bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effects of phytoestrogenic isoflavones on the formation and disposition of paracetamol sulfate in the isolated perfused rat liver
Authors: Lucas Anthony N , Nation Roger L , Milne Robert W , Reynolds Geoffrey D , Evans Allan M 
Published: June 2003

Abstract
This study examines the potential for the phytoestrogenic isoflavones, a type of complementary medicine, to be involved in pharmacokinetic interactions in the liver. Rat livers were isolated and perfused to steady state, in single-pass mode, with either 5 μm paracetamol (n=6), or 5 μm paracetamol with a 50:50 molar mixture of genistein and biochanin A or daidzein and formononetin, at a total isoflavone concentration of 1 and 10 μm (n = 6 for each mixture at each concentration). At 1 μm, neither isoflavone mixture had any effect, while at 10 μm both mixtures decreased the clearance of paracetamol and the formation clearance to paracetamol sulfate. Genistein and biochanin A (10 μm) also increased the biliary extraction of hepatically-generated paracetamol sulfate. Additional livers were perfused with an infusion of 5 μm 14C-paracetamol in the absence (n = 4), or presence, of a 10 μm genistein and biochanin A mixture (n = 4). Analysis of washout perfusate and bile samples (up to 30min after stopping the infusion) revealed that the isoflavones reduced the first-order rate constant for paracetamol sulfate transport into perfusate, but not for transport into bile. The results indicate that isoflavones can reduce the formation of paracetamol sulfate and that its enhanced excretion into bile arises from the inhibition of sinusoidal efflux transport.
In-vitro antileishmanial and trypanocidal activities of arsonoliposomes and preliminary in-vivo distribution in BALB/c mice
Authors: Antimisiaris Sophia G , Ioannou Panayiotis V , Loiseau Philippe M 
Published: June 2003

Abstract
We have studied the antiprotozoal activity of some recently prepared and characterized arsonoliposome formulations. Plain arsonoliposomes and phosphatidylcholine arsonoliposomes prepared with palmitoyl- (C16) or lauroyl-(C12) acyl side chain arsonolipids showed in-vitro antileishmanial activity after a 72-h incubation period against wild-type promastigote forms of Leishmania donovani. The IC50 values ranged from 0.40 to 11.6 μm arsonolipid. Interestingly, all preparations tested were found to be significantly more potent against amphotericin B- or miltefosine-resistant promastigote forms of L. donovani, with IC50 values ranging between 0.21- and 2.33-μm arsonolipid. When tested in-vitro against Trypanosoma brucei brucei, all arsonoliposome formulations were found to have anti-trypanosomal activity after a 24-h incubation period. The fact that the corresponding arsonolipids (dissolved in dimethyl sulfoxide) were found not to be potent against the Leishmania promastigotes or the trypanosomes tested suggested that the formation of liposomes possibly influenced the mode of interaction between the active lipid and the parasites modulating their potency. In addition, a preliminary in-vivo study in BALB/c mice was performed for the initial evaluation of the biodistribution of arsonoliposomes. The accumulation of arsenic in the BALB/c mouse liver in relatively high amounts was an additional advantage of this approach for anti-protozoal therapy, especially for visceral leishmaniasis where parasites are located mainly in the liver.
Two lead drug designs based on chloramphenicol as the parent structure, which express alkylation activity with potential for clinical applications
Authors: Bartzatt Ronald 
Published: June 2003

Abstract
Chloramphenicol is a bacteriostatic antibiotic which acts primarily as an inhibitor of bacterial protein synthesis. Modification of chloramphenicol structure was accomplished by replacing the two hydroxyl groups (—OH) with a chlorine atom for LEAD-1 or a chloroethyl ether group (—OCH2CH2Cl) for LEAD-2. The resulting daughter compounds expressed significant alkylating activity at physiological temperature of 37°C and at pH 7.4. Alkylation activity was evaluated after reaction with guanosine 5′-diphosphate (GDP), l-serine, l-glutamic acid, and p-chloroaniline. The partition coefficient (log P) was determined for chloramphenicol, LEAD-1 and LEAD-2 to be 0.854, 3.409 and 3.10, respectively. The molecular dipole of chloramphenicol, LEAD-1 and LEAD-2 was calculated to be 5.804, 3.961 and 4.097 Debye, respectively. All three structures showed zero violations of the Rule of 5, which indicates good bioavailability. Values for polar surface area (TPSA) indicate an intestinal absorption of 51% and 35% for LEAD-1 and LEAD-2, respectively. The reduction to only one proton donor in LEAD-1 and LEAD-2 structures (chloramphenicol having three proton donors) indicates an improvement of membrane penetration compared to chloramphenicol. 13C NMR analysis of molecular structures was accomplished and fast atom bombardment mass spectrometry analysis of a reaction mixture showed LEAD-1 alkylation of guanosine 5′-diphosphate.
Impairment of the renal p-aminohippurate transport induced by 6-hydroxydopamine
Authors: Cojocel C , Thomson M S 
Published: June 2003

