects on glycaemia were also evaluated.
Long-term administration of olive leaf caused significant improvement in tissue injury induced by streptozotocin treatment; the effect of cinnamon bark was less extent. No effects on blood glucose levels were detected. However, significant decreases in some increased biochemical and haematological parameters of streptozotocin-treated rats were observed. Aspartate aminotransferase, urea and cholesterol levels were significantly decreased by treatment with both plant materials, and alanine aminotransferase by treatment with olive leaf. Cinnamon bark also caused a significant decrease in platelet counts. In addition, any visible toxicity, except decrease in body weight gain, attributable to the long-term use of plant materials was not established in normal rats.
The data indicate that long-term use of olive leaf and cinnamon bark may provide benefit against diabetic conditions. Determination of underlying mechanism(s) of beneficial effects, toxicity to other systems and clinical assessments of related plant materials are major topics requiring further studies.
Stability of Diclofenac Sodium in the Inclusion Complex with β-Cyclodextrin in the Solid State
Authors: Cwiertnia Barbara , Hladon Teresa , Stobiecki Maciej 
Published: October 2002

Abstract
The aim of this study was to characterize the thermal stability of diclofenac sodium both alone and in the inclusion complex with β-cyclodextrin in the solid state, by determination of the number of the products of its decomposition, which were identified by GC-MS.
The molar ratio of diclofenac sodium in the inclusion complex with β-cyclodextrin was 1:1. The decomposition of diclofenac sodium both alone and in inclusion complex with β-cyclodextrin occurred according to the first-order reaction. The HPLC of the samples thermostated at 80°C gave five products of decomposition, which were identified by GC-MS.
Diclofenac sodium in the inclusion complex with β-cyclodextrin was more thermally stable. Thermal decomposition of diclofenac sodium leads to formation of five products, of which 4-chloro-10H-9-acridinone had not been reported previously in the literature.
Pharmacokinetic Differences between Chlorofluorocarbon and Chlorofluorocarbon-free Metered Dose Inhalers of Beclomethasone Dipropionate in Adult Asthmatics
Authors: Harrison Lester I , Soria Inmaculada , Cline Ann C , Ekholm Bruce P 
Published: October 2002

Abstract
We have compared the serum pharmacokinetics of the metabolites of beclomethasone dipropionate after inhalation from chlorofluorocarbon (CFC) and hydrofluoroalkane HFA-134a (HFA) formulations in asthmatic patients.
Twenty-three patients completed this open-label, randomized, single-dose, three-period crossover study. Each patient received in separate periods 200 μg or 400 μg HFA-beclomethasone dipropionate, or 400 μg CFC-beclomethasone dipropionate. Venous blood samples were collected over 24 h for the determination of beclomethasone esters and beclomethasone in the serum.
Significant differences in pharmacokinetics following HFA– and CFC-beclomethasone dipropionate were observed. Following a 400 μg beclomethasone dipropionate dose, the HFA formulation gave mean maximum concentrations (Cmax) and area under the curve (AUC) values of beclomethasone esters of USS pg rnL−1 and 4328 pg h mL−1, respectively, and beclomethasone Cmax and AUC values of 69 pg mL−1 and 682 pg h mL−1, respectively. These values were approximately 2–3-fold those seen with the CFC formulation (beclomethasone esters Cmax and AUC of 380 pg mL−1 and 1764 pg h mL−1, respectively; beclomethasone Cmax and AUC of 41 pg mL−1 and 366 pg h mL−1, respectively). Beclomethasone esters, the major component of beclomethasone dipropionate in the serum, peaked significantly earlier for the HFA formulation (0.8 h) than for the CFC formulation (2h). Tests for dose proportionality of beclomethasone esters pharmacokinetics following HFA-beclomethasone dipropionate showed that the two hydrofluoroalkane strengths were proportional.
The more rapid and greater efficiency of systemic drug delivery of the HFA formulation compared with the CFC formulation can be explained if most of each inhalation from CFC-beclomethasone dipropionate is swallowed and absorbed orally, whereas most of each inhalation from HFA-beclomethasone dipropionate is absorbed through the lungs. There is a need for comprehensive dose-response efficacy trials, with the use of the steep portion of the dose-response relationship, to evaluate the significance of these pharmacokinetic differences.
Inhibition of Aldo-keto Reductases by Phenobarbital Alters Metabolism, Pharmacokinetics and Toxicity of Doxorubicin in Rats
Authors: Behnia Kamelia , Boroujerdi Mehdi 
Published: October 2002

