bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development and Validation of a Recirculatory Physiological Model of the Myocardial Concentrations of Lignocaine after Intravenous Administration in Sheep
Authors: Upton Richard N , Zheng D A , Grant Cliff , Martinez Allison M 
Published: October 2002

Abstract
A recirculatory physiological model of the determinants of the myocardial concentrations of lignocaine after intravenous administration was developed in sheep and validated with the intention of analysing and predicting the outcome of altered dose regimens and various pathophysiological states on the initial myocardial concentrations of lignocaine.
The structure and parameters of the model were determined by hybrid modelling of the time-courses of the pulmonary artery, arterial and coronary sinus concentrations of lignocaine after the intravenous administration of 100 mg of lignocaine over 5 min to 5 chronically instrumented sheep. The model accounted for the determinants of the myocardial concentrations via compartments for venous mixing, the lung (a single-compartment model with a first-order loss) and the heart (a single flow-limited compartment). Recirculation and the remainder of the body were represented as a single tissue pool with a clearance term. The distribution volume of the heart was 0.42 ± 0.009 L, which gave a half-time of myocardium: blood equilibration of 2.37 min. The distribution volume of the lungs was 5.40 ± 0.23 L, with an apparent first-order loss of 1.02 L min−1 representing deep distribution or metabolism. The validity of the model was tested by comparing the predictions of the model with the equivalent data collected in 6 sheep when lignocaine (89 mg) was administered via a complex dose regimen with a faster initial rate of infusion (39.1 mg min−1), declining exponentially to basal infusion rate (7.02 mg min−1) over 8 min. The predictions of the model were in general agreement with these data.
It is concluded that the model was sufficient to account for the effect of altered dose regimens of lignocaine on the time-course of its myocardial concentrations.
Stereoselective Metabolism of the Monoterpene Carvone by Rat and Human Liver Microsomes
Authors: Jäger Walter , Mayer Marion , Platzer Peter , Reznicek Gottfried , Dietrich Hermann , Buchbauer Gerhard 
Published: October 2002

Abstract
The large amounts of carvone enantiomers consumed as food additives and in dental formulations justifies the evaluation of their biotransformation pathway. The in-vitro metabolism of R-(—)- and S-(+)-carvone was studied in rat and human liver microsomes using chiral gas chromatography.
Stereoselective biotransformation was observed when each enantiomer was incubated separately with liver microsomes. 4R, 6S-(—)-Carveol was NADPH-dependently formed from R-(—)-carvone, whereas 4S, 6S-(+)-carveol was produced from S-(+)-carvone. Metabolite formation followed Michaelis-Menten kinetics exhibiting a significant lower apparent Km (Michaelis-Menten Constant) for 4R, 6S-(—)-carveol compared with 4S, 6S-(+)-carveol in rat and human liver microsomes (28.4 ± 10.6 μM and 69.4 ± 10.3 μM vs 33.6 ± 8.5 μM and 98.3 ± 22.4 μM). The maximal formation rate (Vmax) determined in the same microsomal preparations yielded 30.2 ± 5.0 and 32.3 ± 3.9 pmol (mg protein)−1 min−1 in rat liver and 55.3 ± 5.7 and 65.2 ± 4.3 pmol (mg protein)−1 min−1 in human liver microsomes. Phase II conjugation of the carveol isomers by rat and human liver microsomes in the presence of UDPGA (uridine S'-diphosphogluaronic acid) only revealed glucuronidation of 4R, 6S-(—)-carveol. Vmax for glucuronide formation was more than 4-fold higher in the rat liver compared with human liver preparations (185.9 ± 34.5 and 42.6 ± 7.1 pmol (mg protein)−1 min−1, respectively). Km values, however, showed no species-related difference (13.9 ± 4.1 μM and 10.2 ± 2.2 μM).
This study demonstrated stereoselectivity in phase-I and phase-II metabolism for R-(—)- and S-(+)-carvone and might be predictive for carvone biotransformation in man.
Effects of Pegylated Recombinant Human Megakaryocyte Growth and Development Factor on 5-Fluorouracil-induced Thrombocytopenia in Balloon-injured Rats
Authors: Harada Katsuhiko , Tazunoki Yoshiko , Ide Youichi , Takeuchi Akihiko , Kawahara Jun-Ichi , Suzuki Takamoto 
Published: October 2002

