bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interactions of a series of novel spiropyranocoumarin derivatives with reactive oxygen species
Authors: Panteleon Vassiliki , Marakos Panagiotis , Pouli Nicole , Mikros Emmanuel , Andreadou Ioanna 
Published: July 2003

Abstract
A series of new spiro-substituted pyranocoumarin derivatives have been synthesized starting from the commercially available 7-hydroxycoumarin and the conformation of the pyran ring was investigated. The antioxidant activity of the compounds was evaluated in-vitro, by means of three different tests: the interaction with the stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH), the competition with DMSO for hydroxyl radicals scavenging ability and the quenching of superoxide anions generated by the enzymic xanthine–xanthine oxidase system. In the DPPH test the spiroadamantane derivative 13 was the most active and possessed a 40% inhibition at a concentration of 400 μm. All compounds successfully compete with DMSO for hydroxyl radicals generated by the Fe3+/ascorbic acid system. Compound 13 inhibited the oxidation of DMSO (3.125mm) by 93% at 2 mm and by 71% at 0.25 mm. The corresponding second-order rate constants have been estimated and all compounds demonstrated higher rate constants compared with the reference compounds, 7-hydroxycoumarin and mannitol. Derivatives possessing extended conjugation showed the highest inhibitory activity for superoxide anions generated by the xanthine–xanthine oxidase system, although the results of this experiment possessed partial parallelism with the results observed in the other two tests. The overall obtained data indicate that the size of the different spiro- substituents influence the degree of free radical scavenging and demonstrate the importance of extended conjugation for the anti-oxidant activity. Due to its multiple mechanism of protective action, derivative 13 may serve as a lead for the development of analogues that could be useful for the treatment of pathophysiological processes dependent upon reactive oxygen species.
Synergistic Capsicum–tea mixtures with anticancer activity
Authors: Morré D James , Morré Dorothy M 
Published: July 2003

Abstract
We have demonstrated a synergy between a decaffeinated green tea concentrate and a vanilloid-containing Capsicum preparation obtained commercially. At a ratio of 25 parts green tea concentrate to 1 part Capsicum preparation, the resultant product exhibited efficacy in the killing of cancer cells in culture 100-times that of green tea on a weight basis. These studies were guided by assays of the putative catechin-vanilloid target protein tNOX, a cell surface growth-related enzymatic activity specific to cancer. The activity of the protein target was inhibited by the tea catechins and the Capsicum vanilloids. As with growth, the tea and Capsicum preparations evaluated were synergistic in their inhibition of the target enzymatic activity.
Efficient Biliary Excretion of Susalimod, Probably via the Bromosulphthalein Carrier, Studied in a Chronic Bile Fistula Model in Dogs
Authors: Påhlman Ingrid , Wilén Maria , Bowald Staffan 
Published: July 2003

Abstract
Susalimod is a structural analogue of sulphasalazine, known to be extensively excreted in the bile in various animal species and for inducing bile duct hyperplasia after long-term treatment of the dog with doses exceeding 25 mg kg−1. In this study local concentrations of susalimod in the bile duct were determined after oral administration in dogs.
A chronic bile fistula experimental model was designed to affect the bile duct as little as possible. The dogs received repeated oral doses of 25–150 mg kg−1 day−1 for 5 days; these doses had been used in previous toxicology studies. Extremely high biliary concentrations of unchanged susalimod (20 000–43 000 μm) were measured. Biliary excretion approached saturation at the higher doses, resulting in super-proportional increases in peripheral plasma concentrations as the dose was increased. The maximal bile/plasma concentration ratio was 4300. The high biliary clearance was indicative of almost complete first-pass elimination at doses below saturation of the elimination process. Interaction studies with the biliary excretion marker bromosulphthalein (BSP) demonstrated that susalimod and BSP probably share the same carrier transport system in biliary excretion. The elimination of BSP from plasma was prolonged 20 times and the biliary excretion rate was markedly reduced when susalimod was co-administered with BSP.
These results show that susalimod is highly enriched in the bile, in a saturable manner, after oral administration. The compound interacts with the biliary excretion of BSP, suggesting that it shares the same carrier-mediated transport system.
Dose-dependent Intestinal and Hepatic First-pass Metabolism of Midazolam, a Cytochrome P450 3A Substrate with Differently Modulated Enzyme Activity in Rats
Authors: Higashikawa Fumiko , Murakami Teruo , Kaneda Tatsuya , Kato Akiko , Takano Mikihisa 
Published: July 2003

