bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interpretation of mucoadhesive properties of polymer gel preparations using a tensile strength method
Authors: Hägerström Helene , Edsman Katarina 
Published: July 2003

Abstract
We have developed a new tensile strength method for assessing mucoadhesive properties of polymer gels utilising freshly excised porcine nasal mucosa and a texture analyser. In conjunction with this, we propose a method for interpreting the mucoadhesive properties that is based on reasoning about the locus of the failure of a mucoadhesive joint. This involves measuring the cohesiveness of the gel and the mucus layer, respectively, and comparing these results with those obtained from a mucoadhesion measurement. Linear polymers (sodium carboxymethylcellulose, poly(acrylic acid) and sodium hyaluronate) and a cross-linked polymer (poly(acrylic acid)) were used as model polymers in this study. It was shown that the withdrawal speed of the probe should be low, about 0.1 mm s−1, and that a contact time of 2 min was sufficient. In the mucoadhesion measurements there was no dependence of the results on the contact time in the interval 2–20 min. The tensile work appeared to be more applicable than the fracture strength for interpreting mucoadhesive properties. Furthermore, it was concluded that the interpretation procedure offers a good basis by which to assess whether the measured tensile work reflects a cohesive failure of the gel or a true interaction of the gel with the mucus layer.
Synthesis, antiplatelet and vasorelaxing effects of monooxygenated flavones and flavonoxypropanolamines
Authors: Chung Mei-Ing , Han Feng-Wen , Lin Hsien-Cheng , Liou Shorong-Shii , Huang Pao-Ling , Ko Horng-Huey , Chang Ya-Ling , Kang Jaw-Jou , Teng Che-Ming , Lin Chun-Nan 
Published: July 2003

Abstract
A series of flavones and flavonoxypropanolamines were synthesized and tested in-vitro for their ability to inhibit aggregation of washed rabbit platelets and human platelet-rich plasma (PRP), and for vasoconstriction of rat thoracic aorta. The various substituted positions of the hydroxyl group in flavone ring B and the various oxypropanolamine side chains substituted at position C-2′ of flavone modified the antiplatelet effects. All the compounds tested in human PRP showed significant inhibition of secondary aggregation induced by adrenaline (epinephrine), suggesting that the antiplatelet effect of these compounds is mainly due to an inhibitory effect on thromboxane formation. Compounds 11 and 12 also had potent vasorelaxant effects in rat thoracic aorta. Phenylephrine- and high-K+-induced 45Ca2+ influx in aorta were both inhibited by the selected compound 11. This result indicates that the inhibitory effect of 11 on the contractile response caused by high-K+ medium and noradrenaline (norepinephrine) in rat thoracic aorta is mainly due to inhibition of Ca2+ influx through both voltage-dependent and receptor-operated Ca2+ channels.
The impact of P-glycoprotein efflux on enterocyte residence time and enterocyte-based metabolism of verapamil
Authors: Johnson Brendan M , Charman William N , Porter Christopher J H 
Published: July 2003

Abstract
P-glycoprotein (P-gp) can limit the intestinal permeability of a number of compounds and may therefore influence their exposure to metabolizing enzymes within the enterocyte (e.g. cytochrome P450 3A, CYP 3A). In this study, the intestinal metabolic profile of verapamil, the influence of P-gp anti-transport on the cellular residence time of verapamil, and the impact of this change in residence time on the extent of enterocyte-based metabolism have been investigated in-vitro, utilizing segments of rat jejunum and side-by-side diffusion chambers. Verapamil exhibited concentration-dependent P-gp efflux and CYP 3A metabolism. The P-gp efflux of verapamil (1 μm) increased the cellular residence time across the intestinal membrane (approximately 3-fold) in the mucosal to serosal (m to s) direction relative to serosal to mucosal (s to m), yielding significantly greater metabolism (approximately 2-fold), presumably as a result of the prolonged exposure to CYP 3A. Intestinal metabolism of verapamil generated not only norverapamil, but resulted also in the formation of an N-dealkylated product (D-617). Norverapamil and D-617 accumulated significantly in mucosal chambers, relative to serosal chambers, over the time course of the experiment. Based on these in-vitro data, it was apparent that P-gp efflux prolonged the cellular residence time of verapamil (m to s) and therefore increased the extent of intestinal metabolism, and also played a role in metabolite secretion from within the enterocyte.
Stereoselective pharmacokinetics and pharmacodynamics of disopyramide and its metabolite in rabbits
Authors: Horikawa Masato , Yasumuro Misao , Kanno Megumi , Hanada Kazuhiko , Hashiguchi Masayuki , Ogata Hiroyasu 
Published: July 2003

