bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uptake of quinolones by in-vitro human monocyte derived macrophages
Authors: Dorian Martine , Grellet Jean , Saux Marie C 
Published: July 2003

Abstract
We have developed an in-vitro model of monocyte-derived macrophage (MDMØ) to compare fluoroquinolone uptake in monocytes and derived macrophages. Monocyte-derived macrophages were obtained in-vitro by cultivating freshly isolated monocytes for seven days in RPMI 1640 medium, containing foetal calf serum and Rhu granulocyte-macrophage colony stimulating factor. Final suspensions contained 95% viable cells and 63% macrophages. Intra-macrophagic accumulation of ciprofloxacin, ofloxacin or sparfloxacin was measured at equilibrium after 30-min incubation in the presence of 16–18 μg mL−1 antibiotic. The results revealed low intra-cellular accumulation of ofloxacin in MDMØ (intracellular/extracellular ratio: IC/EC = 1.7). Ciprofloxacin and sparfloxacin uptake was significantly higher. The IC/EC ratios were only slightly increased in macrophages when compared with monocytes under the same experimental conditions. These results suggest that maturation of monocyte to macrophage has only a limited effect on basal quinolone uptake. Monocytic maturation cannot explain the important differences between fluoroquinolone accumulation in monocytes and tissue macrophages. Cell activation may be a greater determinant.
Effects of steroidal and non-steroidal antiphlogistic drugs on eicosanoid synthesis in irritated skin: studies with the isolated perfused bovine udder
Authors: Bäumer Wolfgang , Kietzmann Manfred 
Published: July 2003

Abstract
Using the isolated perfused bovine udder as an in-vitro model of skin inflammation, the effects of topically administered arachidonic acid on prostaglandin and leukotriene synthesis have been shown previously. In this study, the effects of indometacin (indomethacin) and clobetasol-17-propionate (administered topically) as well as flunixin meglumine and meloxicam (administered via the perfusion fluid) have been studied. Compared with controls, arachidonic acid caused a significant increase in the dermal prostaglandin E2 (PGE2) and peptidoleukotriene (LTC4/D4/E4) concentration. Topical treatment with indometacin (1.6 mg cm−2) and clobetasol-17-propionate (90 μg cm−2), which were administered 60 min before arachidonic acid administration, inhibited the inflammatory reaction. Flunixin meglumine (1 μg mL−1 perfusion fluid) was administered 30 min after and meloxicam (3 μg mL−1 perfusion fluid) was administered 60 min before arachidonic acid application. Three hours after arachidonic acid administration, a significant inhibition of PGE2 synthesis was induced by flunixin. In contrast, meloxicam showed only a slight effect. The effect of flunixin was comparable with in-vivo results. It is known from animal studies that anti-inflammatory effects of meloxicam are obvious within up to 6 h after treatment. Therefore, the incomplete effect of meloxicam may be explained pharmacokinetically. In conclusion, the described in-vitro model seems to be suitable for studies of pharmacological effects on eicosanoid synthesis in the skin.
Specific inhibition of Type II inosine monophosphate dehydrogenase activity of Tmolt4 T cell human leukaemia cells by 3-methoxy and di-benzohydroxamic acids, maleic hydrazide and malonic acids
Authors: Hall I H , Barnes B J , Ward E S , Wheaton J R , Izydore R A 
Published: July 2003

Abstract
Small-molecular-weight benzohydroxamic and malonic acids and maleic hydrazide proved to be potent inhibitors of the activity of human Tmolt4 leukaemia Type II IMP (inosine monophosphate) dehydrogenase (IMPDH) activity. They were competitive inhibitors with respect to IMPDH demonstrating Ki values in the range 2.57–41.3 μm, less than half the values of the IC50 (μm) for the inhibition of Type II IMPDH. The IC50 μm values positively correlated with the ability of each compound to inhibit crude IMPDH activity, de-novo purine and DNA syntheses and growth of the T leukaemia cell line. Compounds were not inhibitors of Type I IMPDH. Type I IMPDH predominates in normal resting cells compared with Type II which is found in rapidly proliferating cells. Discovery of agents which would selectivity target IMPDH found in proliferating cells should eliminate any antineoplastic therapeutic toxic effects in normal cells of the body.
Radical scavenging and xanthine oxidase inhibitory activity of phenolic compounds from Bridelia ferruginea stem bark
Authors: Cimanga K , Ying L , De Bruyne T , Apers S , Cos P , Hermans N , Bakana P , Tona L , Kambu K , Kalenda D T , Pieters L , Berghe D Vanden , Vlietinck A J 
Published: July 2003