Abstract
We examined whether pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) affected 5-fluorouracil-induced thrombocytopenia without inducing more severe intimal thickening after injury to rat carotid arteries. Rat carotid arteries were injured using a balloon catheter on day 0. 5-Fluorouracil (100 mg kg−1) or vehicle was intravenously administered on day 1 in balloon-injured rats. PEG-rHuMGDF (100 μg kg−1) or vehicle was intravenously administered once a day on days 1–5 to balloon-injured rats given 5-fluorouracil or vehicle.
5-Fluorouracil (100 mg kg−1, i.v.) caused a significant decrease in the platelet count from day 3 and peaked on days 7–9 in balloon-injured rats. PEG-rHuMGDF (100 μg kg−1, i.v.) reduced this decrease on days 9 and 11. The administration of PEG-rHuMGDF did not accelerate the intimal thickening of balloon-injured arteries in rats treated with 5-fluorouracil compared with control balloon-injured rats. PEG-rHuMGDF did not increase plasma tumour growth factor-β (TGF-β1) from days 0–9 in balloon-injured rats compared with control balloon-injured rats.
These results suggest that PEG-rHuMGDF ameliorated 5-fluorouracil-induced thrombocytopenia without accelerating the intimal thickening of balloon-injured arteries.
Histamine Release Induced by Antimicrobial Agents and Effects of Antimicrobial Agents on Vancomycin-induced Histamine Release from Rat Peritoneal Mast Cells
Authors: Toyoguchi Teiko , Ebihara Mitsutaka , Ojima Fumiyoshi , Hosoya Jun , Shoji Tohru , Nakagawa Yoshito 
Published: October 2002

Abstract
Vancomycin and certain fungicides may cause anaphylactoid reactions. We investigated the effects of vancomycin, miconazole and fluconazole on histamine release in rat peritoneal mast cells. Vancomycin and miconazole provoked histamine release in a dose-dependent manner. In contrast, fluconazole did not provoke histamine release at concentrations of 3 times 10−6 - 3 times 10 −3 m.
Vancomycin is efficacious in the treatment of Gram-positive bacterial infections; patients presenting themselves with mixed infections require concomitant therapy with a second antimicrobial agent. We investigated the effect of fosfomycin sodium, cilastatin sodium or fluconazole on vancomycin-induced histamine release. Fosfomycin sodium inhibited vancomycin-induced histamine release but neither cilastatin sodium nor fluconazole inhibited it in the mole ratios of daily doses used in humans.
These results suggest that vancomycin and miconazole provoke histamine release in rat mast cells, but that fluconazole probably does not, while fosfomycin sodium may inhibit vancomycin-induced histamine release.
Protection of Rat Hepatocytes Exposed to CCl4 In-vitro by Cynandione A, a Biacetophenone from Cynanchum wilfordii
Authors: Lee Mi Kyeong , Yeo Hosup , Kim Jinwoong , Kim YOUNG CHOONG 
Published: October 2002

Abstract
To identify hepatoprotective agents from plant sources we use primary cultures of rat hepatocytes injured by CCl4. The hepatoprotective agents are the compounds that mitigate the injury caused by CCl4. Using this system we have investigated the biochemical mechanisms involved in the hepatoprotective activity of cynandione A, a biacetopherone, isolated from the roots of Cynanchum wilfordii Hemsley (Asclepiadaceae). Cynandione A (50 μm) significantly reduced (approximately 50%) the release into the culture medium of glutamic pyruvic transaminase and sorbitol dehydrogenase from the primary cultures of rat hepatocytes exposed to CCl4. Glutathione, superoxide dismutase, catalase and glutathione reductase play important roles in the cellular defence against oxidative stress. Cynandione A appeared to protect primary cultured rat hepatocytes exposed to CCl4 from significant drops in the levels of each of these four specific markers. Cynandione A also ameliorated lipid peroxidation by up to 50% as demonstrated by a reduction in the production of malondialdehyde.
These results suggest that cynandione A protected the hepatocytes from CCl4-injury by maintaining the level of glutathione and by inhibiting the production of malondialdehyde, due to its radical scavenging properties.
Chemical Characterization and Biological Activity of Macfadyena unguis-cati (Bignoniaceae)
Authors: Duarte D S , Dolabela M F , Salas C E , Raslan D S , Oliveiras A B , Nenninger A , Wiedemann B , Wagner H , Lombardi J , Lopes M T P 
Published: October 2002