Abstract
In this study, the effects of 6-hydroxydopamine (6-OHDA) on renal p-aminohippurate transport were investigated in-vitro using rat renal cortical slices. Cisplatin, a known nephrotoxin, was used as positive control. Renal cortical slices were incubated for 60 min in a cisplatin-containing medium (0.83–5.0 μm) at 37°C under a 100% O2 atmosphere. In another series of experiments, renal cortical slices were incubated in a 3.33 μm cisplatin-containing medium for 15–120min or in a cisplatin-free medium. Subsequently, for each series of experiments, kidney slices were incubated at 25°C for 90 min in a media containing p-aminohippurate. In a further series of experiments, renal cortical slices were incubated for 60 min in a 6-OHDA containing medium (3.125–100 μm) at 37°C under a 100% O2 atmosphere. In another series of experiments, renal cortical slices were incubated in a 50 μm 6-OHDA-containing medium for 15–120min or in 6-OHDA-free medium. Subsequently, for each series of experiments, kidney slices were incubated at 25°C for 90 min in a media containing p-aminohippurate. The results of this study where slices were incubated in 6-OHDA- or cisplatin-containing media indicate that both 6-OHDA and cisplatin induced a time- and concentration-dependent decrease in p-aminohippurate accumulation by renal cortical slices. Therefore, similarly to cisplatin, 6-OHDA causes functional injury of renal proximal tubule cells, leading to impairment of transport processes across the cell membrane.
Effects of continuous exposure to digoxin on MDR1 function and expression in Caco-2 cells
Authors: Takara Kohji , Tsujimoto Masayuki , Ohnishi Noriaki , Yokoyama Teruyoshi 
Published: June 2003

Abstract
The Caco-2 cell line has been used widely for studying intestinal permeability and several transport functions, and express the multidrug resistance transporter MDR1/P-glycoprotein. Previously, the transient exposure to digoxin for 24h was found to induce MDR1 mRNA in Caco-2 cells. Here, a digoxin-tolerant Caco-2 subline (Caco/DX) was newly established by the continuous exposure of Caco-2 cells to digoxin, and the effects of continuous exposure to digoxin on MDR1 were examined. The 50% growth inhibitory concentration (IC50) values for digoxin in Caco-2 and Caco/DX cells were 17.2 and 81.4 nm, respectively. The IC50 values for paclitaxel, an MDR1 substrate, were 1.0 and 547 nm, respectively, whereas the cytotoxicity of 5-fluorouracil was comparable in both cells. The uptake and efflux of Rhodamine123, an MDR1 substrate, in Caco/DX cells were significantly less and greater, respectively, than those in Caco-2 cells, and these transports were affected by the addition of ciclosporin. The expression of MDR1 mRNA in Caco/DX cells was approximately 2- and 1.7-fold compared with Caco-2 cells and Caco-2 cells treated with 100 nm digoxin for 24 h, respectively. On the other hand, MRP1 mRNA in Caco/DX cells was unchanged. These observations confirmed that the continuous exposure to digoxin, as well as the transient exposure, induced MDR1 in Caco-2 cells.
Extracts of various species of Epilobium inhibit proliferation of human prostate cells
Authors: Vitalone Annabella , Guizzetti Marina , Costa Lucio G , Tita Beatrice 
Published: June 2003