Abstract
Bridelia ferruginea Benth. (Euphorbiaceae) is a subtropical medicinal plant widely used in traditional African medicine against various diseases, including rheumatic pains. Seven of its constituents (3-O-methylquercetin (1), 3,7,3′,4′-tetra-O-methylquercetin (rutisin, 2), myricetin (3), 3′,4′,5′-tri-O-methylmyricetin (ferrugin, 4), 3,3′,4′,5′-tetra-O-methylmyricetin (5), quercetin 3-O-glucoside (6), and a biflavanol gallocatechin-[4′-O-7]-epigallocatechin (7)) have been evaluated in-vitro in the xanthine-xanthine oxidase enzymatic system for inhibition of xanthine oxidase and radical scavenging activity. Results indicated that compounds 1, 3, 4 and 6 exhibited, at different levels, xanthine oxidase inhibiting and superoxide scavenging activity at micromolar concentrations, whereas compound 7 showed scavenging activity only. Compounds 2 and 5 were inactive in both cases. Study of the structure-activity relationship demonstrated that for flavonoids the xanthine oxidase inhibitory activity was reduced by methylation of the hydroxyl functionality at C-3 and in rings A and B. These results may partly explain and support the use of B. ferruginea stem bark for the treatment of rheumatic pains in traditional medicine.
Inhibition of chemical carcinogenesis by berberine in rats and mice
Authors: Anis K V , Rajeshkumar N V , Kuttan Ramadasan 
Published: July 2003

Abstract
Berberine, an alkaloid isolated from the plant Berberis aristata, has been found to inhibit significantly the carcinogenesis induced by 20-methylcholanthrene (200 μg/0.1 mL/mouse) or N-nitrosodiethylamine (NDEA; 0.02% NDEA in distilled water, 2.5 mL/animal by gavage, five days a week for 20 weeks) in a dose-dependent manner in small animals. Administration of berberine (0.5, 2.5 or 5.0 mg kg−1) could reduce significantly the incidenceof tumour in animals after an injection of 20-methylcholanthrene and increased their life span compared with the control. When berberine (10, 25 or 50 mg kg−1) was administered simultaneously with NDEA, the markers of liver injury (liver weight, γ-glutamyl transpeptidase activity and glutathione S-transferase level) were reduced significantly compared with animals treated with NDEA only, which resulted in all the values being elevated. A similar decrease was noted inthe serum levels of lipid peroxide, bilirubin and glutamate pyruvate transaminase. Morphology of liver tissue and levels of marker enzymes indicated that berberine offered protection against chemical carcinogenesis.
St John's wort (Hypericum perforatum L.): a review of its chemistry, pharmacology and clinical properties
Authors: Barnes Joanne , Anderson Linda A , Phillipson J David 
Published: July 2003

Abstract
The chemical composition of St. John's wort has been well-studied. Documented pharmacological activities, including antidepressant, antiviral, and antibacterial effects, provide supporting evidence for several of the traditional uses stated for St John's wort. Many pharmacological activities appear to be attributable to hypericin and to the flavonoid constituents; hypericin is also reported to be responsible for the photosensitive reactions that have been documented for St. John's wort. With regard to the antidepressant effects of St John's wort, hyperforin, rather than hypericin as originally thought, has emerged as one of the major constituents responsible for antidepressant activity. Further research is required to determine which other constituents contribute to the antidepressant effect.
Evidence from randomised controlled trials has confirmed the efficacy of St John's wort extracts over placebo in the treatment of mild-to-moderately severe depression. Other randomised controlled studies have provided some evidence that St John's wort extracts are as effective as some standard antidepressants in mild-to-moderate depression. There is still a need for further trials to assess the efficacy of St John's wort extracts, compared with that of standard antidepressants, particularly newer antidepressant agents, such as the selective serotonin reuptake inhibitors (recent comparative studies with fluoxetine and sertraline have been conducted). Also, there is a need for further studies in well-defined groups of patients, in different types of depression, and conducted over longer periods in order to determine long-term safety. St John's wort does appear to have a more favourable short-term safety profile than do standard antidepressants, a factor that is likely to be important in patients continuing to take medication.
Concerns have been raised over interactions between St John's wort and certain prescribed medicines (including warfarin, ciclosporin, theophylline, digoxin, HIV protease inhibitors, anticonvulsants, selective serotonin reuptake inhibitors, triptans, oral contraceptives); advice is that patients taking these medicines should stop taking St John's wort, generally after seeking professional advice as dose adjustment of conventional treatment may be necessary.
Tissue distribution of radioactivity following intranasal administration of radioactive microspheres
Authors: Eyles J E , Spiers I D , Williamson E D , Alpar H O 
Published: July 2003