Abstract
The extent to which interactions between enantiomers of disopyramide and between disopyramide and its metabolite, mono-N-dealkylated disopyramide (MND), contribute to stereoselectivity of the anti-arrhythmic effect has been investigated in rabbits by measuring the prolongation of the QUc interval. The plasma unbound fraction of disopyramide enantiomers was constant at a concentration range of 1.44-28.9 μm. An intravenous infusion study of the disopyramide enantiomer or racemate suggested that the S-enantiomer had a pharmacological effect, determined by linear regression analysis, approximately 3.3-times more potent than that of the R-enantiomer. Furthermore, the effect caused by racemic disopyramide was the sum of that elicited by both enantiomers individually. No significant difference was observed between the slope of linear regression analysis of intravenous infusion and that of intravenous bolus injection. Single intravenous bolus injection of MND did not affect the QUc intervals. In conclusion, the S-enantiomer of disopyramide was approximately 3.3-times more potent pharmacologically than the R-enantiomer. The relationship between plasma concentration of the disopyramide enantiomers and pharmacological effect was the sum of each enantiomer individually.
Pharmacokinetics and interspecies scaling of a novel VEGF receptor inhibitor, SU5416
Authors: Sukbuntherng Juthamas , Cropp Gillian , Hannah Alison , Wagner Gregory S , Shawver Laura K , Antonian Lida 
Published: July 2003

Abstract
The pharmacokinetics and allometric relationships of SU5416, a novel small anti-angiogenesis agent, were studied. The pharmacokinetics of SU5416 were examined in mice, rats, dogs, and cancer patients. The in-vitro intrinsic clearance (CLint) was estimated from the in-vitro metabolism study in mouse, rat, dog, monkey and human liver microsomes. The parameters of interest were correlated across species as a function of bodyweight using an allometric approach. The steady-state volume of distribution (Vdss), plasma clearance (CLs), and CLint of SU5416 were well correlated across species. The exponent of the allometric relationship (b) of the corresponding parameters was 0.92, 0.80 and 0.66, respectively. The elimination half-life (t½) was consistent across species and independent of bodyweight. The prediction of CLs, Vdss, CLint, and t½ in humans using the data from mouse, rat, and dog, and monkey (for CLint) was reasonably good (within 4-fold of the observed values). However, an improved prediction (within 2-fold of the observed values) of the corresponding parameters in humans was obtained when extrapolation from only the rodent data was performed, suggesting that the rodent data are sufficient for the scale-up of SU5416 pharmacokinetic parameters in humans. Using allometry, it was possible to achieve reasonable predictions of the pharmacokinetic parameters of SU5416 in cancer patients with various solid tumours.
A validated method for quantitative determination of saponins in notoginseng (Panax notoginseng) using high-performance liquid chromatography with evaporative light-scattering detection
Authors: Li Wenkui , Fitzloff John F 
Published: July 2003

Abstract
A gradient high-performance liquid chromatographic (HPLC) method with evaporative light-scattering detection (ELSD) for the determination of major saponins in a Chinese traditional herbal medicine, Panax notoginseng, is described. Samples were analysed by means of a reverse-phase column (Waters Spherisorb ODS-2, C-18) using acetonitrile and water under gradient conditions as the mobile phase over 60 min. The ELSD used was set at an evaporating temperature of 35°C and pressurized air pressure of 3.4 bars. The detection limit (signal/noise &gt; 3) of the saponins was 50 ng. The method was validated by inter- and intra-day assays and recovery tests.
Topical anti-inflammatory activity of Thymus willdenowii
Authors: Ismaili H , Tortora S , Sosa S , Fkih-Tetouani S , Ilidrissi A , Loggia R Della , Tubaro A , Aquino R 
Published: July 2003