Abstract
This study examined whether various species of Epilobium, a phytotherapeutic agent used in folk medicine as a treatment for benign prostatic hyperplasia, may have an antiproliferative effect in PZ-HPV-7 human prostatic epithelial cells in-vitro. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) test, [methyl-3H]thymidine incorporation into DNA and flow cytometry analysis were used to evaluate cell proliferation. Ethanolic extracts of E. spicatum, E. rosmarinifolium and E. tetragonum inhibited DNA synthesis in PZ-HPV-7 cells. While at high concentrations all extracts were cytotoxic, DNA synthesis was also decreased at levels that caused no or little cytotoxicity. Treatment of cells with Epilobium extracts did not result in a formation of DNA fragments (evaluated by the TUNEL assay) or chromatin condensation (assessed by Hoechst staining). Flow cytometry analysis indicated that Epilobium extracts inhibit the progression of the cell cycle from the G0/G1 phase. These results suggest that extracts of Epilobium inhibit proliferation of human PZ-HPV-7 cells in-vitro by affecting progression of the cell cycle. This study provides some initial biological plausibility for the use of Epilobium extracts in benign prostatic hyperplasia.
Astilbin suppresses delayed-type hypersensitivity by inhibiting lymphocyte migration
Authors: Cai Yu , Chen Ting , Xu Qiang 
Published: June 2003

Abstract
This study examined the effects of astilbin, a flavanone, on delayed-type hypersensitivity reactions and its mechanisms of action on cell migration. Astilbin significantly inhibited the sheep-red-blood-cell-induced footpad reaction and picryl-chloride-induced ear dermatitis without affecting the organ weights, when administered during the effector phase but not the induction phase. The flavanone also significantly inhibited the migration to gelatin of spleen cells isolated from mice with ear dermatitis in a transwell system. Furthermore, the isolated spleen cells from normal mice were incubated with astilbin in the presence of concanavalin A, or those from mice with ear dermatitis were cultured with astilbin. In the supernatants collected, the activity of matrix metalloproteinases (MMPs) MMP-2 and MMP-9 was remarkably inhibited by astilbin. These results suggest that astilbin may inhibit delayed-type hypersensitivity reactions through selectively suppressing the lymphocyte functions, including cell migration, via down-regulating MMP activity.
Selectin-blocking semisynthetic sulfated polysaccharides as promising anti-inflammatory agents
Authors: Höpfner M , Alban S , Schumacher G , Rothe U , Bendas G 
Published: June 2003

Abstract
Selectin-induced leucocytes rolling along the endothelial surface of blood vessels initiate a complex adhesion cascade, which is an essential step in the cellular immune response. Consequently, blocking the binding between the selectins and their ligands represents a promising strategy for suppressing pathological inflammatory reactions. This study describes the effects of an unfractionated heparin and a low-molecular-weight heparin and a series of structurally well-defined semisynthetic glucan sulfates on selectin-mediated cell-rolling with respect to inhibition. To simulate the blood flow characteristics of postcapillary venules, the rolling experiments were performed in a dynamic-flow-chamber system with immobilized selectins and selectin ligand-carrying U937 cells. The influence of the test compounds on cell rolling was measured by the percentage of adherent cells after a certain flow time and the velocity of the rolling cells. Whereas the test compounds displayed no inhibitory effect on E-selectin-mediated cell rolling, they efficiently blocked the rolling induced by P-selectin. The glucan sulfates were much more active than either unfractionated heparin or low-molecular-weight heparin, or the standard inhibitor Sialyl LewisX. Their inhibitory potency turned out to be strongly dependent on various structural parameters, such as sulfation pattern and molecular weight. In conclusion, the semisysnthetic glucan sulfates represent promising candidates in the development of selectin blocking agents.
In-vitro crystallization of indinavir in the presence of ritonavir and as a function of pH
Authors: Li Lilian Y , Rodríguez-Hornedo Naír , Heimbach Tycho , Fleisher David 
Published: June 2003