Abstract
The aim of this study was to increase understanding of the kinetics of microparticle distribution and elimination following intranasal application. To do this we investigated the in-vivo distribution of radioactivity following intranasal instillation of scandium-46 labelled styrene-divinyl benzene 7-μm-diameter microspheres. Groups of BALB/c mice received 0.250 mg (47.5 kBq) particles suspended in either 50-μl or 10-μl volumes of phosphate buffered saline. The in-vivo distribution of radioactivity was influenced by the volume of liquid that was used to instil the microsphere suspension. Comparatively large (50 μl) administration vehicle volumes resulted in substantial bronchopulmonary deposition (∼ 50% of administered dose). Intranasal instillation of microspheres suspended in 10-μl volumes tended to restrict particle deposition initially to the nasal cavity. For both administration vehicle volumes tested, the radioactivity per unit mass of excised nasal-associated lymphoid tissue (NALT) was found to be consistently elevated relative to other tissues. This corroborates the findings of other workers who have previously identified NALT as an active site of microparticle accumulation following intranasal application. Elimination via the alimentary canal was the principal fate of intranasally applied radiolabeled material. No significant concentration of radioactivity within excised gut-associated lymphoid tissue (GALT) (Peyer's patches) was noted. At latter time points we observed, in mice that received the 50-μl volume particle suspension nasally, accumulation of potentially relevant quantities of radioactivity in the liver (0.3% after 576 h) and spleen (0.04% after 576 h). Thus, our data corroborate the notion that epithelial membranes in the lung are probably less exclusive to the entry of microparticulates into systemic compartments than are those mucosae in the gastrointestinal tract or nasopharynx. This effect may contribute to the effectiveness of pulmonary delivered antigen-loaded microparticles as humoral immunogens.
The change in characteristics of microcrystalline cellulose during wet granulation using a high-shear mixer
Authors: Suzuki Tatsuya , Kikuchi Hiroshi , Yamamura Shigeo , Terada Katsuhide , Yamamoto Keiji 
Published: July 2003

Abstract
The objective of this study was to investigate the mechanism of hard granule formation and to demonstrate the applicability of X-ray diffraction methods for studying the polymeric pharmaceutical excipients. Using a high-shear mixer, microcrystalline cellulose (MCC) was granulated with water as the granulating liquid. The hardness of the MCC granules increased with granulation time and the amount of water added. The specific surface area measured by the N2 adsorption method was reduced during the process. Crystallite size of cellulose, calculated by Scherrer's equation adapted for wide angle X-ray diffraction method, decreased with granulation time and with increasing amounts of water added. Debye plots for X-ray small scattering patterns suggested that the average magnitude of the continuous solid region in MCC granules became significantly greater, whereas the specific surface area of the MCC granules, calculated from Debye plots, became smaller in comparison with that of intact MCC. These findings suggested that the long-chain structures in MCC were disrupted, resulting in smaller units with shorter chain lengths due to the strong shear force of the impeller. These smaller units then form a network within the granules. Thus, MCC granules are strengthened with longer granulation time and greater amounts of water, resulting in a more intricate network. The change in MCC chain length and physical structure can be experimentally detected using the small-angle X-ray scattering and wide-angle powder X-ray diffraction methods.
Water quantitatively induces the mucoadhesion of liquid crystalline phases of glyceryl monooleate
Authors: Lee Jaehwi , Young Simon A , Kellaway Ian W 
Published: July 2003

Abstract
The possible role of water inthe mucoadhesion phenomenon exhibitedby the liquid crystalline phases of glyceryl monooleate was investigated using an in-vitro tensile strength technique. The mucoadhesion of the liquid crystalline phases of glyceryl monooleate was found to occur following uptake of water. The mucoadhesive force of the cubic phase was consistent since it is not capable of taking up additional water. An increase in pre-load period greatly facilitated the mucoadhesion of glyceryl monooleate (0% w/w initial water content), suggesting that the mucoadhesion is dependent upon the extent of the dehydration of the substrate. A good linear relationship between initial water content of the liquid crystalline phases and mucoadhesive force led to the conclusion that the mucoadhesive force increased with decreasing initial water concentration. Rheological properties of the liquid crystalline phases were also studied to allow a correlation between physical changes and mucoadhesion of the liquid crystalline phases, revealing that higher water concentrations in the liquid crystalline phases led to a more ordered structure that showed less mucoadhesion. The results of this study indicated that the mucoadhesive force ofthe liquid crystalline phases of glyceryl monooleate is determined by the capability to take up water from a water-rich environment. It may, therefore, be advantageous to use the lamellar phase as a buccal drug carrier as opposed to the relatively less mucoadhesive cubic phase.
Percutaneous absorption of the montoterpene carvone: implication of stereoselective metabolism on blood levels
Authors: Jäger Walter , Mayer Marion , Reznicek Gottfried , Buchbauer Gerhard 
Published: July 2003