Abstract
The dose-dependent first-pass metabolism of midazolam, a cytochrome P450 (CYP) 3A substrate, was separately estimated in the intestine and liver after administration into a jejunal loop of rats with differently modulated enzyme activity. Modulation of CYP3A enzyme activity of Sprague-Dawley rats was performed by pretreating the rats with inducers such as dexamethasone or by co-administering ketoconazole (an inhibitor) with midazolam.
Bioavailabilities of midazolam administered into the jejunal loop at a dose of 10 μmol were 12% in untreated (control) rats, and 2% in dexamethasone-pretreated rats. Coadministered ketoconazole (2 μmol) significantly increased the bioavailability to 53% and 7%, respectively, in these rats. The intestinal first-pass metabolism of midazolam administered into the jejunal loop at a dose of 50nmol in untreated and dexamethasone-pretreated rats, estimated by the mesenteric blood-collecting method in-situ, was 25% and 49% of absorbed amount, respectively. The intestinal first-pass metabolism of midazolam was reduced when ketoconazole (0.5 μmol) was co-administered or when the dose of midazolam was increased to 0.5 μmmol in these rats. Assuming that the contribution of intestinal first-pass metabolism could be negligible when midazolam was administered at a much higher dose of 10 μmol, the estimated hepatic first-pass metabolism of midazolam at a dose of 10 μmol in untreated rats, dexamethasone-pretreated rats, untreated rats given ketoconazole, and dexamethasone-pretreated rats given ketoconazole was, respectively, 86, 97, 46, and 92% of the amounts absorbed.
In conclusion, the dose-dependent intestinal first-pass metabolism and the hepatic first-pass metabolism of midazolam in rats with differently modulated CYP3A activities was quantitatively estimated by in-vivo and in-situ absorption studies.
Debromination of (α-Bromoiso-valeryl)urea Catalysed by Rat Blood
Authors: Kitamura Shigeyuki , Kuwasako Mie , Sugihara Kazumi , Tatsumi Kiyoshi , Ohta Shigeru 
Published: July 2003

Abstract
(α-Bromoiso-valeryl) urea, a sedative or hypnotic, is metabolized to (3-methylbutyryl)urea by reductive debromination. This study was designed to evaluate the role of blood in the debromination of (α-bromoiso-valeryl) urea.
Rat blood containing an electron donor had significant debrominating activity toward (α-bromoiso-valeryl)urea. This debromination proceeded by enzymatic and non-enzymatic processes which required both NADH (or NADPH) and flavin mononucleotide (FMN), under anaerobic conditions. The debrominating activity was sensitive to inhibition by carbon monoxide, and the pH optimum was 8.5. When FMN was replaced by flavin adenine dinucleotide (FAD) or riboflavin, similar results were obtained. The optimum concentration of flavins was 10−4m. The reductive debromination was also mediated by rat erythrocytes, but not by plasma. When the blood or erythrocytes were boiled, the debrominating activity was not abolished, but was enhanced, suggesting that the activity arises from the haemoglobin in erythrocytes, and haemoglobin had debrominating activity when supplemented with both a reduced pyridine nucleotide and a flavin. Furthermore, haematin had significant debrominating activity in the presence of these cofactors. The activity of haematin was also observed with the photochemically reduced form of FMN.
The results imply that the debromination proceeds in two steps—enzymatic or non-enzymatic reduction of a flavin such as FAD, FMN or riboflavin by NADPH or NADH, then non-enzymatic reductive debromination of (α-bromoiso-valeryl)urea to (3-methyl-butyryl)urea catalysed by the haem group of rat haemoglobin in the presence of the reduced flavin.
Reductive Debromination of (α-Bromoiso-valeryl)urea by Intestinal Bacteria
Authors: Kitamura Shigeyuki , Kuwasako Mie , Ohta Shigeru , Tatsumi Kiyoshi 
Published: July 2003