Abstract
The aim of this study was to investigate the in-vitro crystallization of indinavir as a function of pH alteration and in the presence of another protease inhibitor, ritonavir. Crystallization processes were studied for indinavir sulfate, indinavir free base and a commercial indinavir capsule dosage form, respectively. Crystallization induction times were determined with varying initial concentration of supersaturated solution, and in the presence or absence of seed material. In-vitro induction times were found to be significantly shorter for the indinavir capsule dosage form compared with that of indinavir sulfate and indinavir free base. Induction times were inversely proportional to the final concentration in pH 7 buffer for all materials, and were significantly shortened in the presence of seeds. The crystal morphology of indinavir varied under different crystallization conditions. This study demonstrated the potential for precipitation of indinavir upon pH elevation, while also suggesting that the presence of impurities or seeding material significantly shortens the induction time for indinavir crystal formation. This induction time period falls well within the gastric emptying time following the intake of a high-caloric meal, and within small intestinal transit time. The results of this study are in agreement with the clinical observation that a high-calorie protein meal significantly reduces the oral bioavailability of indinavir in man, accompanying a pH elevation in the stomach.
Protective effect of N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine (PF 9601N), a novel MAO-B inhibitor, on dopamine-lesioned PC12 cultured cells
Authors: Perez V , Romera M , Lizcano J M , Marco J L , Unzeta M 
Published: June 2003

Abstract
Oxidative stress may play a role in the pathogenesis of Parkinson's disease. We have standardised a new model of dopaminergic-cell toxicity that uses dopamine, which is able to generate free radicals, as a toxin. The effect of this catecholamine on cell viability (MTT staining) was dose-dependent, reaching 65% of cell loss at a dopamine concentration of 300 μm. In this model, the protective effect of a novel MAO-B inhibitor, N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine (PF 9601N), was studied and compared with the effect of l-deprenyl assayed under the same experimental conditions. Whereas PF 9601N (50 μm and 100 μm) showed a significant protective effect, this was not the case with l-deprenyl. This different behaviour could be explained in terms of difference in antioxidant capacity. The toxicity induced in PC12 cells by 300 μm dopamine was partially reversed by incubating it in the presence of GBR-12909, a dopamine-transporter blocker. The results indicated that, besides the intracellular toxicity effect of dopamine, another non-specific extracellular mechanism could be involved.
Polycation gene delivery systems: escape from endosomes to cytosol
Authors: Cho Yong Woo , Kim Jong-Duk , Park Kinam 
Published: June 2003

Abstract
Clinical success of gene therapy based on oligonucleotides (ODNs), ribozymes, RNA and DNA will be greatly dependent on the availability of effective delivery systems. Polycations have gained increasing attention as a non-viral gene delivery vector in the past decades. Significant progress has been made in understanding complex formation between polycations and nucleic acids, entry of the complex into the cells and subsequent entry into the nucleus. Sophisticated molecular architectures of cationic polymers have made the vectors more stable and less susceptible to binding by enzymes or proteins. Incorporation of specific ligands to polycations has resulted in more cell-specific uptake by receptor-mediated mechanisms. However, there are still other barriers limiting the transfection efficiency of polycation gene delivery systems. There is a consensus that polycation-DNA complexes (polyplexes) enter cells via the endocytotic pathway. It is not clearly understood, however, how the polyplexes escape (if they do) from endosomes, how DNA is released from the polyplexes or how the released DNA is expressed. The primary focus of this article is to review various polycation gene delivery systems, which are designed to translocate DNA from endosomes into cytosol. Many polycation gene delivery systems have tried to mimic the mechanisms that viruses use for the endosomal escape. Polycation gene delivery systems are usually coupled with synthetic amphipathic peptides mimicking viral fusogenic peptides, histidine-based gene delivery systems for pH-responsive endosomal escape, polycations with intrinsic endosomolytic activity by the proton sponge mechanism and polyanions to mimic the anionic amphiphilic peptides.
Restoration of antibacterial activity of β-lactams by epigallocatechin gallate against β-lactamase-producing species depending on location of β-lactamase
Authors: Zhao Wei-Hua , Asano Nozomi , Hu Zhi-Qing , Shimamura Tadakatsu 
Published: June 2003