Abstract
Macfadyena unguis-cati (L.) has been widely used in folk medicine as an anti-inflammatory, antimalarial and antivenereal. The purpose of this study was to chemically characterize the main plant components, and to evaluate the biological properties of some of the fractions derived from leaves (MACb) and liana (MACa) of this plant.
Chemical characterization allowed the identification of the compounds corymboside, vicenin-2, quercitrin, chlorogenic acid, isochlorogenic acid, lupeol, β-sitosterol, β-sitosterylglucoside, allantoin and lapachol.
The biological screening of fractions and/or purified substances derived from fractions revealed antitumoral and antitrypanosomal activities in fractions MACa/lapachol and MACb/MACb21, respectively. The anti-lipoxygenase and anti-cyclooxygenase effect seen in fractions MACa and MACb showed a partial correlation with the anti-inflammatory property attributed to this plant.
Membrane Permeation by Multidrug-resistance-modulators and Non-modulators: Effects of Hydrophobicity and Electric Charge
Authors: Castaing Madeleine , Brouant Pierre , Loiseau Alain , Santelli-Rouvier Christiane , Santelli Maurice , Alibert-Franco Sandrine , Mahamoud Abdallah , Barbe Jacques 
Published: October 2002

Abstract
This study was designed to test the hypothesis that lipophilic cationic drugs with only roughly similar structures mediate the reversal of multidrug-resistance (MDR) by interacting with membrane phospholipids. The permeation properties of MDR-modulators and non-modulators were studied by quantifying their ability to induce the leakage of Sulphan blue through the membrane of negatively charged unilamellar liposomes.
Of the 22 compounds under investigation, only those bearing a net positive electric charge per molecule (z) ≥0.2 induced dye leakage. All these efficient drugs are well-known MDR-modulators: calcium-channel blockers (propranolol, verapamil, diltiazem and dipyridamole), calmodulin antagonists (clomipramine and thioridazine) and antiparasitic agents (mepacrine, thioacridine derivatives and quinine). The non-modulators tested, including antineoplasic agents and steroids, did not induce any membrane permeation. The permeation process was a co-operative one (1.1 &lt; Hill coefficient &lt; 4.1) and the permeation doses inducing 50% dye leakage (PD50) were 1.9–11.2 mm. The permeation ability of the MDR-modulators (log(1/PD50)) increased significantly with octanol-buffer distributions per unit net electric charge ((logD)/z).
The results provide evidence that a complex interplay occurs between the electric charge and the lipophilicity of the MDR-modulators when a dye leakage is induced through model membranes, and probably also when the MDR is reversed in leukaemic cells.
Effect of P450 Isozyme-selective Inhibitors on In-vitro Metabolism of Retinoic Acid by Rat Hepatic Microsomes
Authors: Ahmad Mobashar , Nicholls Paul J , Smith H John , Ahmadi Masoud 
Published: October 2002

Abstract
Cytochrome P450-mediated 4-hydroxylation of retinoic acid is an important pathway in the termination of its biological action and the activity of certain P450 isozymes has been studied in non-induced male rat hepatic microsomes using isozyme-selective inhibitors.
The importance of the activity of the isozyme to retinoic acid metabolism was, 2A6 (diethyl dithiocarbamate as selective inhibitor) &gt; 1A1/1A2 (7,8-benzoflavone) &gt;&gt; 1A1 (ellipticine) &gt; 3A4 (naringenin, ketoconazole) as shown by the respective apparent IC50 values of 0.12, 0.34, 2.7, 9.25 and 13.5 μm with 2C8–10, 2D6 and 2E1 having little effect on metabolism.
It is concluded that although the P450 3A family normally constitutes half the total rat hepatic P450 activity, other hepatic isozymes (1A1, 1A2 and 2A6) are also involved in retinoic acid metabolism. This suggests that the horizons for the design of potential anticancer agents acting through inhibition of retinoic acid metabolism may be widened to include structures which do not resemble the established hetereocyclic base P450 3A4 inhibitors.
Protective Effect of N-Acetylcysteine on Rat Liver Cell Membrane During Methanol Intoxication
Authors: Dobrzyñska I , Skrzydlewska E , Kasacka I , Figaszewski Z 
Published: October 2002