Abstract
The reductive debromination of the hypnotic (α-bromoiso-valeryl)urea to (3-methylbutyryl)urea by intestinal bacteria has been studied.
The caecal contents of rats, mice, hamsters, guinea-pigs and rabbits had significant debrominating activity toward (α-bromoiso-valeryl)urea. The cell-free extract of intestinal bacteria from the caecal contents of rats had debrominating activity in the presence of both flavin mononucleotide (FMN) and NADH (or NADPH) under anaerobic conditions. Seven pure strains of intestinal bacteria were also tested and the highest activity was observed with Clostridium sporogenes.The cell-free extract of Clostridium sporogeneshad debrominating activity in the presence of both FMN and NADH (or NADPH), and this activity was inhibited by sodium arsenite and potassium cyanide. The activity of the cellfree extract was also supported by the photochemically reduced form of FMN. The debromination in intestinal bacteria seems to proceed in two steps—reduction of flavins by bacterial flavin reductase(s) in the presence of NADPH or NADH, and then the reductive debromination of (α-bromoiso-valeryl)urea to (3-methylbutyryl)urea by bacterial dehalogenase(s) using the reduced flavins as an electron donor.
These results indicate that intestinal bacteria play a role in the reductive debromination of (α-bromoiso-valeryl)urea to (3-methylbutyryl)urea in animals. The debromination is inhibited by oxygen and dependent on flavins.
Interspecies Pharmacokinetic Comparisons and Allometric Scaling of Napsagatran, a Low Molecular Weight Thrombin Inhibitor
Authors: Lavé Thierry , Portmann Renée , Schenker Gabriela , Gianni Alvaro , Guenzi Alberto , Girometta Maria-Angela , Schmitt Monique 
Published: July 2003

Abstract
The objective of this work was to assess the pharmacokinetics of napsagatran, a low molecular weight thrombin inhibitor, after intravenous administration in a variety of laboratory animals, and prospectively to help design the first pharmacokinetic studies in man. Napsagatran is actively excreted into the bile and urine of various species and pronounced species-differences in its pharmacokinetics are observed. It is, therefore, an interesting compound to use in tests of the limitations of presently available inter-species scaling methods.
The present data suggest that allometric exponent values which are consistent with the values expected for physiological processes and small organic molecules are not necessarily associated with successful predictions in man when active transport processes are involved in the disposition of the compounds. For example, compared with the values observed in man, the clearance (CL), non-renal clearance (CLnr) and the volume of distribution at steady state (Vdss) were over-predicted by 3-, 7- and 2-fold, respectively, by use of allometry. Of the species tested, the cynomolgus monkey seemed to be the most useful for predicting kinetics in man when the approach based on concentration-time transformations was used. Thus, for half-life (t½), CL and Vdss, the observed mean values of 1.7 h, 459 mL min−1 and 24 L kg−1 in man were very close to the values predicted from the cynomolgus monkey (1.7h, 652 mL min−1 and 22 L kg−1, respectively).
The results show that there are large inter-species differences for kidney and liver excretion of napsagatran. This is probably because of the involvement of active transport processes, which compromised the kinetic extrapolation from animal to man, although a more thorough investigation of the transporters involved in the disposition of napsagatran is necessary to enable better understanding of the species differences observed.
Synthesis and Hypolipidaemic Evaluation of a Series of α-Asarone Analogues Related to Clofibrate in Mice
Authors: Labarrios Fernando , Garduño Leticia , Vidal Maria Del Rosario , Garcia Raul , Salazar Maria , Martinez Elizdath , Diaz Francisco , Chamorro German , Tamariz Joaquin 
Published: July 2003

Abstract
A series of α-asarone analogues related to clofibrate, containing an acetic acid group at C-2 of the aromatic ring, has been prepared as the acids or as the ethyl and methyl esters. The corresponding alcohols were also synthesized by reduction of the ethyl esters. The compounds were examined in hyperlipidaemic male mice to evaluate their ability to modify serum lipoprotein cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides after oral administration of 40 and 80 mg kg−1 for 6 days.
Except for methyl 2-methoxy-5-nitro-4-(2-propenyl)phenoxyacetate at either dose, these clofibrate-related phenoxyacetic acid derivatives were found to have significant hypocholesterolaemic activity. Levels of low-density lipoprotein cholesterol and triglycerides were significantly reduced and those of high-density lipoprotein cholesterol were elevated. 2-Methoxy-5-nitro-4-(2-propenyl)phenoxyacetic acid was active at both doses in all the tests. Clofibrate (150 mg kg−1) was more potent at reducing low-density lipoprotein cholesterol. No activity was detected for the alcohol derivatives.
These preliminary results suggest that this class of compound might have more promise as potential hypolipidaemic agents than other α-asarone derivatives. Further investigation and characterization should be performed to determine the mode of action of these agents on lipid metabolism.
Autocatalytic Degradation and Stability of Obidoxime
Authors: Rubnov Shai , Shats Igor , Levy Daniel , Amisar Shai , Schneider Hava 
Published: July 2003