Abstract
The topical anti-inflammatory activity of Thymus willdenowii Boiss (Labiatae) leaves, a herbal drug used in Moroccan folk medicine, has been studied using the croton oil ear test in mice. A bioassay-oriented fractionation procedure showed that the activity concentrates in the chloroform extract, which has a potency similar to that of indometacin, the non-steroidal anti-inflammatory drug used as reference (ID50 (dose giving 50% oedema inhibition) = 83 μg cm−2 and 93 μg cm−2, respectively). The main compounds responsible for the anti-inflammatory activity of T. willdenowii are ursolic acid and oleanolic acid. The flavonoids luteolin-3′-O-glucuronide and eriodictyol-7-O-glucoside were found for the first time in the genus Thymus.
Comparison of the growth-inhibitory effect of Hypericum perforatum L. extracts, differing in the concentration of phloroglucinols and flavonoids, on leukaemia cells
Authors: Hostanska Katarina , Bommer Silvia , Weber Michel , Krasniqi Blerim , Saller Reinhard 
Published: July 2003

Abstract
In this study we compared, simultaneously, the growth-inhibitory effect of Hypericum perforatum L. extracts, containing various amounts of hyperforin (A 3.25%; B 2.21%; C 0.21% w/w) and flavonoids (A and B 5.3%; C 10% w/w), but closely same amounts of naphthodiantrones (0.3%) on two leukaemic cell lines K562 and U937 in the WST-1 assay. The GI50 (concentration of extracts which caused 50% of cell growth inhibition) for H. perforatum extracts analysed and characterized by HPLC for their biologically active constituents was 248.3–621.3 μg mL−1 in K562 and 378.2–911.7 μg mL−1 in U937 cells. The corresponding values of the three main groups were 1.6–3.9 μm naphthodianthrones, 1.0–40.7 μm phloroglucinols and 30.5–68.5 μm flavonoids. The results of this study supported the hypothesis that, apart from hyperforin and flavonoids, other components of the extract could be involved in its growth-inhibitory effect that it exerts without light activation.
Effect of surfactant on fabrication and characterization of paclitaxel-loaded polybutylcyanoacrylate nanoparticulate delivery systems
Authors: Mitra Amitava , Lin Senshang 
Published: July 2003

Abstract
The feasibility of applying biodegradable polybutylcyanoacrylate (PBCA) nanoparticulate delivery systems (NDSs) for the controlled release of paclitaxel was investigated. Paclitaxel-loaded and unloaded PBCA-NDSs containing various surfactants (dextran 70, cholesterol, polyvinyl alcohol and lecithin) were prepared by anionic polymerization. The effects of surfactant (1% w/v), surfactant combination (1% w/v each), and surfactant concentration (0.05, 1.0 and 2.5% w/v) on PBCA-NDSs were evaluated and characterized by particle size, zeta potential, entrapment efficiency, and in-vitro paclitaxel release kinetics. The physicochemical characteristics of PBCA-NDSs incorporated with various surfactants were significantly improved compared with PBCA-NDS without any surfactant, by decreasing particle size at least 3-fold as well as by increasing the zeta potential up to 18-fold to minimize the agglomeration of nanoparticles. Moreover, PBCA-NDSs incorporated with various surfactants demonstrated higher entrapment efficiency of paclitaxel. Results from the in-vitro release kinetic studies indicated that a more controlled biphasic zero-order release pattern of paclitaxel was observed for PBCA-NDSs incorporated with various surfactants. Compared with dextran 70 and polyvinyl alcohol, the naturally occurring lipids, lecithin and cholesterol, indicated greater advantages in improving the physicochemical properties of PBCA-NDSs, in terms of smaller particle size, higher zeta potential and better drug entrapment efficiency, and better controlled release of paclitaxel, in terms of lower release rate and prolonged action from PBCA-NDSs.
Formulation and evaluation of metronidazole acid gel for vaginal contraception
Authors: El-Gizawy Sanaa A , Aglan Nagwa I 
Published: July 2003

Abstract
In this study, the efficacy of metronidazole as a local spermicidal agent was investigated. The drug was formulated in a concentration of 5% as an acid gel for vaginal application as a local contraception. The minimum spermicidal concentration of metronidazole was evaluated in-vitro and found to be 0.2% w/v. The formulated gel showed instant immobilization and death of all sperm within 30 s. A clinical study was conducted to determine the drug concentrations in vaginal secretions of healthy women and women with symptoms suggesting genital tract infection every 15 min for a 1-h period after application of 1 g of the gel in the vagina. Drug concentrations in the infected group were significantly lower (P&lt;0.05) than those in the healthy group at all time intervals. The drug concentrations in vaginal secretions after 1 h of vaginal medication remained above the determined minimum spermicidal concentration (0.2%) in the two groups. Measurement of vaginal pH before and after medication revealed a significant drop (P&lt;0.05) in pH to its normal value in both healthy and infected groups as a result of gel application. In conclusion, the designed gel has potential advantages of achieving a long retention time and effective drug concentrations in the vagina for at least 1 h after application, and of maintaining vaginal pH within its normal range.
Contribution of organic anion transporting polypeptide OATP-C to hepatic elimination of the opioid pentapeptide analogue [d-Ala2, d-Leu5]-enkephalin
Authors: Nozawa Takashi , Tamai Ikumi , Sai Yoshimichi , Nezu Jun-Ichi , Tsuji Akira 
Published: July 2003