Abstract
Methanol is oxidized in-vivo to formaldehyde and then to formate, and these processes are accompanied by the generation of free radicals. We have studied the effect of N-acetylcysteine on liver cell membrane from rats intoxicated with methanol (3.0 g kg−1).
Evaluation of the effect was achieved by several methods. Lipid peroxidation and surface charge density were measured. An ultrastructural study of the liver cells was undertaken. The concentration of marker enzymes of liver damage (alanine aminotransferase and aspartate aminotransferase) in blood serum was measured.
Methanol administration caused an increase in lipid peroxidation products (approximately 30%) as well as in surface charge density (approximately 60%). This might have resulted in the membrane liver cell damage visible under electron microscopy and a leak of alanine aminotransferase and aspartate aminotransferase into the blood (increase of approximately 70 and 50%, respectively). Ingestion of N-acetylcysteine with methanol partially prevented these methanol-induced changes. Compared with the control group, lipid peroxidation was increased by approximately 3% and surface charge density by approximately 30%. Alanine aminotransferase and aspartate aminotransferase activity increased by 9 and 8%, respectively, compared with the control group.
The results suggested that N-acetylcysteine was an effective antioxidant in methanol intoxication. It may have efficacy in protecting free radical damage to liver cells following methanol intoxication.
Sedum telephium L. Polysaccharide Content Affects MRC5 Cell Adhesion to Laminin and Fibronectin
Authors: Raimondi L , Banchelli G , Dalmazzi D , Mulinacci N , Romani A , Vincieri F F , Pirisino R 
Published: October 2002

Abstract
In traditional medicine the fresh leaves and juice of Sedum telephium L. are used as wound-healing promoters. Cell adhesion represents a primary event in wound repair and in tissue homeostasis, and therefore we have investigated the effect of Sedum juice and its main fractions, polysaccharides and flavonols, on human fibroblast (MRC5) adhesion to fibronectin and laminin.
Our findings revealed that total Sedum juice strongly inhibited cell adhesion to laminin and fibronectin (EC50 1.03 ± 0.12 mg mL−1). This anti-adhesive feature was concentrated mainly in the two polysaccharide fractions (EC50 values comprised between 0.09 and 0.44 mg mL−1). The flavonol fractions did not seem to contribute to this effect.
A first attempt to elucidate the polysaccharide-related anti-adhesive feature of Sedum juice was also performed.
The results confirmed that natural polysaccharides, with chemical structures different from heparin, were able to interfere with integrin-mediated cell behaviour and they contributed to the outstanding effects of Sedum juice and to the role of polysaccharides in cell-matrix interaction.
Review Nimesulide: Some Pharmaceutical and Pharmacological Aspects—An Update
Authors: Singla Anil K , Chawla M , Singh A 
Published: October 2002

Abstract
Nimesulide, a non-steroidal anti-inflammatory drug (NSAID), is administered orally or rectally twice daily for a variety of inflammation and pain states. This is a unique NSAID, not only because of its chemical structure but also because of its specific affinity to inhibit cyclooxygenase-2 (COX-2), thus exerting milder effects on the gastrointestinal mucosa. Current data on selective COX-2 inhibitors suggest that they may have an efficacy similar to that of standard NSAIDs. Initial general clinical experience with selective COX-2 inhibitors appears to show that they are particularly promising in individuals at risk because of renal diseases, hypertension or congestive heart failure.
Various experimental models and clinical studies have demonstrated the anti-inflammatory efficacy of nimesulide. Nimesulide is superior, or at least comparable in efficacy, to other NSAIDs, but is better tolerated and has less potential for adverse reactions. Thus, selective COX-2 inhibitors should have anti-inflammatory effects devoid of side effects on the kidney and stomach. They may also demonstrate new important therapeutic benefits as anticancer agents as well as help prevention of premature labour and even retard the progression of Alzheimer's disease. No clinically significant drug interactions have been reported for nimesulide.
Not much has been reported about the pharmaceutical aspects of nimesulide. Its poor aqueous solubility poses bioavailability problems in-vivo. This could be overcome by the formation of inclusion complexes with β-cyclodextrin, as has been reported by various researchers. However, absence of any in-vivo data regarding the relative absorption of nimesulide from β-cyclodextrin complex compared with that from conventional formulations of the drug makes the use of such fast-releasing complexes rather questionable. Only a limited number of assay procedures (HPLC, spectrophotometric, spectrofluorimetric) for the determination of nimesulide and its metabolite in plasma/urine samples or in dosage forms have been reported in the literature.
The purpose of this review is to provide a concise overview of the pharmacological and pharmaceutical profile of nimesulide. Various investigations carried out recently are reported, although older references to research performed on nimesulide have also been included, where appropriate.
Uptake of Ibuprofen, Indomethacin and Ketoprofen into Isolated Rabbit Parietal Cells
Authors: Deninger Michael J , Schoenwald Ronald D 
Published: October 2002