Abstract
The degradation of obidoxime chloride (toxogonin), a reactivator of inhibited cholinesterase in organophosphorus poisoning, in concentrated (250 mg mL−1) acidic solutions was studied by HPLC at several temperatures to determine the degradation mechanism.
The degradation had an autocatalytic profile, which was found to result from the formation of formaldehyde during the degradation process. The activation energy of the hydrolysis was 26.2 kcal mol−1. The shelf-life (t90, the time by which 10% of the drug has degraded) at 25°C was calculated by several methods and found to be more than 37 years. Autocatalysis, a mechanism found only rarely in the degradation of pharmaceuticals, has not been reported in previous studies of obidoxime hydrolysis.
In-vivo Evaluation of Indium-111-Diethylenetriaminepentaacetic Acid-labelling for Determining the Sites and Rates of Protein Catabolism in Mice
Authors: Mukai Takahiro , Arano Yasushi , Nishida Koyo , Sasaki Hitoshi , Saji Hideo , Nakamura Junzo 
Published: July 2003

Abstract
Pharmacokinetic analyses of protein pharmaceuticals are of prime importance for their clinical application. Because many proteins have pharmacological activity at low concentrations, radiolabelling of proteins is widely used to identify the sites and determine the rates of protein catabolism in-vivo due to the high sensitivity of detection of radioactivity. Recently, a metallic radionuclide, 111In, has been used to trace the pharmacokinetics of proteins of interest after conjugation of the proteins with diethylenetriaminepentaacetic acid (DTPA). In this study, galactosyl-neoglycoalbumin (NGA) was reacted with the cyclic dianhydride of DTPA and labelled with 111In to estimate the validity of this radiolabelling procedure for pharmacokinetic analyses. For comparison, we also evaluated direct radioiodination, because directly-radioiodinated proteins are widely used to assess the pharmacokinetics of proteins of interest.
The hepatic radioactivity profile after intravenous injection of [131I]NGA or [111In]DTPA-NGA into mice was analysed pharmacokinetically, and the first-order rate constant representing the elimination of the respective radiometabolite from hepatic parenchymal cells was determined.
The results indicated that direct radioiodination is inappropriate for pursuing the pharmacokinetics of the proteins, because of rapid elimination of the radioactivity from the sites of protein catabolism. These findings also implied that the [111In]DTPA label could be used to identify the catabolic sites and determine the rates of catabolism of proteins with relatively short biological half-lives, although characterization of radiolabelled species at the sites of accumulation would be required for accurate determination of the catabolic sites of proteins.
Resistance to Glutathione Depletion in Diabetic and Non-diabetic Human Erythrocytes In-vitro
Authors: Coleman Michael D , Rustioni Charlotte V 
Published: July 2003

Abstract
We have investigated the resistance of erythrocytes from diabetics and non-diabetics to glutathione depletion caused by p-benzoquinone, 1-chloro-2,4-dinitrobenzene (CDNB), diethyl maleate and 4-aminophenol.
Incubation of erythrocytes with 4-aminophenol (2mm) caused a precipitous reduction (&gt;80%) in cellular glutathione levels although there was no significant difference between 4-aminophenol-mediated glutathione depletion in the diabetic and non-diabetic cells. p-Benzoquinone and CDNB were both associated with a less severe initial reduction in glutathione levels (&gt;50% at 30 min) although p-benzoquinone caused greater depletion (P &lt; 0.001) at 4.5 h (21.1 ± 3.1%, non-diabetic; 20.0 ± 1.0%, diabetic) compared with CDNB (49.2± 2-2%, non-diabetic; 51.3 ± 1.1% diabetic). Although there was no significant difference between the two types of cell in terms of level of depletion, administration of diethyl maleate caused a significant reduction in glutathione levels at 30 min (P &lt; 0.0005), 3.5h (P &lt; 0.05) and 4.5h (P &lt; 0.05) in erythrocytes from diabetic man compared with those from non-diabetic man. Co-administration of buthionine sulphoximine (20 mm) and 4-aminophenol (l mm) also led to a significant reduction in glutathione levels in diabetic cells at 30 min (P &lt; 0.05), 3.5h (P &lt; 0.02) and 4.5h (P &lt; 0.007) compared with those in non-diabetic cells.
The observations that diabetic red cells' resistance to depletion was similar to that of non-diabetic cells for three of the four depletors, and that the combination of 4-aminophenol and buthionine sulphoximine-mediated inhibition of glutathione synthesis was required to illustrate differences suggests that diabetic complications might be a result of the long-term effect of small deficiencies in oxidative self-defence mechanisms such as glutathione.
Simultaneous Use of Sodium Deoxycholate and Dipotassium Glycyrrhizinate Enhances the Cellular Transport of Poorly Absorbed Compounds Across Caco-2 Cell Monolayers
Authors: Sakai Michinori , Imai Teruko , Ohtake Hiroshi , Azuma Hidekazu , Otagiri Masaki 
Published: July 2003