Abstract
The objective of this study was to examine the transport activity of the human organic anion transporter OATP-C (SLC21A6) for oligopeptides that are eliminated rapidly from the systemic circulation. We focused on an opioid peptide analogue, [d-Ala2, d-Leu5]-enkephalin (DADLE), a linear pentapeptide modified to be stable. [3H]DADLE was taken up by rat isolated hepatocytes in a saturable manner and highly accumulated in the liver after intravenous administration to rats. The uptake of [3H]DADLE by the isolated hepatocytes was inhibited by several organic anions and pentapeptides, but not by tetra- or tripeptides. When OATP-C was expressed in Xenopus laevis oocytes, a significant increase in uptake of [3H]DADLE was observed. Moreover, the inhibitory effects of various compounds, including some peptides, on [3H]estrone-3-sulfate uptake by OATP-C were similar to those observed in [3H]DADLE uptake by rat isolated hepatocytes. In conclusion, it was demonstrated that OATP-C contributes to the rapid hepatic excretion of peptides and peptide-mimetic drugs.
Inhibitory effect of erythromycin on potassium currents in rat ventricular myocytes in comparison with disopyramide
Authors: Hanada Erika , Ohtani Hisakazu , Hirota Michiko , Uemura Noriko , Nakaya Haruaki , Kotaki Hajime , Sato Hitoshi , Yamada Yasuhiko , Iga Tatsuji 
Published: July 2003

Abstract
Disopyramide, a class la antiarrhythmic agent, has been reported to induce torsades de pointes (TdP) associated with excessive QT prolongation in electrocardiogram (ECG), especially when concomitantly administered with erythromycin, a macrolide antibiotic agent. In this study, we have evaluated the effects of erythromycin on action potential duration (APD) and potassium currents in rat ventricular myocytes in comparison with disopyramide. We have evaluated the relationship between in-vitro potassium current inhibition and in-vivo QT prolongation observed in a previous study. Action potentials and membrane potassium currents, including delayed rectifier current (IK) and transient outward current (Ito), were recorded using a whole-cell patch clamp method in enzymatically-dissociated ventricular cells. Erythromycin and disopyramide prolonged APD in a concentration-dependent manner. Disopyramide (10–100 μm) and erythromycin (100 μm) led to increases in the APD at 90% repolarization level. Disopyramide reduced IK (IC50 = 37.2 + 0.17 μm) and Ito (IC50 = 20.9 + 0.13 μm) while erythromycin reduced IK (IC50 = 60.1 + 0.29 μm) but not Ito. The observed prolongation of APD might be ascribed to the inhibition of potassium currents. Erythromycin produced the prolongation of APD and the inhibition of potassium currents with a lag time after addition of the drugs, which suggested that erythromycin might not reach potassium channels from outside the ventricular cells. The potency of disopyramide was almost equivalent under in-vitro and in-vivo conditions. However, potency of erythromycin in-vitro was far weaker than that in-vivo reported in a previous study, presumably due to a difference in the uptake of erythromycin into ventricular myocytes between in-vivo and in-vitro conditions. Therefore, when drug-induced risks of QT prolongation are to be evaluated, the difference of potencies between in-vitro and in-vivo should be taken into consideration.
Screening pharmaceutical preparations containing extracts of turmeric rhizome, artichoke leaf, devil's claw root and garlic or salmon oil for antioxidant capacity
Authors: Betancor-Fernández Alejandro , Pérez-Gálvez Antonio , Sies Helmut , Stahl Wilhelm 
Published: July 2003