Abstract
The combined effects of (–)-epigallocatechin gallate (EGCg) and β-lactams were investigated against various β-lactamase-producing clinical isolates, including 21 Staphylococcus aureus, 6 Escherichia coli, 3 Klebsiella pneumoniae and 8 Serratia marcescens strains. Penicillin in combination with EGCg at 12.5μg mL−1 showed the most potent synergy against 100% penicillinase-producing S. aureus. However, cefotaxime or imipenem in combination with higher concentration of EGCg (100 μg mL−1) only showed slight synergy against 2 of 17 Gram-negative rods. Similar to the effect on the penicillinase from S. aureus, however, EGCg also directly inhibited the extracted β-lactamases from the Gram-negative rods, thereby protecting β-lactams from inactivation. The different effects of the combinations on different β-lactamase-producing species were confirmed to be related to the cellular locations of β-lactamases. In contrast to a 32.7% extracellular fraction of total β-lactamase activity in a penicillinase-producing S. aureus, the fractions were 0.6%, 0.6% and 1.2% in a TEM-derived extended-spectrum β-lactamase-producing E. coli, an inhibitor-resistant β-lactamase-producing K. pneumoniae and an IMP-producing S. marcescens, respectively. In conclusion, the combination of penicillin with EGCg showed potent synergy against penicillinase-producing S. aureus in-vitro. The combinations of β-lactams and EGCg against β-lactamase-producing Gram-negative rods do indicate a limitation owing to the cellular location of β-lactamases.
Microemulsions as colloidal vehicle systems for dermal drug delivery. Part IV: investigation of microemulsion systems based on a eutectic mixture of lidocaine and prilocaine as the colloidal phase by dynamic light scattering
Authors: Shukla Anuj , Krause Annett , Neubert Reinhard H H 
Published: June 2003

Abstract
Stable oil-in-water (o/w) microemulsions used as vehicles for dermal drug delivery have been developed using lidocaine (lignocaine) and prilocaine in oil form (eutectic mixture), a blend of a high (Tween 80, hydrophilic-lipophilic balance (HLB) = 15.0) and a low (Poloxamer 331, HLB = 1.0) HLB surfactant and propylene glycol-water as hydrophilic phase. These microemulsions were able to solubilize up to 20% eutectic mixture of lidocaine and prilocaine without phase separation. The dispersity of the oil phase was investigated by dynamic light scattering. Small colloidal droplets for stable microemulsions of 5∼10 nm were observed. At constant surfactant and hydrophilic phase concentration, increasing the total drug concentration in the microemulsion resulted in an increase in the droplet size of the dispersed, colloidal phase. It was observed that a monolayer of surfactant surrounds the oil (eutectic mixture) core. Colloidal droplets of the microemulsion interact via hard sphere with supplementary attractive interaction. This observed interparticle attractive interaction could explain the observed phase behaviour with respect to change in the basicity of the hydrophilic phase as well as the increase in volume fraction of the dispersed, colloidal phase. It was also observed that the stability and size of this dispersed phase depends on the pH of the composition. Because these microemulsions formed stable, isotropic systems in the range of pH 9.5 to 10.4 with alkali buffer or NaOH solution instead of water as hydrophilic phase, so one can produce microemulsions in this pH area.
De-agglomeration of micronized benzodiazepines in dissolution media measured by laser diffraction particle sizing
Authors: Zhao Feng-Ying , Stewart Peter J 
Published: June 2003

Abstract
The objective of this research was to develop a method to characterize the degree of particle agglomeration using laser diffraction particle sizing, following the addition of benzodiazepine interactive mixtures to water. Interactive mixtures of diazepam, nitrazepam and oxazepam (up to 20% w/w) were prepared by mixing micronized benzodiazepines with lactose granules (250–355μm). Micronized sodium lauryl sulfate and cetrimide (up to 5% w/w) were added to the benzodiazepine-lactose interactive mixes to produce ternary mixtures. Particle size distributions of benzodiazepines, after addition of the interactive mixtures to water, were determined using laser diffraction particle sizing. Bimodal distributions representing dispersed particles and agglomerates were observed initially after lactose carrier dissolution. Partial agglomerate to dispersed particle transition occurred during a 60-min observation period for all mixtures, reaching a constant level of agglomeration after this time. Interactive mixtures with higher benzodiazepine concentrations displayed transition profiles with higher levels of agglomeration. The presence of surfactant in interactive mixtures dramatically decreased agglomeration. Sodium lauryl sulfate was more effective than cetrimide in dispersing agglomerates. The shape of the transition curves during de-agglomeration demonstrated the presence of stable agglomerates that remained after the initial transition; these may be important in explaining dissolution and absorption rates.