Abstract
The absorption-enhancing effect of a combination of sodium deoxycholate and dipotassium glycyrrhizinate in Caco-2 cell monolayers has been compared with that of the enhancers when used alone, and the mechanism of the enhancement was partially elucidated.
The effect of the combined compounds was evaluated by measurement of transepithelial electrical resistance (TEER) and the cellular permeability of the water-soluble model compounds sodium fluorescein (MW 376.3) and fluorescein isothiocyanate dextran (MW 4400). The TEER of the monolayers decreased with increasing concentrations of dipotassium glycyrrhizinate in combination with 0.02% (w/v) sodium deoxycholate for 20 min, and reached a minimum at 1% (w/v) dipotassium glycyrrhizinate. Although a combination of 0.02% (w/v) sodium deoxycholate and 1% (w/v) dipotassium glycyrrhizinate enhanced the cellular permeability of sodium fluorescein and fluoresceinisothiocyanate dextran, 0.02% (w/v) sodium deoxycholate and 1% (w/v) dipotassium glycyrrhizinate alone had no effect on either the TEER of the monolayers or the cellular transport of the water-soluble compounds. Sequential and separate exposure of the monolayers to each enhancer for 10 min had no effect on the TEER, but a marked decrease in TEER was observed when both compounds were used in combination. The enhancing effect of the combination of sodium deoxycholate and dipotassium glycyrrhizinate was inhibited by H7, a protein kinase C (PKC) inhibitor, suggesting that dipotassium glycyrrhizinate might enhance the activation of PKC via sodium deoxycholate. The combined use of these two enhancers had no toxic effects.
These results provide useful, basic information on the action of these absorption enhancers on drugs for which absorption is limited owing to polarity or molecular size, or both.
The Role of an α-Amino Group on H+-dependent Transepithelial Transport of Cephalosporins in Caco-2 Cells
Authors: Raeissi Shamsi D , Li Jibin , Hidalgo Ismael J 
Published: July 2003

Abstract
The role of an α-amino group on interaction with the intestinal and renal peptide carriers (PEPT 1 and PEPT 2, respectively) has been the subject of much investigation. Studies have differed in their conclusions about the role of an α-amino group on carrier-mediated absorption. Most studies have used brush-border membrane vesicles or perfused intestinal segments. These techniques enable the determination of membrane uptake and luminal disappearance, respectively, but not transepithelial transport. Transepithelial transport should be more predictive of absorption because it includes basolateral efflux, which could be the rate-limiting process in drug absorption. The objective of this study was to evaluate the influence of an α-amino group on PEPT 1-mediated transepithelial transport in Caco-2 cells.
The apical-to-basolateral permeability coefficients of cephalosporins with or without a free α-amino group were determined in the presence and absence of a pH gradient. Permeability coefficients obtained under these conditions were used to calculate a permeability ratio (i.e. Papp (pH 6.0)/Papp (pH 7.4)), which should indicate whether PEPT 1 is involved in transport. For cephalosporins with an α-amino group (cephalexin, cefaclor, cefadroxil, cephradine, cephaloglycin) the permeability ratios ranged between 1.77 and 2.77. In contrast, the permeability ratios for cephalosporins without an α-amino group were 1 (approx.; range = 0.74–1.26).
These data suggest that the presence of an α-amino group on cephalosporins increases their PEPT 1-mediated transepithelial transport in Caco-2 monolayers.