Abstract
Pharmaceutical preparations derived from natural sources such as vegetables often contain compounds that contribute to the antioxidant defence system and apparently play a role in the protection against degenerative diseases. In the present study, commercial preparations containing extracts of turmeric, artichoke, devil's claw and garlic or salmon oil were investigated. The products were divided into fractions of different polarity, and their antioxidant activity was determined using the Trolox equivalent antioxidant capacity (TEAC) assay. This test is based on the efficacy of the test material to scavenge 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) derived radicals. Total phenols were determined in all fractions as well as specific carotenoids in the most lipophilic fraction to assess their contribution to the antioxidant activity. For comparison, the radical scavenging effect of selected constituents of the extracts such as curcumin, luteolin, kaempferol, chlorogenic acid, harpagoside, β-carotene and α-tocopherol was investigated and compared with that of Trolox. Curcumin, luteolin, kaempferol, chlorogenic acid and β-carotene showed an antioxidant activity superior to Trolox in the TEAC assay; harpagoside was barely active. All fractions of the turmeric extract preparation exhibited pronounced antioxidant activity, which was assigned to the presence of curcumin and other polyphenols. The antioxidant activity corresponding to the artichoke leaf extract was higher in the aqueous fractions than in the lipophilic fractions. Similarly, devil's claw extract was particularly rich in water-soluble antioxidants. Harpagoside, a major compound in devil's claw, did not contribute significantly to its antioxidant activity. The antioxidant capacity of the garlic preparation was poor in the TEAC assay. That of salmon oil was mainly attributed to vitamin E, which is added to the product for stabilization. In all test preparations, the antioxidant activity was significantly correlated with the content of total phenolic compounds.
Prediction of human pharmacokinetics from animal data and molecular structural parameters using multivariate regression analysis: volume of distribution at steady state
Authors: Wajima Toshihiro , Fukumura Kazuya , Yano Yoshitaka , Oguma Takayoshi 
Published: July 2003

Abstract
The aim of this study was to develop a regression equation for predicting volume of distribution at steady state (Vdss) in humans to enable application to various types of drugs using animal experimental data for rats and dogs and some molecular structural parameters. The Vdss data for rats, dogs and humans of 64 drugs were obtained from literature. The compounds have various structures, pharmacological activities and pharmacokinetic characteristics. In addition, the molecular weight, calculated partition coefficient (clogP), and the number of hydrogen bond acceptors were used as possible descriptors related to the Vdss in humans. Multivariate regression analyses, multiple linear regression analysis and the partial least squares (PLS) method were used to predict Vdss in humans. Interaction terms were also introduced into the regression analysis to evaluate the non-linear relationship. For the data set used in the present study, PLS with quadratic term descriptors gave the best predictive performance. The PLS model using Vdss data for only two animal species and using easily calculated structural parameters could generally predict Vdss in humans better than an allometric method. In addition, the PLS model with only animal data gave almost the same predictive performance as the PLS model with quadratic term descriptors. This model may be easier to use and be practical in a realistic situation, and could predict Vdss in humans better than the allometric method.
Regional transport and metabolism of ropivacaine and its CYP3A4 metabolite PPX in human intestine
Authors: Berggren Sofia , Lennernäs Pernilla , Ekelund Mats , Weström Björn , Hoogstraate Janet , Lennernäs Hans 
Published: July 2003

Abstract
The major aim of this study was to investigate the CYP3A4 metabolism and polarized transport of ropivacaine and its metabolite 2′,6′-pipecoloxylidide (PPX) in tissue specimens from the human small and large intestine. Ropivacaine has been shown to be effective in the treatment of ulcerative colitis in human colon. This study was conducted using a modified Ussing-chamber technique with specimens from jejunum, ileum and colon collected from 11 patients. The local kinetics of ropivacaine and PPX were assessed from their concentration–time profiles in mucosal and serosal compartments. The permeability (Papp) in the absorptive direction for both ropivacaine and PPX increased regionally in the order jejunum &lt; ileum &lt; colon. Ropivacaine was not found to be subjected to any carrier-mediated intestinal efflux. However, the CYP3A4 metabolite left the human enterocyte in a polarized manner and both the extent of CYP3A4 metabolism of ropivacaine and the extrusion of its metabolite to the mucosal chamber were more efficient in jejunum than in ileum. P-glycoprotein was probably not involved in the metabolite extrusion. No other metabolite than PPX was found. This in-vitro study with human intestinal tissues provides new mechanistic insights into regional transport and metabolism of drugs.