Abstract
The purpose of this study was to determine whether an enantioselective difference in the metabolism of topically applied R-(—)- and S-(+)-carvone could be observed in man. In a previous investigation we found that R-(—)- and S-(+)-carvone are stereoselectively biotransformed by human liver microsomes to 4R,6S-(—)- and 4S,6S-(+)-carveol, respectively, and 4R,6S-(—)-carveol is further glucuronidated. We therefore investigated the metabolism and pharmacokinetics of R-(—)- and S-(+)-carvone in four healthy subjects using chiral gas chromatography as the analytical method. Following separate topical applications at a dose of 300 mg, R-(—)- and S-(+)-carvone were rapidly absorbed, resulting in significantly higher Cmax levels for S-(+)-carvone (88.0 vs 23.9 ng mL−1) and longer distribution half-lives (t2α1) (19.4 vs 7.8 min), resulting in 3.4-fold higher areas under the blood concentration-time curves (5420 vs 1611 ng min mL−1). The biotransformation products for both enantiomers in plasma were below detection limit. Analysis of control- and β-glucuronidase pretreated urine samples, however, revealed a stereoselective metabolism of R-(—)-carvone to 4R,6S-(—)-carveol and 4R,6S-(—)-carveol glucuronide. No metabolites could be found in urine samples after S-(+)-carvone application. These data indicate that stereoselectivity in phase-I and phase-II metabolism has significant effects on R-(—)- and S-(+)-carvone pharmacokinetics. This might serve to explain the increased blood levels of S-(+)-carvone.
In-vivo kinetics of the interaction between midazolam and erythromycin in rats, taking account of metabolic intermediate complex formation
Authors: Takedomi Sayuri , Matsuo Hirotami , Yamano Katsuhiro , Ohtani Hisakazu , Sawada Yasufumi 
Published: July 2003

Abstract
To predict, quantitatively, the extent of drug interaction during repeated administration of a metabolic inhibitor, we analysed the effects of erythromycin treatment under several regimens on the area under the concentration curve (AUC) of midazolam in rats. Midazolam was administered into the portal vein 12 h after erythromycin treatment for 1, 2 or 3 days, or 12, 24, 36, 48, 72 and 96 h after erythromycin treatment for 4 days, and the plasma-concentration profiles of midazolam were analysed to assess the AUC. Moreover, the contents of total cytochrome P450 and inactive metabolic intermediate (MI) complex were simultaneously quantitated. While the AUC value of midazolam was not affected by the administration of erythromycin for 1 day, repeated administration of erythromycin evoked an increase in AUC ratio (AUC in erythromycin-treated rats/AUC in vehicle-treated rats), which reached a maximum value of 1.99 at 12 h after 4 days' treatment with erythromycin. The total content of cytochrome P450 in liver microsomes was unaffected by erythromycin treatment. Although the MI complex was undetectable after 1 day's treatment with erythromycin, its content increased with duration of erythromycin treatment, and the complex disappeared after the end of erythromycin treatment with a half-life of 12.3 h. In conclusion, the interaction between erythromycin and midazolam could be well predicted when the formation of MI complex in the liver was taken into account.
Synthesis of flavonoids and their effects on aldose reductase and sorbitol accumulation in streptozotocin-induced diabetic rat tissues
Authors: Lim Soon Sung , Jung Sang Hoon , Ji Jun , Shin Kuk Hyun , Keum Sam Rok 
Published: July 2003