Abstract
Doxorubicin is an effective anticancer agent that is limited by numerous adverse effects, cardiotoxicity causing the most concern. Its alcohol metabolite, doxorubicinol, and free radicals have been implicated in the aetiology of this toxicity. This study was based on the premise that inhibition of aldo-keto reductases would improve the efficacy of doxorubicin by reducing its toxic metabolites and modifying its pharmacokinetics. We assessed the effect of in-vitro inhibition of aldo-keto reductases on the metabolism of doxorubicin in cytosolic fractions of heart and liver of rats in the presence of Na-phenobarbital.
The inhibition was confirmed by a significant reduction in the formation of doxorubicinol. The results of the in-vitro study were further evaluated in-vivo. The concentrations of doxorubicin in plasma, bile and urine and its major metabolites in bile and urine were measured in Na-phenobarbital-pretreated rats. Each rat received 100 mg kg−1/day intraperitoneal injection of sodium phenobarbital for three days followed by a single intravenous dose of 10 mg kg−1 [14C-14]doxorubicin (sp. act. 0.2 μCi mg−1) on the fourth day. The levels of drug in all biological samples were measured by HPLC. The pretreatment resulted in an increase in biological half-life (5.8 ± 1.5 vs 3.7 ± 0.93 h control group, P &lt; 0.05) and area under plasma concentration-time curve (19.6 ± 1.7 vs 14.65 ± 1.68 mg h L−1 control group, P &lt; 0.05). The cumulative amount of doxorubicinol in the bile and urine of pretreated animals was reduced significantly. In terms of % dose, the amount in the bile declined from 4.2 ± 0.8% in control to 2.4 ± 0.3% and in urine from 0.18 ± 0.08% to 0.12 ± 0.07%. There were no significant changes in doxorubicin aglycone and doxorubicinol aglycone. Serum creatine kinase levels were measured as a biomarker of damage to cardiac muscle. The area under creatine kinase level-time curve was reduced by approximately 50% in phenobarbital-pretreated animals.
The results indicate that the inhibition of aldo-keto reductase could provide a useful approach to improve the safety of doxorubicin by reducing its alcohol metabolite. Furthermore, if the reduction in the area under the serum creatine kinase-time curve represents a reduced damage to heart muscle, it can be concluded that doxorubicinol plays an important role in this injury.
Conditions of yield and cyclic plasticity around inclusions
Authors: Ciavarella M 
Published: October 2002

In this paper the stress field in the proximity of a circular (cylindrical) inclusion is considered. The conditions for in-plane plastic flow in the matrix are examined from a classical elasticity solution obtained by Goodier. Elementary cases are considered such as remote loading ranging from pure tensile and pure shear to equibiaxial tension. For proportional loading, it is argued that the upper bound to the shakedown limit is always twice the elastic limit; therefore, within the limits of our assumptions, if the elastic stress concentration for the equivalent stress is greater than two, there is a possibility of cyclic plasticity before bulk yielding, which means that possibly an arbitrarily large plastic strain can cumulate with increasingly high risk of exhaustion of ductility and void nucleation or detachment of the interface. Consequently, conditions under which it is possible to reach twice the elastic limit before full-scale yielding are shown in the Dundurs plane representing all possible combinations of elastic parameters. Following these lines, it is shown that there is no possibility of cyclic plasticity under remote shear; there is a limited area of the Dundurs plane for tension, including the hole case; finally, in the equibiaxial limiting case, cyclic plasticity is always possible for any combination of elastic properties.
On the relaxation of interface stresses during creep of ferritic steel weldments
Authors: Kimmins S T , Smith D J 
Published: October 2002

This paper examines the interaction between materials joined together that individually have high and low degrees of creep resistance. A specific example considered is an overtempered layer of the heat-affected zone of a ferritic steel weldment which lies between stronger materials. Experimental evidence is reviewed which shows that adjacent strong and weak layers of material creep relatively independently of each other when a tensile stress is applied perpendicular to the plane of the layer. Finite element analyses are presented of a simplified model of a narrow and weak layer of material sandwiched within much stronger material. A constant load is applied perpendicular to the plane of the weak layer and the stress and strain distributions are considered after the accumulation of a significant degree of creep deformation. If the finite element mesh is constructed in a conventional manner it is shown that significant constraint of the narrow, weak layer is to be expected. However, if the mesh is modified so as to allow sliding of adjacent elements then the constraint of the weak zone can be virtually eliminated. It is proposed that finite element models of creeping weld interfaces need to be modified to allow a greater relaxation of the interface stress if they are to agree with experimental studies.