Abstract
In the United States and other countries, non-steroidal anti-inflammatory drugs (NSAIDs) can be purchased without a prescription. Due to their widespread use, the drugs' most common side effect, gastric toxicity, becomes a more serious concern. Gastric toxicity can occur directly by contact with mucous membranes or indirectly by the inhibition of prostaglandin production in the gastric mucosa. We have studied the uptake of NSAIDs in gastric tissue, specifically parietal cells removed from the rabbit stomach.
New Zealand White rabbits were killed and then used to harvest parietal cells. The purified cells were used to study the uptake of ibuprofen, indomethacin and ketoprofen (NSAIDs) over time and under different experimental conditions.
The effects of concentration were investigated for all three NSAIDs. In addition, indomethacin and ibuprofen were used to investigate the mechanism of uptake. Studies were determined for the effects of varied extracellular pH from pH 6 to 8, and inhibitory conditions from depressed temperature (5°C), metabolic inhibitors (sodium azide and 2,4-dinitro-phenol), an ionophore (nigericin) and a sodium free support medium. The interaction of NSAIDs with lysed parietal cells was investigated also.
Initial rate data indicated that Michaelis-Menten kinetics were apparent; however, poor solubility of all three NSAIDs prevented complete characterization of the inclusion of a passive transport mechanism. Uptake showed a statistically significant increase (P = 0.01 to 0.05) as pH decreased, also suggesting contribution from a passive mechanism. Studies with inhibitors showed minimal effects. However, uptake at equilibrium for the ionophore, nigericin, showed a 10-fold increase over the control for ibuprofen (P = 0.005) and a 1.4-fold increase for indomethacin (P = 0.04). Depressed temperature (5°C) increased the initial rate and uptake at equilibrium 2.1- and 2.2-fold, respectively, for ibuprofen (P &lt; 0.01). For indomethacin depressed temperature increased the initial rate and uptake at equilibrium 2.7- and 5.2-fold, respectively (P &lt; 0.01). The increases at 5°C suggests that adsorption may be an important uptake component. Experiments with lysed parietal cells showed a non-specific uptake phenomenon, suggesting an adsorption component was occurring also.
Effect of Loperamide on Na+/d-Glucose Cotransporter Activity in Mouse Small Intestine
Authors: Klaren P H M , Giesberts A N , Chapman J , White S J , Taylor C J , Hardcastle P T , Hardcastle J 
Published: October 2002

Abstract
The μ-opioid agonist loperamide is an antidiarrhoeal drug which inhibits intestinal motility and secretion. Its anti-absorptive effects are less well investigated, but may be mediated through calmodulin. We have investigated further the effect of loperamide on the intestinal Na+-dependent d-glucose transporter (SGLT1). Brush-border membrane vesicles were prepared from mouse small intestine, and uptake of [3H]glucose was measured.
Na+-dependent glucose uptake displayed the typical overshoot at 34 s; the peak value was 1.6 nmol mg−1. The overshoot disappeared in the presence of phlorizin or when Na+ was replaced by K+. Extravesicular loperamide dose-dependently inhibited SGLT1 activity with an IC50 value of 450 μmol L−1. Loperamide displayed a mixed inhibition type: the apparent Vmax decreased from 0.9 to 0.5 nmol mg−1/15 s, the apparent Km increased from 0.23 to 1.13 mmol L−1 glucose. Na+ kinetics were more complex, but loperamide inhibited net glucose uptake by 90% at 100 mmol L−1 Na+. Glucose uptake was unchanged by agents affecting calmodulin activity. Loperamide inhibited intestinal Na+, K+-ATPase activity, whilst sucrase activity was unaffected.
SGLT1 activity was inhibited by loperamide, but this effect was not mediated through calmodulin. As this action is only evident at high concentrations of loperamide a non-specific mechanism may be involved.