Abstract
Aldose reductase, the key enzyme of the polyol pathway, and oxidative stress are known to play important roles in the complications of diabetes. A drug with potent inhibition of aldose reductase and oxidative stress, therefore, would be a most promising drug for the prevention of diabetic complications. The purpose of this study was to develop new compounds with these dual-effects through synthesis of chalcone derivatives and by examining the structure-activity relationships on the inhibition of rat lens aldose reductase as well as on antioxidant effects. A series of 35 flavonoid derivatives were synthesized by Winget's condensation, oxidation, and reduction of appropriate acetophenones with appropriate benzaldehydes. The inhibitory activity of these derivatives on rat lens aldose reductase and their antioxidant effects, measured using Cu2+ chelation and radical scavenging activities on 1,1-diphenyl-picrylhydrazyl in-vitro, were evaluated. Their effect on sorbitol accumulation in the red blood cells, lenses and sciatic nerves of streptozotocin-induced diabetic rats was also estimated. Among the new flavonoid derivatives synthesized, those with the 2′,4′-dihydroxyl groups in the A ring such as 2,4,2′,4′-tetrahydroxychalcone (22), 2,2′,4′-trihydroxychalcone (11), 2′,4′-dihydroxy-2,4-dimethylchalcone (21) and 3,4,2′,4′-tetrahydroxychalcone (18) were found to possess the highest rat lens aldose reductase inhibitory activity in-vitro, their IC50 values (concentration of inhibitors giving 50% inhibition of enzyme activity) being 1.6 times 10−7, 3.8 times 10−7, 4.0 times 10−7 and 4.6 times 10−7 M, respectively. All of the chalcones tested except 3, 18, 23 with o-dihydroxy or hydroquinone moiety showed a weak free radical scavenging activity. In the in-vivo experiments, however, compound 18 with o-dihydroxy moiety in the B ring showed the strongest inhibitory activity in the accumulation of sorbitol in the tissues. It also showed the strongest activity in transition metal chelation and free radical scavenging activity. Of the 35 4,2′-dihydroxyl and 2′,4′-dihydroxyl derivatives of flavonoid synthesized, including chalcone, flavone, flavanone, flavonol and dihydrochalcone, some chalcone derivatives synthesized were found to possess aldose reductase inhibition and antioxidant activities in-vitro as well as inhibition in the accumulation of sorbitol in the tissues in-vivo. 3,4,2′,4′-Tetrahydroxychalcone (18, butein) was the most promising compound for the prevention or treatment of diabetic complications.
Design, synthesis and biological evaluation of a sulfonylcyanoguanidine as thromboxane A2 receptor antagonist and thromboxane synthase inhibitor
Authors: Dogné Jean-Michel , Wouters Johan , Rolin Stéphanie , Michaux Catherine , Pochet Lionel , Durant François , Delarge Jacques , Masereel Bernard 
Published: July 2003

Abstract
The synthesis and the structure of N-isopropyl-N′-[2-(3′-methylphenylamino)-5-nitrobenzenesulfonyl] urea (14) was drawn from two thromboxane A2 receptor antagonists structurally related to torasemide. Compound 14 showed an IC50 value of 22 nm for the thromboxane A2 (TXA2) receptor of human washed platelets. Compound 14 prevented platelet aggregation induced by arachidonic acid (0.6 mm) and U-46619 (1 μm) with an IC50 value of 0.45 and 0.15 μm, respectively. Moreover, 14 relaxed the rat isolated aorta and guinea-pig trachea precontracted by U-46619, a TXA2 agonist. Its efficacy (IC50) was 20.4 and 5.47 nm, respectively. Finally, 14 (1 μm) completely inhibited TXA2 synthase of human platelets. The pKa value and the crystallographic data of 14 were determined and used to propose an interaction model between the TXA2 antagonists related to torasemide and their receptor.
Comparison of chemical components and antioxidant capacity of different Echinacea species
Authors: Sloley B Duff , Urichuk Liana J , Tywin Connie , Coutts Ronald T , Pang Peter K T , Shan Jacqueline J 
Published: July 2003

Abstract
Alcoholic extracts of the roots and leaves of three Echinacea species (E. purpurea, E. angustifolia and E. pallida) were analysed for the presence of characteristic chemicals by HPLC directly coupled to ultraviolet absorbance and electrospray mass spectrometric detectors. The method permitted rapid characterization and tentative identification of a large number of caffeoyl conjugates and alkamides in all the samples investigated. The roots of the three species differed markedly in their contents of characteristic compounds. Cichoric acid and verbascoside predominated in extracts of E. purpurea root whereas cynarine and dodeca-2E,4E,8Z,10Z/E-tetraenoic acid isobutylamide were the major chemicals characteristic of E. angustifolia root extracts. Echinacoside and 6-O-caffeoylechinacoside predominated in extracts of E. pallida roots. Characteristic alkamides were also examined by electrospray tandem mass spectrometry (MS/MS) and these compounds provided characteristic fragmentation patterns. Extracts of the roots and leaves of all three species were found to have antioxidant properties in a free radical scavenging assay and in a lipid peroxidation assay.